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ω-3 fatty acids contribute to the asthma-protective effect of unprocessed cow's milk
Abstract
Background:
Living on a farm has repeatedly been shown to protect children from asthma and allergies. A major factor involved in this effect is consumption of unprocessed cow's milk obtained directly from a farm. However, this phenomenon has never been shown in a longitudinal design, and the responsible milk components are still unknown.
Objectives:
We sought to assess the asthma-protective effect of unprocessed cow's milk consumption in a birth cohort and to determine whether the differences in the fatty acid (FA) composition of unprocessed farm milk and industrially processed milk contributed to this effect.
Methods:
The Protection Against Allergy-Study in Rural Environments (PASTURE) study followed 1133 children living in rural areas in 5 European countries from birth to age 6 years. In 934 children milk consumption was assessed by using yearly questionnaires, and samples of the "usually" consumed milk and serum samples of the children were collected at age 4 years. Doctor-diagnosed asthma was parent reported at age 6 years. In a nested case-control study of 35 asthmatic and 49 nonasthmatic children, 42 FAs were quantified in milk samples.
Results:
The risk of asthma at 6 years of age was reduced by previous consumption of unprocessed farm milk compared with shop milk (adjusted odds ratio for consumption at 4 years, 0.26; 95% CI, 0.10-0.67). Part of the effect was explained by the higher fat content of farm milk, particularly the higher levels of ω-3 polyunsaturated FAs (adjusted odds ratio, 0.29; 95% CI, 0.11-0.81).
Conclusion:
Continuous farm milk consumption in childhood protects against asthma at school age partially by means of higher intake of ω-3 polyunsaturated FAs, which are precursors of anti-inflammatory mediators.
... There has been evidence that during the first years of life, unpasteurized cows' milk is a contributory factor to asthma, but this effect is reduced by heating the milk [186]. Higher-fat unpasteurized milk, along with butter and n-3 polyunsaturated fatty acids (PUFAs), adds to this result [187]. ...
... Furthermore, considering the relationship between asthma and food allergy in atopic patients, other studies showed that sensitization to cow's milk or eggs is a risk factor for the development of bronchial hyper-responsiveness [191]. In fact, a recent study evaluated the beneficial effect of cow's milk avoidance in terms of the improvement in symptom control in patients with uncontrolled asthma by standard treatment [187]. ...
... Obesity and asthma are two extremely prevalent diseases in children worldwide that are correlated. Even though the underlying mechanism has not yet been fully elucidated, early dietary intervention, as a modifiable and supportive factor in the prevention and management of asthma associated with pediatric obesity, is well recognized [76,[149][150][151][152][153][155][156][157][158][159]165,175,176,178,[186][187][188]203,210,[212][213][214]317,318]. Novel prevention and treatment approaches are attained because of the heterogeneity of asthma pathogenesis. ...
Childhood obesity rates have dramatically risen in numerous countries worldwide. Obesity is likely a factor in increased asthma risk, which is already one of the most widespread chronic respiratory pathologies. The pathogenic mechanism of asthma risk has still not yet been fully elucidated. Moreover, the role of obesity-related inflammation and pulmonary overreaction to environmental triggers, which ultimately result in asthma-like symptoms, and the importance of dietary characteristics is well recognized. Diet is an important adjustable element in the asthma development. Food-specific composition of the diet, in particular fat, sugar, and low-quality nutrients, is likely to promote the chronic inflammatory state seen in asthmatic patients with obesity. An unbalanced diet or supplementation as a way to control asthma more efficiently has been described. A personalized dietary intervention may improve respiratory symptoms and signs and therapeutic response. In this narrative review, we presented and discussed more recent literature on asthma associated with obesity among children, focusing on the risk of asthma among children with obesity, asthma as a result of obesity focusing on the role of adipose tissue as a mediator of systemic and local airway inflammation implicated in asthma regulation, and the impact of nutrition and nutrients in the development and treatment of asthma. Appropriate early nutritional intervention could possibly be critical in preventing and managing asthma associated with obesity among children.
... However, killing microorganisms does not guarantee the absolute safety of infant food, due to endotoxin, lipoteichoic acid, peptidoglycan, and teichoic acid mannose. The endotoxin structure on the surface of Gram-negative bacteria can remain in food due to its strong thermal stability [3,4]. The residual endotoxin may have adverse effects on the immune development and intestinal health of infants. ...
... The shelf life of milk can be prolonged by homogenization and heat treatment. Unfortunately, milk processing reduces the protective effect of milk against asthma and allergies [3,5,6]. Milk processing greatly changes the composition of milk and has a significant impact on its fat content and heat-sensitive components. ...
... Milk processing greatly changes the composition of milk and has a significant impact on its fat content and heat-sensitive components. The hot processing method changes the content of n-3 polyunsaturated fatty acids in milk [3]. At the same time, heat damage to whey protein components and alkaline glutaminase in milk increases the risk of allergies [6]. ...
Endotoxin is a complex molecule derived from the outer membrane of Gram-negative bacteria, and it has strong thermal stability. The processing of infant food can kill pathogenic bacteria but cannot remove endotoxin. Because the intestinal structure of infants is not fully developed, residual endotoxin poses a threat to their health by damaging the intestinal flora and inducing intestinal inflammation, obesity, and sepsis, among others. This paper discusses the sources and contents of endotoxin in infant food and methods for preventing endotoxin from harming infants. However, there is no clear evidence that endotoxin levels in infant food cause significant immune symptoms or even diseases in infants. However, in order to improve the safety level of infant food and reduce the endotoxin content, this issue should not be ignored. The purpose of this review is to provide a theoretical basis for manufacturers and consumers to understand the possible harm of endotoxin content in infant formula milk powder and to explore how to reduce its level in infant formula milk powder. Generally, producers should focus on cleaning the milk source, securing the cold chain, avoiding long-distance transportation, and shortening the storage time of raw milk to reduce the level of bacteria and endotoxin. After production and processing, the endotoxin content should be measured as an important index to test the quality of infant formula milk powder so as to provide high-quality infant products for the healthy growth of newborns.
... Evidence suggests these short-chain fatty acids have potential anti-inflammatory effects due to their influence on the regulation of various molecular signaling pathways [51], and around 11% of the fat content of milk is SCFA [52]. Studies suggest that intake of dairy products, high fat or raw, lowers inflammatory markers in adults and increases the intake of the anti-inflammatory ω-3 polyunsaturated fatty acid in children, respectively [53,54]. These findings, along with findings defining alterations to milk properties, demonstrate the impact milk quality may have on lung health and support observations found in the current study. ...
... When considering the potential mechanisms by which milk elicits its effects on human lung health, it is important to consider the many homologous components of bovine milk such as immunoglobulins, lactoferrin, lactadherin, and various cytokines that may enhance the immune activity upon consumption and absorption [54]. Low-fat dairy intake also has implications in positive clinical outcomes of moderately improved lung density, measured by CT scan, the mechanisms of which were not fully elucidated [20]. ...
... Diet-derived small RNAs are also implicated in gene expression regulation at the level of the consumer. The analogous nature of many miRNAs, from bovine to human, implicates the role of milk-derived non-coding RNAs in targeting genes related to inflammation including in disease settings such as asthma [54,56,57]. Therefore, lung function and immunity may be modulated by dairy consumption. ...
Per the Centers for Diseases Control and Prevention, asthma prevalence has steadily risen since the 1980s. Using data from the National Health and Nutrition Examination Survey (NHANES), we investigated associations between milk consumption and pulmonary function (PF). Multivariable analyses were performed, adjusted for a priori potential confounders for lung function, within the eligible total adult population (n = 11,131) and those self-reporting asthma (n = 1,542), included the following variables: milk-consumption, asthma diagnosis, forced vital capacity (FVC), FVC%-predicted (%), forced expiratory volume in one-second (FEV1), FEV1% and FEV1/FVC. Within the total population, FEV1% and FVC% were significantly associated with regular (5+ days weekly) consumption of exclusively 1% milk in the prior 30-days (β:1.81; 95% CI: [0.297, 3.325]; p = 0.020 and β:1.27; [0.16, 3.22]; p = 0.046). Among participants with asthma, varied-regular milk consumption in a lifetime was significantly associated with FVC (β:127.3; 95% CI: [13.1, 241.4]; p = 0.002) and FVC% (β:2.62; 95% CI: [0.44, 4.80]; p = 0.006). No association between milk consumption and FEV1/FVC was found, while milk-type had variable influence and significance. Taken together, we found certain milk consumption tendencies were associated with pulmonary function values among normal and asthmatic populations. These findings propound future investigations into the potential role of dairy consumption in altering lung function and asthma outcomes, with potential impact on the protection and maintenance of pulmonary health.
... The two studies summarized below [74,75] based on the Protection Against Allergy-Study in Rural Environments (PASTURE) prospective (longitudinal) birth cohort (1133 children living in rural areas of 5 European countries) were included in the Sozańska review [83]. These studies compared different bovine milks (farm milks (raw and boiled); and commercial 'shop' milks (centrifuged, homogenized and pasteurized or ultraheat treated (UHT)). ...
... These studies compared different bovine milks (farm milks (raw and boiled); and commercial 'shop' milks (centrifuged, homogenized and pasteurized or ultraheat treated (UHT)). Brick and colleagues [75] conducted a nested case control study based on 84 children at 6 years of age (35 asthmatic and 49 non-asthmatic). Fatty acids were quantified in farm and commercial milk samples for 42 children. ...
The microbiome revolution brought the realization that diet, health, and safety for humans in reality means diet, health, and safety for the human holobiont/superorganism. Eating healthier means much more than just feeding human cells. Our diet must also nourish the combination of our microbiome and our connected physiological systems (e.g., the microimmunosome). For this reason, there has been an interest in returning to ancestral “complete” unprocessed foods enriched in microbes, including raw milks. To contribute to this inevitable “nourishing the holobiont” trend, we introduce a systematic risk–benefit analysis tool (evidence mapping), which facilitates transdisciplinary state-of-the-science decisions that transcend single scientific disciplines. Our prior paper developed an evidence map (a type of risk–benefit mind map) for raw vs. processed/pasteurized human breast milk. In the present paper, we follow with a comprehensive evidence map and narrative for raw/natural vs. processed/pasteurized cow’s milk. Importantly, the evidence maps incorporate clinical data for both infectious and non-communicable diseases and allow the impact of modern agricultural, food management, and medical and veterinary monitoring outcomes to be captured. Additionally, we focus on the impact of raw milks (as “complete” foods) on the microimmunosome, the microbiome-systems biology unit that significantly determines risk of the world’s number one cause of human death, non-communicable diseases.
... According to the authors, this protective action of n-3 PUFA may be connected with their anti-inflammatory properties. Moreover, in the same cohort, a maternal diet rich in butter and unskimmed cow's milk during pregnancy influenced the immune system of the fetus with promotion of IFN-gamma production [21]. ...
... According to the authors, this protective action of n-3 PUFA may be connected with their anti-inflammatory properties. Moreover, in the same cohort, a maternal diet rich in butter and unskimmed cow's milk during pregnancy influenced the immune system of the fetus with promotion of IFNgamma production [21]. In an experimental model of allergen-induced asthma, raw, but not heated, milk prevented airway hyper-responsiveness and reduced the total number of eosinophils, neutrophils, macrophages and lymphocytes in bronchoalveolar lavage fluid (BAL) and IL-5 and IL-13 production by lung T cells after allergen exposure. ...
The steep increase in asthma prevalence, observed worldwide in recent decades, has created an urgent need to search for effective methods of its prevention. Among other environmental factors, changes in diet habits and the potential influence of individual food components on immunological processes have been extensively studied as a potential method of intervention in primary prevention of asthma. The preventive role of some nutrients has been confirmed: unpasteurized milk reduced the risk of asthma in epidemiological studies, vitamin D supplementation was effective in preventing the transient forms of wheezing in small children and high maternal intake of fish oil reduced the risk of persistent wheeze and asthma in children. However, not all studies provided consistent results, and many food ingredients are still pending for defining their role in asthma development. Moreover, a novel approach looking not only at single food ingredients, but the whole dietary patterns and diversity has recently been proposed. In this paper, we discuss the current role of nutrients in asthma primary prevention and the reasons for inconsistencies in the study results. We look at single diet components, but also the whole dietary patterns. We describe the proposed mechanisms of action at different stages of life, identify the role of modifiers and delineate future perspectives on the application of nutrients in targeting strategies for asthma primary prevention.
... Brick et al. (20). ...
... The study showed that the consumption of unpasteurized farm milk compared to the shop milk was associated with a protective effect on asthma (aOR for consumption at the age of 4 years (95% CI): 0.26 (0.10-0.67)). The author further showed that the part of the effect could be explained by the higher fat content of the farm milk, especially the higher levels of ω-3 polyunsaturated FAs (aOR (95% CI): 0.29 (0.11-0.81)) (20). The study by Perking and Strachan investigated the relationship between farming environment and developing allergic problem and suggests that one of the possible mechanism for this observed protective effect may be through greater consumption of farm or unpasteurized milk. ...
p>In this review, we discuss an immunobiology model of farm exposure towards the protective effect of asthma. Unraveling the protective effect of farming exposure could help develop novel strategies to prevent asthma. Asthma is a chronic airway inflam- mation that causes coughing, wheezing, chest tightness or shortness of breath. The reasons for the increase in the prevalence of asthma worldwide is still unclear but has been hypothesized to be attributable to westernization/urbanization of rural regions thus resulting in the loss of rural farming environmental. In this review we discuss the effect of the environmental factors, specif- ically farming, on the risk of asthma in children. Here, we will summarize the main findings of 27 studies related to 11 different cohorts. Several studies have shown preventive effect of traditional farming on the prevalence and incidence of asthma in child- hood. Furthermore, consumption of unpasteurized cow’s milk, exposure to farm animals as well as fodder have been shown to have a protective effect on asthma. The precise mechanism of the protective effect is still unclear. There are assumptions, that maternal/childhood exposures to farm animals result in higher microbial exposures through which the protective effect might be mediated. Also, consumption of unpasteurized milk (when consumed during pregnancy by mother or early childhood by children) can modulate cytokine production patterns which could be responsible for the observed protective effect.
Conclusion.
This review provides evidence of the protective effect of farming environment i.e., exposure to farm animals, their fodder as well as consumption of unpasteurized cow’s milk suggesting that novel strategies could be developed to prevent asthma.</p
... More importantly, the endotoxin structure could stay in dairy products during food processing, due its powerful thermal stability (Brick et al., 2016;Jang et al., 2018). Then, the residual endotoxin might have adverse impacts on the intestinal health by inducing intestinal inflammation (Wu et al., 2021). ...
To support milk production and milk quality, ruminant animals like dairy cows are particularly fed using concentrate containing high grain and starch. Nonetheless, this type of regimen feeding could induce subacute rumen acidosis condition. Then, these circumstances cause the lysis of gram-negative bacteria accompanied by endotoxin release in gut. More importantly, gut endotoxin could be translocated to mammary gland, whereby this condition negatively affects to milk safety. The aim of the review is to update and summarize the current knowledge regarding high-grain diet and the occurrence of endotoxin in milk of dairy cows. The data suggest that there is interplay between high-grain feeding for dairy cows to endotoxin contamination in milk.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Alpine regions are characterized by exceptional natural resources, cultural heritage,
healthy climate, and long tourism tradition. Tourism is a major component of
economic growth, with several employment opportunities, and of great importance
for the Alpine regions, with many positive effects on the local and regional population.
Natural resources can determine the development of competitive tourism destinations and drive the development of nature-based value chains aimed at enhancing
tourists’ health and well-being. Historically, the small size of most enterprises,
the difficulties in establishing collaborative relationships between industry operators, and the lack of strategic projects aimed at the use and exploitation of natural
resources, have hindered a systematic development of a nature-based health tourism
(NHT) value chain. Nowadays, tourist market segments are changing the industry
competitiveness with the request for more nature-based experiential programs, integrating both rewarding elements of beauty, relaxation, and regeneration, and more
demanding elements such as preventative activities and sports. There is an increasing
consciousness of the importance of local environmental and cultural preservation,
the search for relax and stress-relieving products, and the overall authenticity of
the vacation experience. Beyond lifestyle changes, key trends reshaping the health
tourism landscape in Alpine regions include population ageing, climate change, and
consequences of the COVID-19 pandemic both in terms of business losses and the
need for natural remedies against these virus’s long-term effects.
This background challenges health tourism operators to rethink the industry
dynamics with a more innovation-driven strategy and business development, as well
as facilitation of transnational cooperation among all kinds of actors. These include
sectoral and specialized agencies such as destination management organizations,
business support organizations, and tourism organizations; regional councils and
municipalities in charge of policy-making and tourism strategy development; tourism
facilities and companies (especially small- and medium-sized enterprises); universities and research centres that conduct applied research and development within the
health tourism sector and related sectors, based on natural resources or health-related
issues; interest groups and networks supporting nature-based and sustainable health
tourism. Despite the richness of natural resources and health-promoting activities that spread among Alpine regions, the NHT landscape is characterized by innovation
spatial fragmentation, lack of access to knowledge, and little transversal cooperation
for value creation and sharing.
Aimed to address these key territorial challenges, the HEALPS2 project “Healing
Alps: Tourism based on natural health resources as strategic innovation for the development of Alpine regions” was funded in the Priority “Innovative Alpine Space” of
the Interreg Alpine Space program. The key objective of the project was to improve
the framework conditions for utilizing the Alpine natural health resources by leveraging existing and newly developed NHT products and service chains to enhance
access to knowledge and sharing of experiences at a transnational level. The main
project activities took place from October 2019 to June 2022 and involved 11 organizations from 6 countries, i.e. Austria, Italy, Slovenia, Germany, France, and Switzerland. The collaboration between the project partners led to the development of a set of
innovation practices and digital solutions, properly combined with the latest research
results in tourism and health-related issues and the requirements of health tourism
stakeholders collected in several events organized at the local and regional level. The
vision of the project is to contribute to the positioning of the Alpine Space as a globally attractive health-promoting place, with a virtuous process of value generation
and sharing among Alpine assets, actors, and territories.
This book incorporates the key knowledge and experiences, in terms of concepts,
tools, and practices, developed within the HEALPS2 project, here organized into
eight chapters. The content was purposefully organized to dedicate to the core assets
for an Alpine NHT industry excellence, i.e. the natural resources and their healing
effects; the digital tools enhancing the collection, advanced analytics and spread
of data on NHT industry for supporting strategic decision-making; the innovation
practices and communication strategies to properly engage the industry stakeholders.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Tourism has been one of the most important economic sectors in the Alps for many years. However, not least because of the cuts due to the pandemic, new and innovative approaches are needed to meet current challenges such as climate change, shortage of skilled workers or demographic change in order to make Alpine tourism fit for the future. The topic of health offers great potential in this context. With the KPI approach, therefore, a possible access to a nature-based health tourism with medical evidence is presented, which should support the actors from the tourism practice in the further development of the Alpine tourism. At the same time, the KPI approach also offers possibilities to enable an overall more sustainable development of the Alpine region. This paper places the KPI approach in a larger development framework and explains the underlying analytical system based on selected indicators.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
This work describes the challenges, techniques, and methodologies to develop a digital tool that aims to improve framework conditions and tools for better utilization of Alpine natural resources in health tourism. Starting from the literature analysis and an online survey, the system implemented a comprehensive knowledge base adopted for an ontology-based Decision Support System leveraging on identified Key Performance Indicators (KPIs). Relying on this knowledge, the digital tool provides a list of tailored and customized recommendations for each destination within the Alpine area. This result helps the stakeholders capitalize on the nature-based health tourism potentials of their region in relation to the existence of the natural resources and different target users’ health conditions. This strategic digital tool is developed as a web-based application for destinations’ policy-makers and managers to fill the online survey and receive customized suggestions, recommendations, and insights on how to further exploit their natural resources in order to enhance nature-based health tourism.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
The Alpine space disposes of excellent prerequisites to respond to the increasing demand of nature-based health tourism. Despite a growing scientific knowledge on the manifold benefits of human interaction with Alpine natural resources, the health tourism potential has not yet been fully exploited by Alpine regions. Based on major push and pull factors, the current state of scientific knowledge on the healing potential of nine selected natural Alpine resources is presented and discussed with regard to their health tourism potential. Major research gaps as well as starting points for future studies are demonstrated. In this way, the present work contributes to an applicable knowledge base on the health benefits of Alpine resources to enhance regional innovation capacity in terms of sustainable health tourism development. As tourism regions are increasingly taking evidence-based approaches to health tourism and regional development, the resulting lighthouses will contribute to the positioning of the Alpine space as globally attractive healing environment.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Participatory stakeholder engagement in strategy-making, for industries such as Nature-based Health Tourism (NHT), enhances the delivery of more useful and applicable strategies, with also higher chances to reach intended goals if compared to conventional top-down planning processes. This chapter describes the methodology identified and carried out in the HEALPS2 project to efficiently reach and engage stakeholders of Alpine NHT and to form a stakeholder group at the transnational level (including the engagement of EU-level ac-tors and networks). Based on the Quadruple Helix concept, the methodology integrates a process of stakeholder engagement and endorsement along three steps; the identification of the key points and the problems to be tackled for a successful stakeholder engagement; and the development of Regional and Transnational Stakeholder Groups that extend to the cooperation with EU-wide networks. Developing health tourism products and service chains, and sustaining them with strategies and policies, is a complex undertaking. The adoption of the stakeholder engagement approaches throughout the HEALPS2 project showed that it is of utmost importance to properly identify, involve and communicate with the stakeholders who effectively complement the success of the project, and its outcomes, in enhancing NHT competitiveness.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Communication activities play a pivotal role in the management of research projects, especially those involving several partners and stakeholders from different countries. The Interreg Alpine Space HEALPS2 project relies on a transnational and transversal approach to improve the framework conditions and tools for alpine health tourism, and therefore proposes a communication strategy based on specific objectives. These objectives guide the communication activities at an internal and external level, with the latter being declined for different targets and stakeholders. In this Chapter, the communication activities are described, starting from the general and specific objectives-oriented approach, to the local realization. The general strategy and the analysis are illustrated, then are demonstrated through a regional use case—the Parco Regionale Alpe Veglia-Alpe Devero and Parco Regionale Alta Valle Antrona.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Innovation is considered essential to the growth and long-term sustainability of health tourism companies and destinations. Continuous innovation takes place to improve the industry competitiveness, but especially the tourists’ experience and wellness with new product offerings. This Chapter collects and describes the innovation practices proposed and developed in some pilot regions of the HEALPS2 project consortium. The innovation practices identified in the project can be subdivided into three types, i.e., innovation techniques, innovation supporting tools, and innovative product offerings. All the practices were designed to target several operators of the Nature-based Health Tourism (NHT) industry, from tourism facilities and companies (especially small- and medium-sized enterprises) to regional councils and municipalities in charge of policy-making and tourism strategy development. HEALPS 2 innovation practices and techniques can be purposefully integrated at the regional and local level for a more innovation-driven industry strategy and business development, as well as facilitation of transnational cooperation among key actors, also beyond Alpine regions and NHT destinations.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
Nature-based health tourism is experiencing a resurgence. To determine its potential as a development opportunity for alpine destinations, it is necessary to analyse both the demand and supply side. Two surveys were conducted: a representative survey of the population of six countries of the Alpine Space exploring the perception of the Alps as a healthy destination in general and on the personal assessment of the health effect of natural resources in particular and an exploratory survey of tourism stakeholders in destination management, accommodation and gastronomy as well as (health) tourism services with a focus on the expected economic developments and the relevance of individual target groups for nature-based health tourism. The results demonstrate the need for a strategic development process which aligns perceptions with destination strategy and pre-existing offers. Two potential strategies are briefly outlined: 1. destinations with non-locally specific alpine natural health resources can develop broad tourism experiences for health conditions that occur across society with health a secondary aspect in marketing. 2. destinations featuring locally specific natural health resources with proven evidence can develop offers for a specific condition and are thus able to target a very specific group.
... Similar to the exposure to environmental microbes on farms, farm milk consumption during pregnancy and early childhood shows the strongest effect. However, it has to be mentioned that most studies are cross-sectional (level IIa) [84,85]. These associations do not confirm a causal relationship, and further investigation to identify specific protective agents or mechanisms is required. ...
The competitiveness of nature-based Health Tourism (NHT) industry, especially in the Alpine regions, is increasingly linked to the sustainability and exploitation of unique natural resources of tourism destinations, which often lack the access to knowledge and networks of stakeholders to improve their offerings. In this sense, the use of digital tools can open up further opportunities to reconsider value offerings and better access different knowledge resources and relationships within the industry network. This Chapter illustrates the collaborative design approach adopted in HEALPS2 for the development of an ontology-based Decision Support System for health tourism destinations. The resulting ontology aims to model the relationships between the available natural resources, the value offerings and the target groups of NHT destinations. Moreover, the Collaborative Design approach foresees the involvement of end-users (i.e. not only tourism destinations, but also the network of stakeholders, and the actual and potential future tourists) as both sources of knowledge and validators of the ontology and its outputs, aiming to inform decision-making processes in a shared knowledge model that leverages on digital tools.
... 58 In a nested case-control study of 84 children comparing from the PASTURE birth cohort study, those without asthma at 6 years old had significantly higher consumption of unprocessed farm milk, which has a higher n-3 fatty acids content. 59 Similar to pregnant women, the effect of PUFA intake on developing asthma might be modified by gene-nutrient interaction. In children with fatty acid deficiency variants, a higher intake of fish-derived EPA and DHA was strongly associated with reduced asthma risk up to midadolescence. ...
Asthma is a complex disease, caused by a combination of genetic and environmental factors. The prevalence of asthma is increasing too rapidly to be attributable to genetic factors alone. Thus, environmental factors are becoming increasingly recognized as the cause of asthma. Modifying these environmental factors may be a simple approach for asthma prevention. To date, dietary intervention is an interesting modifiable factor because it can be implemented at the population level. The modification of systemic inflammation, oxidation, and microbial composition might be a mechanistic basis for prevention. This review summarizes the mechanistic basis and evidence from clinical studies on the association between dietary factors and asthma development. We also summarize the recommendations from many organizations and regional guidelines to assist the practicing physician to improve patient care.
... This theory overlaps somewhat with the theory of urbanization/the hygiene hypothesis in some cases, such as in the case of some epidemiological studies that observed lower rates of allergic disease in children that were raised in rural environments linked to exposure to stables as well as raw bovine milk [27]. The Protection Against Allergy Study in Rural Environments (PASTURE) was a study that followed over one thousand children living in rural areas in Europe from birth to age 6 years and found that the risk of developing asthma by age 6 was decreased if there was previous consumption of unprocessed farm milk in comparison to store bought milk [28]. This study concluded that the higher levels of fat content in farm milk, in particular ω-3 polyunsaturated fatty acids, could in part explain this effect. ...
Purpose of Review
To summarize the most up-to-date literature on allergic diseases with an emphasis on understanding the increase in prevalence of allergic diseases.
Recent Findings
As atopy continues to rise, there is increasing evidence that genetic factors in addition to environmental factors contribute to the development of allergic disease. There is research to support that worsening air pollution and climate change as well as lifestyle changes such as an increase in saturated fats and sugars in the diet, antibiotic use, changes in the gut microbiome, and a shift towards a more sterile, more urbanized environment could all increase the likelihood of developing allergic diseases.
Summary
While the options available for management of allergic diseases are increasing and improving, the prevalence of allergic disease continues to rise. Further investigation of how we can influence the changes in our environment leading to increases in atopy as well as the genetics involved is crucial in order to prevent the development of allergic diseases.
... Indeed, even allergic children could tolerate raw milk better than pasteurized shop milk, showing less allergic symptoms upon drinking raw milk in a human pilot study (205). The atopy preventive effect of milk correlates with the amount of whey proteins present in the milk (206,207) and is lost by thermal treatment (204,208). ...
Although iron is one of the most abundant elements on earth, about a third of the world's population are affected by iron deficiency. Main drivers of iron deficiency are beside the chronic lack of dietary iron, a hampered uptake machinery as a result of immune activation. Macrophages are the principal cells distributing iron in the human body with their iron restriction skewing these cells to a more pro-inflammatory state. Consequently, iron deficiency has a pronounced impact on immune cells, favoring Th2-cell survival, immunoglobulin class switching and primes mast cells for degranulation. Iron deficiency during pregnancy increases the risk of atopic diseases in children, while both children and adults with allergy are more likely to have anemia. In contrast, an improved iron status seems to protect against allergy development. Here, the most important interconnections between iron metabolism and allergies, the effect of iron deprivation on distinct immune cell types, as well as the pathophysiology in atopic diseases are summarized. Although the main focus will be humans, we also compare them with innate defense and iron sequestration strategies of microbes, given, particularly, attention to catechol-siderophores. Similarly, the defense and nutritional strategies in plants with their inducible systemic acquired resistance by salicylic acid, which further leads to synthesis of flavonoids as well as pathogenesis-related proteins, will be elaborated as both are very important for understanding the etiology of allergic diseases. Many allergens, such as lipocalins and the pathogenesis-related proteins, are able to bind iron and either deprive or supply iron to immune cells. Thus, a locally induced iron deficiency will result in immune activation and allergic sensitization. However, the same proteins such as the whey protein beta-lactoglobulin can also transport this precious micronutrient to the host immune cells (holoBLG) and hinder their activation, promoting tolerance and protecting against allergy. Since 2019, several clinical trials have also been conducted in allergic subjects using holoBLG as a food for special medical purposes, leading to a reduction in the allergic symptom burden. Supplementation with nutrient-carrying lipocalin proteins can circumvent the mucosal block and nourish selectively immune cells, therefore representing a new dietary and causative approach to compensate for functional iron deficiency in allergy sufferers.
... 56 By contrast, high levels of polyunsaturated fatty acids, especially v-3 polyunsaturated fatty acids, were associated with a lower risk of asthma, 43,58,59 by inhibiting the production of inflammatory mediators. 60 Additionally, studies showed that enhanced glycolysis facilitates the activation of various immune cells (eg, macrophages, T H 2 or T H 17 cells) 61 and proinflammatory responses of airway epithelial cells. 62 Furthermore, lactate-the end product of anaerobic glycolysis-also promotes inflammation by reshaping CD4 1 T-cell effector phenotypes (eg, switching to T H 17 cells). ...
ABSTRAC
Background
Severe bronchiolitis (i.e., bronchiolitis requiring hospitalization) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear.
Objective
To examine the integrated role of airway microbiome (both taxonomy and function) and host response in asthma development in this high-risk population.
Methods
In a multicenter prospective cohort study of 244 infants with severe bronchiolitis (median age, 3 months), we examined their nasopharyngeal metatranscriptome (microbiome) and transcriptome (host), and metabolome at hospitalization. We investigated the longitudinal relationship of 1) major bacterial species (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis), 2) microbial function, and 3) host response with risks of developing asthma by age 6 years.
Results
First, the abundance of S. pneumoniae was associated with greater risks of asthma (P=0.01), particularly in infants with non-rhinovirus infection (Pinteraction=0.04). Second, of 328 microbial functional pathways differentially-enriched by asthma development, the top pathways (e.g., fatty acid and glycolysis pathways; FDR<1×10⁻¹²) were driven by these three major species (e.g., positive association of S. pneumoniae with glycolysis; FDR<0.001). These microbial functional pathways were validated with the parallel metabolome data. Third, 104 transcriptome pathways were differentially-enriched (FDR<0.05)—e.g., downregulated interferon-α and -γ and upregulated T cell activation pathways. S. pneumoniae was associated with most differentially-expressed transcripts (e.g., DAGLB; FDR<0.05).
Conclusion
By applying metatranscriptomics, transcriptomics, and metabolomics approaches to a multicenter cohort of infants with bronchiolitis, we found an interplay between major bacterial species, their function, and host response in the airway, and their longitudinal relationship with asthma development.
... The increase in allergic disease and asthma in the past decades has been attributed to changes in lifestyle and/or environmental factors [1]. There has been a decline in the consumption of milk in this period [1] and thus there is a great interest in determining the impact of drinking or avoiding milk, including raw farm milk, breastfeeding, and intake of milk during pregnancy, on the development of allergic disease and asthma [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Previous observational studies have suggested a possible protective effect of drinking milk on asthma [12,14]. ...
Background
Previous observational studies have indicated a protective effect of drinking milk on asthma and allergy. In Mendelian Randomization, one or more genetic variants are used as unbiased markers of exposure to examine causal effects. We examined the causal effect of milk intake on hay fever, asthma, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) by using the lactase rs4988235 genotype associated with milk intake.
Methods
We performed a Mendelian Randomization study including 363,961 participants from the UK Biobank.
Results
Observational analyses showed that self-reported milk-drinkers vs. non-milk drinkers had an increased risk of hay fever: odds ratio (OR) = 1.36 (95% CI 1.32, 1.40, p < 0.001), asthma: OR = 1.33 (95% CI 1.38, 1.29, p < 0.001), yet a higher FEV1: β = 0.022 (SE = 0.004, p < 0.001) and FVC: β = 0.026 (SE = 0.005, p < 0.001). In contrast, genetically determined milk-drinking vs. not drinking milk was associated with a lower risk of hay fever: OR = 0.791 (95% CI 0.636, 0.982, p = 0.033), and asthma: OR = 0.587 (95% CI 0.442, 0.779, p = 0.001), and lower FEV1: β = − 0.154 (standard error, SE = 0.034, p < 0.001) liter, and FVC: β = − 0.223 (SE = 0.034, p < 0.001) liter in univariable MR analyses. These results were supported by multivariable Mendelian randomization analyses although not statistically significant.
Conclusions
As opposed to observational results, genetic association findings indicate that drinking milk has a protective effect on hay fever and asthma but may also have a negative effect on lung function. The results should be confirmed in other studies before any recommendations can be made.
... Dairy processing plants usually use thermal sterilization to eliminate pathogenic bacteria from raw milk. However, conventional sterilization methods cannot effectively remove the heat-resistant LPS synthesized by Gram-negative bacteria [4,41,42]. LPS is an important outer membrane virulence factor of C. sakazakii [43]. Thus, the contamination of C. sakazakii in raw milk may remain due to the failure to effectively eliminate it during processing, thus, threatening the health of newborns. ...
Lipopolysaccharide (LPS) can remain in dairy products after the sterilization of milk powder and may pose a threat to the health of infants and young children. There is a large amount of alkaline phosphatase (ALP) in raw milk, which can remove the phosphate bond of LPS, thus, detoxifying it. ALP is regarded as an indicator of the success of milk sterilization due to its strong heat resistance. ALP can alleviate the toxicity of LPS in enteritis and nephritis models, but the mechanism by which oral-intake of ALP protects liver tissue from LPS stimulation is unclear. In this study, an in vivo acute mouse liver injury model was induced by C. sakazakii LPS (200 μg/kg) and used to verify the protective mechanism of ALP (200 U/kg) on mice livers. The related pathways were also verified by in vitro cell culture. Enzyme linked immunosorbent assays (ELISAs), quantitative reverse transcription PCR (RT-qPCR) and western blotting were used to detect the levels of inflammatory factors at the protein level and RNA level, and to confirm the inflammation of liver tissue caused by LPS. ALP was found to alleviate acute liver injury in vitro by activating miR-146a. We found that ALP could up-regulate the level of miR146a and subsequently alleviates the expression of TLR4, TNF-α, matured IL-1β, and NF-κB in mouse liver tissue and hepatocytes; thus, reducing liver inflammation. Herein, we demonstrated for the first time that oral-intake of ALP protected liver tissue by up-regulating the expression of miR-146a and alleviating inflammatory reactions; thus, providing a research basis for the proper processing of milk. This study also suggests that producers should improve the awareness of the protective effects of bioactive proteins in raw milk.
... The consumption of raw cow's milk, another factor thought to mediate antiallergic effects of farming although not only or not necessarily due to its microbial content (Brick et al. 2016;Van Neerven and Savelkoul 2019), is also decreasing in parallel to the decrease in farming. Independently of what are the exact substances responsible for the protective effects of unprocessed cow's milk, the epigenetic mechanism of DNA methylation has been shown to be involved, with the prominent example of FOXP3 demethylation and subsequent activation of Treg cells (Lluis et al. 2014;Schaub et al. 2009). ...
There has been a substantial increase in the incidence and the prevalence of allergic disorders in the recent decades, which seems to be related to rapid environmental and lifestyle changes, such as higher exposure to factors thought to exert pro-allergic effects but less contact with factors known to be associated with protection against the development of allergies. Pollution is the most remarkable example of the former, while less contact with microorganisms, lower proportion of unprocessed natural products in diet, and others resulting from urbanization and westernization of the lifestyle exemplify the latter. It is strongly believed that the effects of environmental factors on allergy susceptibility and development are mediated by epigenetic mechanisms, i.e. biologically relevant biochemical changes of the chromatin carrying transcriptionally-relevant information but not affecting the nucleotide sequence of the genome. Classical epigenetic mechanisms include DNA methylation and histone modifications, for instance acetylation or methylation. In addition, microRNA controls gene expression at the mRNA level. Such epigenetic mechanisms are involved in crucial regulatory processes in cells playing a pivotal role in allergies. Those include centrally managing cells, such as T lymphocytes, as well as specific structural and effector cells in the affected organs, responsible for the local clinical presentation of allergy, e.g. epithelial or airway smooth muscle cells in asthma. Considering that allergic disorders possess multiple clinical (phenotypes) and mechanistic (endotypes) forms, targeted, stratified treatment strategies based on detailed clinical and molecular diagnostics are required. Since conventional diagnostic or therapeutic approaches do not suffice, this gap could possibly be filled out by epigenetic approaches.
... So ist bekannt, dass das Trinken von Rohmilch vor Allergien schützt [4,5,6], deren Verzehr wegen der Gefahr von Krankheitserregern aber nicht empfohlen wird. Der Allergieschutz in der Rohmilch scheint hier auch von den Molkeproteinen [7,8] auszugehen und geht beim Kochen verloren [4]. ...
Recent epidemiological studies link iron deficiency with atopy. Iron deficiency during pregnancy increases the risk in children for atopic diseases. The risk to develop anemia is also increased in allergic subjects. Iron deficiency can activate immune cells, leads to expansion of Th2 but not Th1 cells, and promotes B cell class switch. As such, iron deficiency lay the foundation for allergic sensitization. Also, mast cells are activated in iron-deprived conditions, whereas iron repletion hinders degranulation. Our studies demonstrate that lipocalin proteins like the whey protein beta-lactoglobulin can transport micronutrients such as iron into immune cells (holo-BLG). Replenishment with micronutrients has a calming effect on immune cells and promotes tolerance. Since 2019, several clinical trials have been conducted in allergic subjects, where dietary intervention with holo-BLG reduced the symptom burden. Supplying immune cells with micronutrients through holo-BLG represents thus a new dietary approach to compensate for the functional iron deficiency in allergic subjects.
... Last but not least, the content of omega-3 fatty acids in milk seems to be crucial for allergy protection, again more of them being present in raw milk than in processed milk [25]. ...
Background
Numerous factors such as microbiota and their products are discussed in the context of the hygiene hypothesis and the associated allergy-preventive farm effect. Besides inhalation of dust from farms, consumption of raw milk also counteracts the development of asthma and allergies. Since cattle barns and cow’s milk in particular have been described as effective, the involvement of a bovine protein seems likely. β‑Lactoglobulin (BLG) is a major protein in milk and, as a member of the lipocalin family, has an intramolecular pocket that allows binding to hydrophobic ligands.
Results
Our in vitro and in vivo studies show that unloaded BLG promotes the development of allergy, while loaded, so-called holo-BLG, prevents allergies. BLG associated with zinc could also be detected in stable dust and ambient air of cattle farms.
Conclusion
It seems obvious that in addition to microbes and their products, holo-BLG also plays an important role in the protective farm effect. Therefore, in a newly developed lozenge for dietary management of allergies, based on the farm effect, zinc attached to holo-BLG is one of the key ingredients.
... Raw cow's milk consumption has been reported to protect against childhood asthma and allergies [16][17][18][19][20]. If the risk of infections could be overcome, consumption of raw milk would be an attractive preventive strategy for allergic diseases. ...
The mechanism underlying the allergy-protective effects of raw cow’s milk is still unknown, but the modulation of the gut microbiome may play a role. The effects of consuming raw cow’s milk or processed milk on fecal microbial communities were therefore characterized in an experimental murine model. C3H/HeOuJ mice were treated with raw milk, pasteurized milk, skimmed raw milk, pasteurized milk supplemented with alkaline phosphatase (ALP), or phosphate-buffered saline (PBS) for eight days prior to sensitization and challenge with ovalbumin (OVA). Fecal samples were collected after milk exposure and after OVA sensitization, and microbiomes were characterized using 16S ribosomal RNA gene amplicon sequencing. Treatment with raw milk prior to OVA sensitization increased the relative abundance of putative butyrate-producing bacteria from the taxa Lachnospiraceae UCG-001, Lachnospiraceae UCG-008, and Ruminiclostridium 5 (Clostridial clusters XIVa and IV), while it decreased the relative abundance of Proteobacterial genera such as Parasutterella, a putative pro-inflammatory bacterial genus. This effect was observed after eight days of raw milk exposure and became more pronounced five weeks later, after allergic sensitization in the absence of milk. Similar trends were observed after treatment with skimmed raw milk. Conversely, the feeding of pasteurized milk led to a loss of allergy protection and a putative dysbiotic microbiome. The addition of ALP to pasteurized milk restored the protective effect observed with raw milk and mitigated some of the microbial community alterations associated with milk pasteurization. Raw milk-induced protection against food allergic symptoms in mice is accompanied by an increased relative abundance of putative butyrate-producing Clostridiales and a decreased relative abundance of putative pro-inflammatory Proteobacteria. Given the safety concerns regarding raw milk consumption, this knowledge is key for the development of new, microbiologically safe, preventive strategies to reduce the incidence of allergic diseases.
... In addition, considering the pivotal role of gut bacteria and the metabolites synthesized by them from dietary components such as SCFA, nutrition can strongly modify the effects of microbes on host immunity and health. Furthermore, microbes and their elements or metabolic products are integral elements of some foods, especially of more traditional origin [2,241]. Perinatal and some other epigenetically mediated effects of microbes on human immunity and health are shortly outlined below and summarized in Figure 8 and Table 1. ...
Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.
... Due to environment diversity, multiple protective environmental factors were found in different studies. The contact factors included livestock, pets, 45 farm crops, 38 unpasteurized milk, [46][47][48] breastfeeding, farm or village cultivation activities, 32,49 and fishing. 50 The major findings from these studies are summarized in Table. ...
Allergic asthma is a public health problem that affects human health and socioeconomic development. Studies have found that the prevalence of asthma has significantly increased in recent years, which has become particularly pronounced in developed countries. With rapid urbanization in China in the last 3 decades, the prevalence of asthma has increased significantly in urban areas. As changes in genetic backgrounds of human populations are limited, environmental exposure may be a major factor that is responsible for the increased prevalence of asthma. This review focuses on environmental components of farms and rural areas that may have protective effects in reducing the development of asthma. Farm and rural related microorganism- and pathogen-associated molecular patterns are considered to be important environmental factors that modulate host's innate and adaptive immune system to induce protection effects later in life. Environmental microbial-related immunotherapy will also be discussed as the future research direction for the prevention of allergic asthma.
Bronchial asthma is a prevalent and increasingly chronic inflammatory lung disease affecting over 300 million people globally. Initially considered an allergic disorder driven by mast cells and eosinophils, asthma is now recognized as a complex syndrome with various clinical phenotypes and immunological endotypes. These encompass type 2 inflammatory endotypes characterized by interleukin (IL)-4, IL-5, and IL-13 dominance, alongside others featuring mixed or non-eosinophilic inflammation. Therapeutic success varies significantly based on asthma phenotypes, with inhaled corticosteroids and beta-2 agonists effective for milder forms, but limited in severe cases. Novel antibody-based therapies have shown promise, primarily for severe allergic and type 2-high asthma. To address this gap, novel treatment strategies are essential for better control of asthma pathology, prevention, and exacerbation reduction. One promising approach involves stimulating endogenous anti-inflammatory responses through regulatory T cells (Tregs). Tregs play a vital role in maintaining immune homeostasis, preventing autoimmunity, and mitigating excessive inflammation after pathogenic encounters. Tregs have demonstrated their ability to control both type 2-high and type 2-low inflammation in murine models and dampen human cell-dependent allergic airway inflammation. Furthermore, microbes, typically associated with disease development, have shown immune-dampening properties that could be harnessed for therapeutic benefits. Both commensal microbiota and pathogenic microbes have demonstrated potential in bacterial-host interactions for therapeutic purposes. This review explores microbe-associated approaches as potential treatments for inflammatory diseases, shedding light on current and future therapeutics.
The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during gestation and into early life when maternal lifestyle factors shape immune development of the newborn. Breast milk further shapes gut colonisation, supporting the development of tolerance to commensal bacteria and harmless antigens while preventing outgrowth of pathogens. Environmental microbial and lifestyle factors that disrupt this process can dysregulate immune homeostasis, predisposing infants to atopic disease and childhood asthma. In health, the low biomass lung microbiome, together with inhaled environmental microbial constituents, establishes the immunological setpoint that is necessary to maintain pulmonary immune defence. However, in disease, perturbations to immunological and physiological processes allow the upper respiratory tract to act as a reservoir of pathogenic bacteria, which can colonise the diseased lung and cause severe inflammation. Studying these host-microbe interactions in respiratory diseases holds great promise to stratify patients for suitable treatment regimens and biomarker discovery to predict disease progression. Preclinical studies show that commensal gut microbes are in a constant flux of cell division and death, releasing microbial constituents, metabolic byproducts, and vesicles that shape the immune system and can protect against respiratory diseases. The next major advances may come from testing and utilizing these microbial factors for clinical benefit and exploiting the predictive power of the microbiome by employing multi-omics analysis approaches.
Milk is an essential source of protein for infants and young children. At the same time, cow’s milk is also one of the most common allergenic foods causing food allergies in children. Recently, cow’s milk allergy (CMA) has become a common public health issue worldwide. Modern food processing technologies have been developed to reduce the allergenicity of milk proteins and improve the quality of life of patients with CMA. In this review, we summarize the main allergens in cow’s milk, and introduce the recent findings on CMA responses. Moreover, the reduced effects and underlying mechanisms of different food processing techniques (such as heating, high pressure, γ-ray irradiation, ultrasound irradiation, hydrolysis, glycosylation, etc.) on the allergenicity of cow’s milk proteins, and the application of processed cow’s milk in clinical studies, are discussed. In addition, we describe the changes of nutritional value in cow’s milk treated by different food processing technologies. This review provides an in-depth understanding of the allergenicity reduction of cow’s milk proteins by various food processing techniques.
Background
An important ‘window of opportunity’ for early life exposures has been proposed for the development of atopic eczema and asthma.
Objective
However it is, unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life.
Methods
In the PASTURE birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (N=769). Fecal samples at age 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parental reported symptoms and/or physician’s diagnosis of hay fever in the last 12 months using questionnaires at age 10.5 years.
Results
Farm children had half the risk of hay fever at age 10.5 years (adjusted odds-ratio (aOR) [95% CI]=0.50 [0.31; 0.79]) compared to non-farm children. While early life events such as gut microbiome richness at age 12 months (aOR=0.66 [0.46; 0.96]) and exposure to animal sheds in the first three years of life (aOR=0.26 [0.06; 1.15]) were determinants of hay fever, the continuous consumption of farm milk from infancy up-to school age was necessary to exert the protective effect (aOR=0.35 [0.17; 0.72]).
Conclusion
While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories.
Asthma is a common, complex heterogeneous disease often beginning in early life and is characterized by reversible airflow obstruction. The phenotypic differences that exist in children with asthma may impact underlying comorbid conditions and pharmacologic treatment choices. Prenatal factors for increased risk of asthma could include maternal diet and the maternal microbiome. Evidence also suggests that postnatal microbial exposures and colonization contribute to the risk of allergic diseases and asthma. After confirming the diagnosis, asthma management in children centers on 3 broad areas: pharmacologic treatment, treatment of underlying comorbidities, and education of the patient and caregivers on the importance of adherence and device technique. Moreover, social determinants of health significantly impact on symptom burden and treatment response.
This chapter discusses the research on the influence of the environment of a livestock farm in the protection against the occurrence of allergic diseases during the life of an individual. It was the observation of an unprecedented increase in allergic diseases in the European, American and Japanese populations after Second World War that precipitated the implementation of research in these areas. Since the 1990s, a large number of cross‐sectional epidemiological studies have supplemented the initial observations of the 1980s. The combination of these epidemiological results gave rise to the explanatory hypothesis of “hygiene”, capable of accounting for the observations by resituating them in the immunological concepts of the time. As in the population‐based studies, it was the observation of protection by raw milk consumption that was also the most consistent finding in the analyses from the Protection Against Allergy: Study in Rural Environments cohort.
Asthma and allergies are major health problems and exert an enormous socioeconomic burden. Besides genetic predisposition, environmental factors play a crucial role in the development of these diseases in childhood. Multiple worldwide epidemiological studies have shown that children growing up on farms are immune to allergic diseases and asthma. Farm‐related exposures shape children's immune homeostasis, via mediators such as N‐glycolylneuraminic acid or arabinogalactan, or by diverse environmental microbes. Moreover, nutritional factors, such as breastfeeding or farm milk and food diversity, inducing short‐chain fatty acids‐producing bacteria in the intestine, contribute to farm‐related effects. All farm‐related exposures induce an anti‐inflammatory response of the innate immunity and increase the differentiation of regulatory T cells and T helper cell type 1. A better understanding of the components of the farm environment, that are protective to the development of allergy and asthma, and their underlying mechanisms, will help to develop new strategies for the prevention of allergy and asthma.
Introduction
The consumption of dairy products contributes to health, nutrition, and livelihoods globally. However, dairy products do not come without microbiological food safety risks for consumers. Despite this risk, common hygiene measures in high-income countries, particularly pasteurisation, ensures that milk is safe, and is indeed frequently mandated by law. Nevertheless, over the past two decades, there has been a global increase in the number of consumers in high-income developed countries actively seeking out unpasteurised milk in liquid and product forms for perceived nutritional and health benefits, and improved taste. The often-anecdotal claims upon which consumers make such choices are not all supported by scientific evidence; however, some recent research studies have investigated (and in some cases demonstrated) the positive impact of unpasteurised milk consumption on the prevalence of asthma, atopy, rectal cancer and respiratory illness.
Methods
To investigate the significance of unpasteurised milk and milk product consumption for human health in high-income countries, outbreak data between the years 2000 and 2018 were obtained for the United States of America, Canada, the European Union, the United Kingdom, Japan, New Zealand and Australia, which were then categorized into three World Health Organisation subregions: AMR A, EUR A and WPR A. Outbreak dynamic variables such as pathogens, the place of consumption, numbers of outbreaks and deaths per million capita, the average number of cases per outbreak and regulations were described and analysed using R Studio. To provide an overview of unpasteurised milk-related disease outbreaks, a rapid evidence review was also undertaken to establish an overview of what is known in the current literature about hazards and drivers of consumption.
Results
Foodborne outbreaks associated with unpasteurised dairy consumption have risen in high-income countries over the period 2000 to 2018, with Campylobacter spp. being the most common aetiological agent responsible, followed by Escherichia coli and Salmonella spp. The most common places of consumption are on farms or in households, indicating individuals choose to drink unpasteurised milk, rather than a widespread distribution of the product, for example, at social events and in schools. Further study is needed to better understand contributing factors, such as cultural differences in the consumption of dairy products.
Conclusion
There are several observable health benefits linked to consuming raw milk, but outbreaks associated with unpasteurised milk and milk products are on the rise. It cannot be definitively concluded whether the benefits outweigh the risks, and ultimately the decision lies with the individual consumer. Nevertheless, many countries have regulations in place to protect consumer health, acknowledging the definite risks to human health that unpasteurised dairy foods may pose, particularly from microbial hazards.
Background:
The persistently high prevalence of allergic diseases in Western industrial nations and the limited possibilities of causal therapy make evidence-based recommendations for primary prevention necessary.
Methods:
The recommendations of the S3 guideline Allergy Prevention, published in its last version in 2014, were revised and consulted on the basis of a current systematic literature search. The evidence search was conducted for the period 06/2013 - 11/2020 in the electronic databases Cochrane and MEDLINE, as well as in the reference lists of current reviews and through references from experts. The literature found was screened in two filtering processes, first by title and abstract, and the remaining papers were screened in the full text for relevance. The studies included after this were sorted by level of evidence, and the study quality was indicated in terms of potential bias (low/high). The revised recommendations were formally agreed and consented upon with the participation of representatives of the relevant professional societies and (self-help) organizations (nominal group process). Of 5,681 hits, 286 studies were included and assessed.
Results:
Recommendations on maternal nutrition during pregnancy and breastfeeding as well as on infant nutrition in the first months of life again play an important role in the updated guideline: Many of the previous recommendations were confirmed by the current data. It was specified that breastfeeding should be exclusive for the first 4 - 6 months after birth, if possible, and that breastfeeding should continue with the introduction of complementary foods. A new recommendation is that supplementary feeding of cow's milk-based formula should be avoided in the first days of life if the mother wishes to breastfeed. Furthermore, it was determined that the evidence for a clear recommendation for hydrolyzed infant formula in non-breastfed infants at risk is currently no longer sufficient. It is therefore currently recommended to check whether an infant formula with proven efficacy in allergy prevention studies is available until the introduction of complementary feeding. Finally, based on the EAACI guideline, recommendations were made for the prevention of chicken egg allergy by introducing and regularly giving thoroughly heated (e.g., baked or hard-boiled) but not "raw" chicken egg (also no scrambled egg) with the complementary food. The recommendation to introduce peanut in complementary feeding was formulated cautiously for the German-speaking countries: In families who usually consume peanut, the regular administration of peanut-containing foods in age-appropriate form (e.g., peanut butter) with the complementary diet can be considered for the primary prevention of peanut allergy in infants with atopic dermatitis (AD). Before introduction, a clinically relevant peanut allergy must be ruled out, especially in infants with moderate to severe AD. There is still insufficient evidence for an allergy-preventive efficacy of prebiotics or probiotics, vitamin D, or other vitamins in the form of supplements so that recommendations against their supplementation were adopted for the first time in the current guideline. Biodiversity plays an important role in the development of immunological tolerance to environmental and food allergens: there is clear evidence that growing up on a farm is associated with a lower risk of developing asthma and allergic diseases. This is associated with early non-specific immune stimulation due to, among other things, the greater microbial biodiversity of house dust in this habitat. This aspect is also reflected in the recommendations on animal husbandry, on which a differentiated statement was made: In families without a recognizable increased allergy risk, pet keeping with cats or dogs should not generally be restricted. Families with an increased allergy risk or with children with already existing AD should not acquire a new cat - in contrast, however, dog ownership should not be discouraged. Interventions to reduce exposure to dust mite allergens in the home, such as the use of mite allergen-proof mattress covers ("encasings"), should be restricted to patients with already proven specific sensitization against house dust mite allergen. Children born by caesarean section have a slightly increased risk of asthma - this should be taken into account when advising on mode of delivery outside of emergency situations. Recent work also supports the recommendations on air pollutants: Active and passive exposure to tobacco smoke increase the risk of allergies, especially asthma, and should therefore be avoided. Exposure to nitrogen oxides, ozone, and small particles (PM 2.5) is associated with an increased risk, especially for asthma. Therefore, exposure to emissions of nitrogen oxides, ozone, and small particles (PM 2.5) should be kept low. The authors of this guideline are unanimously in favor of enacting appropriate regulations to minimize these air pollutants. There is no evidence that vaccinations increase the risk of allergies, but conversely there is evidence that vaccinations can reduce the risk of allergies. All children, including children at risk, should be vaccinated according to the current recommendations of the national public health institutes, also for reasons of allergy prevention.
Conclusion:
The consensus of recommendations in this guideline is based on an extensive evidence base. The update of the guideline enables evidence-based and up-to-date recommendations for the prevention of allergic diseases including asthma and atopic dermatitis.
Rationale: In murine models, microbial exposures induce protection from experimental allergic asthma through innate immunity. Objectives: Our aim was to assess the association of early life innate immunity with the development of asthma in children at risk. Methods: In the PASTURE farm birth cohort, innate T-helper cell type 2 (Th2), Th1, and Th17 cytokine expression at age 1 year was measured after stimulation of peripheral blood mononuclear cells with LPS in n = 445 children. Children at risk of asthma were defined based on single-nucleotide polymorphisms at the 17q21 asthma gene locus. Specifically, we used the SNP rs7216389 in the GSDMB gene. Wheeze in the first year of life was assessed by weekly diaries and asthma by questionnaire at age 6 years. Measurements and Main Results: Not all cytokines were detectable in all children after LPS stimulation. When classifying detectability of cytokines by latent class analysis, carrying the 17q21 risk allele rs7216389 was associated with risk of wheeze only in the class with the lowest level of LPS-induced activation: odds ratio (OR), 1.89; 95% confidence interval [CI], 1.13-3.16; P = 0.015. In contrast, in children with high cytokine activation after LPS stimulation, no association of the 17q21 risk allele with wheeze (OR, 0.63; 95% CI, 0.29-1.40; P = 0.258, P = 0.034 for interaction) or school-age asthma was observed. In these children, consumption of unprocessed cow's milk was associated with higher cytokine activation (OR, 3.37; 95% CI, 1.56-7.30; P = 0.002), which was in part mediated by the gut microbiome. Conclusions: These findings suggest that within the 17q21 genotype, asthma risk can be mitigated by activated immune responses after innate stimulation, which is partly mediated by a gut-immune axis.
There has been a tremendous increase in the prevalence of allergic diseases asthma, atopic dermatitis, allergic rhinitis, and food allergy in the Western world. The management of patients suffering from allergic diseases is despite the recent implementation of novel treatment strategies still a major unmet clinical need. The analysis of epigenetic modifications in allergic diseases has recently attracted substantial interest, as epigenetic modifications might mediate the effects of the environment as well as the genome on the development of or protection from allergic diseases. Beyond understanding the role of epigenetic changes in the etiology and trajectory of allergic diseases, the analysis of epigenetic changes, in particular DNA methylation and miRNA expression changes, has the technical prerequisites for a successful biomarker and their use has therefore great potential to assist in the detection, management and—possibly—prevention of allergic diseases as diagnostic tools. Epigenetic changes can be used to assess tolerance following immunotherapy, and potentially predict the success of therapy at an early time point. Furthermore, the epigenome might also be a target of therapeutic intervention through modulation of the microbiome, strengthening of epithelial barriers with histone deacetylase inhibitors, epigenetic editing or miRNA-based oligonucleotide therapies.
Endotoxin in dairy products may pose risks to consumers’ health, but the effects of raw-milk total bacterial count (TBC) and thermal treatment temperature on endotoxin content of dairy products are not clear. In this study, TBC of raw milk and processed milk with different thermal treatment temperatures were detected by pilot processing experiment. We then verified it by detecting the endotoxin content of commercial dairy products. TBC was determined by conventional culture method, and the changes in alkaline phosphatase (ALP) and lactoperoxidase (LPO) activities in bovine milk before and after heat treatment were determined. The levels of fatty acids in bovine milk were detected by gas chromatography using a flame ionization detector (GC-FID). In the pilot experiment, raw milk was treated at 72, 75, 80, 85, 90, 95, 100, 105, 110, 115, and 120 ℃ for 15 s. After that, the raw milk was stored at 20 ℃ for 24 hours and 48 hours to greatly increase the TBC, and treated at 75 ℃ for 15 s and 90 ℃ for 15 s. The results show that the endotoxin content of sterilized milk increased with the increase in TBC and thermal treatment temperature. With the increase in thermal treatment temperature, the activities of ALP and LPO with endotoxin inhibition decreased. In addition, a total of 226 dairy samples were tested. The endotoxin content of 37 commercial PM milk samples were 6 EU/ml to 231 EU/ml, with 31 EU/ml to 1437 EU/ml for 40 commercial UHT milk samples, and 6 EU/ml to 9080 EU/ml for 149 reconstituted IFM samples. There was a significant difference in the endotoxin content of different dairy products (P < 0.05), and there was no significant difference between domestic and imported IFM (P > 0.05). This study found that TBC and thermal treatment temperature of raw milk could affect the endotoxin content of dairy products.
Background:
The influence of diet in early childhood on later allergic diseases is currently a highly debated research topic. We and others have suggested that an increased diet diversity in the first year of life has a protective effect on the development of allergic diseases.
Objective:
The aim of this follow-up study was to investigate associations between diet in the 2nd year of life and later allergic diseases.
Methods:
1014 children from rural areas in 5 European countries (PASTURE birth cohort) were included. Information on feeding practices in their 2 nd year of life and allergic diseases were collected up to age 6 years. Multivariate logistic regressions were performed, with different models considering reverse causality, such as excluding children with a positive sensitization to egg and/or cow's milk at the age of 1 year.
Results:
An increased food diversity score during the 2nd year of life, was negatively associated with the development of asthma. Consumption of dairy products and eggs in the 2nd year of life showed an inverse association with reported allergic outcomes. Consumption of butter was strongly associated with protection against asthma and food sensitization. Egg was inversely associated to atopic dermatitis (OR 0.17, 95% CI 0.04-0.77). Yogurt and cow's milk were inversely associated against food allergy (OR for yogurt 0.05, 95% CI 0.01-0.55; OR for cow's milk 0.31, 95% CI 0.11-0.89).
Conclusion:
Increased food diversity in the 2nd year of life is inversely associated with the development of asthma, and consumption of dairy products might have a protective effect on allergic diseases.
Background
Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort.
Methods
We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)‐based classifications for milk products. The data were analyzed using a joint model for longitudinal and time‐to‐event data.
Results
At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat‐treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat‐treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction.
Conclusions
High consumption of infant formula and other strongly heat‐treated milk products may be associated with the development of asthma.
Environmental exposures during pregnancy that alter both the maternal gut microbiome and the infant’s risk of allergic disease and asthma include a traditional farm environment and consumption of unpasteurized cow’s milk, antibiotic use, dietary fiber and psychosocial stress.
Multiple mechanisms acting in concert may underpin these associations and prime the infant to acquire immune competence and homeostasis following exposure to the extrauterine environment. Cellular and metabolic products of the maternal gut microbiome can promote the expression of microbial pattern recognition receptors, as well as thymic and bone marrow hematopoiesis relevant to regulatory immunity. At birth, transmission of maternally derived bacteria likely leverages this in utero programming to accelerate postnatal transition from a Th2 to Th1 and Th17 dominant immune phenotypes and maturation of regulatory immune mechanisms, which in turn reduce the child’s risk of allergic disease and asthma. Although our understanding of these phenomena is rapidly evolving, the field is relatively nascent, and we are yet to translate existing knowledge into interventions that substantially reduce disease risk in humans. Here we review evidence that the maternal gut microbiome impacts the offspring’s risk of allergic disease and asthma, discuss challenges and future directions for the field, and propose the hypothesis that maternal carriage of Prevotella copri during pregnancy decreases the offspring’s risk of allergic disease via production of succinate which in turn promotes bone marrow myelopoiesis of dendritic cell precursors in the fetus.
Allergic asthma, a globally growing respiratory disease, is associated with airway hyperresponsiveness (AHR), airway remodeling, mucus hypersecretion and T-helper type (Th) 2 inflammatory responses. Donkey milk, similar to human milk in composition, has potential in asthma remission considering its anti-inflammatory properties and components. We explored the effects of oral administration with donkey milk powder (DML; 0.4, 2, and 10 g/kg) on mice under ovalbumin (OVA) challenge. We found DMP ameliorated AHR and postponed manifestation of asthma. Additionally, DMP relieved the injury and fibrosis of airway epithelium. Besides, it alleviated mucin 5AC (MUC5AC) accumulation along with goblet cell hyperplasia in lung tissues and also downregulated the stimulated MUC5AC expression in human airway epithelial cell line NCI-H292. Moreover, DMP reduced airway eosinophilia and the increased Th2 cytokines in bronchoalveolar lavage fluid as well as serum immunoglobulin E, and inhibited NF-κB P65 activity. These results indicated preventive effects of DMP on OVA-induced asthma.
Hintergrund: Zahlreiche Faktoren wie Mikrobiota und deren Produkte werden im Zusammenhang mit der Hygienehypothese und dem damit assoziierten allergiepräventiven Farmeffekt diskutiert. Neben dem Einatmen der Stäube auf Bauernhöfen wirkt auch der Konsum von Rohmilch der Entstehung von Asthma und Allergien entgegen. Da besonders Rinderställe und Kuhmilch als wirksam beschrieben wurden, scheint die Beteiligung eines bovinen Proteins wahrscheinlich. β-Lactoglobulin (BLG) ist ein Hauptprotein in Milch und besitzt als Lipocalin eine intramolekulare Tasche, welche eine Bindung an hydrophobe Liganden ermöglicht. Ergebnisse: Unsere Studien zeigen, dass unbeladenes BLG die Entstehung einer Allergie begünstigt, während beladenes, sogenanntes holo-BLG, allergiepräventiv wirkt. BLG konnte mit Zink assoziiert auch im Stallstaub und in der Umgebungsluft von Rinderfarmen nachgewiesen werden. Schlussfolgerung: Es scheint daher naheliegend, dass zusätzlich zu Mikroben und deren Produkten auch holo-BLG eine wichtige Rolle im schützenden Farmeffekt spielt. In einer neu entwickelten Lutschtablette zum Diätmanagement bei Allergien ist Zink an holo-BLG daher, basierend auf dem Bauernhof-Effekt, einer der Schlüsselbestandteile. Zitierweise: Mayerhofer H, Pali-Schöll I. The farm effect revisited: from β-lactoglobulin with zinc in cowshed dust to its application. Allergo J Int 2021; 30:135-40 https://doi.org/10.1007/s40629-021-00174-6
A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4th and 12th month of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52–28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2–56.1, p < 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.
The lipocalin beta-lactoglobulin (BLG) is a major protein compound in cow’s milk, and we detected it in cattle stable dust. BLG may be a novel player in the farm protective effect against atopic sensitization and hayfever. In previous studies, we demonstrated that only the ligand-filled holo-form of BLG prevented sensitization to itself. Here, we investigated whether holo-BLG could, in an innate manner, also protect against allergic sensitization to unrelated birch pollen allergens using a murine model. BALB/c mice were nasally pretreated four times in biweekly intervals with holo-BLG containing quercetin–iron complexes as ligands, with empty apo-BLG, or were sham-treated. Subsequently, mice were intraperitoneally sensitized two times with apo-BLG or with the unrelated birch pollen allergen apo-Bet v 1, adjuvanted with aluminum hydroxide. After subsequent systemic challenge with BLG or Bet v 1, body temperature drop was monitored by anaphylaxis imaging. Specific antibodies in serum and cytokines of BLG- and Bet v 1-stimulated splenocytes were analyzed by ELISA. Additionally, human peripheral blood mononuclear cells of pollen allergic subjects were stimulated with apo- versus holo-BLG before assessment by FACS. Prophylactic treatment with the holo-BLG resulted in protection against allergic sensitization and clinical reactivity also to Bet v 1 in an unspecific manner. Pretreatment with holo-BLG resulted in significantly lower BLG-as well as Bet v 1-specific antibodies and impaired antigen-presentation with significantly lower numbers of CD11c+MHCII+ cells expressing CD86. Pretreatment with holo-BLG also reduced the release of Th2-associated cytokines from Splenocytes in BLG-sensitized mice. Similarly, in vitro stimulation of PBMCs from birch pollen allergic subjects with holo-BLG resulted in a relative decrease of CD3+CD4+ and CD4+CRTh2 cells, but not of CD4+CD25+CD127− Treg cells, compared to apo-BLG stimulation. In conclusion, prophylactic treatment with holo-BLG protected against allergy in an antigen-specific and -unspecific manner by decreasing antigen presentation, specific antibody production and abrogating a Th2-response. Holo-BLG therefore promotes immune resilience against pollen allergens in an innate manner and may thereby contribute to the farm protective effect against atopic sensitization.
Milk processing is designed to ensure milk safety, but is milk processing essential? Raw milk consumption has been touted for its nutritional qualities, taste, and health benefits. While no case-controlled studies support claims of superior benefits of raw milk over pasteurized milk, evidence demonstrates the risks associated with raw milk consumption. And perhaps the strongest argument for allowing for consumption of raw milk is the personal liberty to choose what one consumes. The article elaborates on regulations associated with milk and the raw milk debate.
Background
Pseudo-allergic reactions are potentially fatal hypersensitivity responses caused by mast cell activation. α-linolenic acid (ALA) is known for its anti-allergic properties. However, its potential anti-pseudo-allergic effects were not much investigated.
Purpose
To investigate the inhibitory effects of ALA on IgE-independent allergy in vitro, and in vivo, as well as the mechanism underlying its effects.
Methods/study designs
The anti-anaphylactoid activity of ALA was evaluated in passive cutaneous anaphylaxis reaction (PCA) and systemic anaphylaxis models. Calcium imaging was used to assess intracellular Ca²⁺ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of Lyn-PLCγ-IP3R-Ca²⁺ and Lyn-p38/NF-κB signaling pathway.
Results
ALA (0, 1.0, 2.0, and 4.0 mg/kg) dose-dependently reduced serum histamine, chemokine release, vasodilation, eosinophil infiltration, and the percentage of degranulated mast cells in C57BL/6 mice. In addition, ALA (0, 50, 100, and 200 μM) reduced Compound 48/80 (C48/80) (30 μg/ml)-or Substance P (SP) (4 μg/ml)-induced calcium influx, mast cell degranulation and cytokines and chemokine release in Laboratory of Allergic Disease 2 (LAD2) cells via Lyn-PLCγ-IP3R-Ca²⁺ and Lyn-p38/NF-κB signaling pathway. Moreover, ALA (0, 50, 100, and 200 μM) inhibited C48/80 (30 μg/ml)- and SP (4 μg/ml)-induced calcium influx in Mas-related G-protein coupled receptor member X2 (MrgX2)-HEK293 cells and in vitro kinase assays confirmed that ALA inhibited the activity of Lyn kinase. In response to 200 μM of ALA, the activity of Lyn kinase by (7.296 ± 0.03751) × 10⁻⁵ units/μl and decreased compared with C48/80 (30 μg/ml) by (8.572 ± 0.1365) ×10⁻⁵ units/μl.
Conclusion
Our results demonstrate that ALA might be a potential Lyn kinase inhibitor, which could be used to treat pseudo-allergic reaction-related diseases such as urticaria.
Omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are found naturally in fish oil and are commonly thought to be anti-inflammatory nutrients, with protective effects in inflammatory diseases including asthma and allergies. The mechanisms of these effects remain mostly unknown but are of great interest for their potential therapeutic applications. Large numbers of epidemiological and observational studies investigating the effect of fish intake or omega-3 fatty acid supplementation during pregnancy, lactation, infancy, childhood, and adulthood on asthmatic and allergic outcomes have been conducted. They mostly indicate protective effects and suggest a causal relationship between decreased intake of fish oil in modernized diets and an increasing number of individuals with asthma or other allergic diseases. Specialized pro-resolving mediators (SPM: protectins, resolvins, and maresins) are generated from omega-3 fatty acids such as EPA and DHA via several enzymatic reactions. These mediators counter-regulate airway eosinophilic inflammation and promote the resolution of inflammation in vivo. Several reports have indicated that the biosynthesis of SPM is impaired, especially in severe asthma, which suggests that chronic inflammation in the lung might result from a resolution defect. This article focuses on the beneficial aspects of omega-3 fatty acids and offers recent insights into their bioactive metabolites including resolvins and protectins.
Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.
RATIONALE: Clinical and epidemiologic approaches have identified two distinct sets of classifications for asthma and wheeze phenotypes.
OBJECTIVES: To compare epidemiologic phenotype definitions identified by latent class analysis (LCA) with clinical phenotypes based on patient histories, diagnostic work-up, and treatment responses. To relate phenotypes to genetic and environmental determinants as well as diagnostic and treatment-related parameters.
METHODS: LCA was performed in an international multicenter birth cohort based on yearly questions about current wheeze until age 6 years. Associations of wheeze classes and clinical phenotypes with asthma-related characteristics such as atopy, lung function, fraction of exhaled nitric oxide, and medication use were calculated using regression models.
MEASUREMENTS AND MAIN RESULTS: LCA identified five classes, which verified the clinically defined wheeze phenotypes with high sensitivity and specificity; the respective receiver operating characteristics curves displayed an area under the curve ranging from 84% (frequent wheeze) to 85% (asthma diagnosis) and 87% (unremitting wheeze) to 97% (recurrent unremitting wheeze). Recurrent unremitting wheeze was the most specific and unremitting wheeze at least once the most sensitive definition. The latter identified a subgroup of children with decreased lung function, increased genetic risk, and in utero smoke exposure (ODDS RATIO, 2.03; 95% CONFIDENCE INTERVAL, 1.12-3.68; P = 0.0191), but without established asthma diagnosis and treatment.
CONCLUSIONS: Clinical phenotypes were well supported by LCA analysis. The hypothesis-free LCA phenotypes were a useful reference for comparing clinical phenotypes. Thereby, we identified children with clinically conspicuous but undiagnosed disease. Because of their high area under the curve values, clinical phenotypes such as (recurrent) unremitting wheeze emerged as promising alternative asthma definitions for epidemiologic studies.
The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection of mice with Toxoplasma gondii, inflammatory monocytes acquire a tissue-specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, inflammatory monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology in response to pathogen challenge that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 led to enhanced neutrophil activation and host mortality after infection. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal-mediated damage to the gut. Collectively, our results place inflammatory monocyte-derived PGE2 at the center of a commensal-driven regulatory loop required to control host-commensal dialog during pathogen-induced inflammation.
Relative deficiency of dietary omega 3 polyunsaturated fatty acids (n-3 PUFA) has been implicated in the rising allergy prevalence in Westernized countries. Fish oil supplementation may provide an intervention strategy for primary allergy prevention. The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease.
In a double-blind randomized controlled trial, 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control (olive oil), from birth to age 6 months. PUFA levels were measured in 6-month-old infants' erythrocytes and plasma and their mothers' breast milk. Eczema, food allergy, asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age.
At 6 months of age, infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher (both P < .05) and erythrocyte arachidonic acid levels were lower (P = .003) in the fish oil group. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema (P = .033) and recurrent wheeze (P = .027), the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes. Specifically, between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization, eczema, asthma, or food allergy.
Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease.
To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age.
Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial.
Adelaide, South Australia.
706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial.
The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks' gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA.
Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age.
No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen.
n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood.
Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
Between January 2006 and December 2007, a total of 4,579 test-day observations for contents of milk fatty acids (FA) were obtained from 2,218 lactations of 1,109 ewes belonging to 14 Churra dairy flocks. The 36 analyzed FA were quantified as grams per 100 g of total FA and were grouped as 18 dependent variables: 10 FA, 6 groups of FA, and 2 FA indexes. Flock, day of testing within flock (TD), ewe age, stage of lactation, and season effects contributed significantly to variations in FA. The 2 most important variation factors were flock (3 to 30% of total variance) and TD (35 to 70% of total variance). The percentage of variance explained by the TD effect for conjugated linoleic acid (CLA, C18:2 cis-9, trans-11) and linolenic acid (C18:3 cis-9, cis-12, cis-15) was particularly high: 60.7 and 68.2%, respectively. The season effect was also a very important variation factor, closely linked to feeding. The most significant seasonal variations were observed in polyunsaturated FA, with the highest values occurring in spring and summer and the lowest in winter. More specifically, CLA and linolenic acid contents were 44 and 30% higher in spring-summer than in winter. As the age of the ewe increased, the monounsaturated and polyunsaturated FA decreased and the short- and medium-chain saturated FA increased. The CLA and the CLA/C18:1 trans-11 Delta(9)-desaturase index increased significantly throughout lactation. The correlation coefficient between rumenic acid (CLA) and vaccenic acid was high (0.47) because of the precursor-product relationship via the Delta(9)-desaturase enzyme. The correlation coefficients were high between C10:0 and C12:0 (0.79), C12:0 and C14:0 (0.73), and C14:0 and C16:0 (0.29), probably because of their similar metabolic origin. Positive correlations were also obtained among the C(18) FA family. All the studied factors of FA variation would be considered as fixed effects in the statistical models used for estimation of genetic and phenotypic parameters from test-day records of commercial flocks.
Environment and lifestyle contribute to the development of asthma in children. Understanding the relevant factors in this relationship may provide methods of prevention. The role of diet in the development of asthma in pre-school children was investigated.
Data from 2978 children participating in a prospective birth cohort study were used. Food frequency data were collected at the age of 2 years and related to asthma symptoms reported at the age of 3 years.
The prevalence of recent asthma at age 3 was lower in children who consumed (at age 2) full cream milk daily (3.4%) than in those who did not (5.6%) and in those who consumed butter daily (1.5%) than in those who did not (5.1%). The prevalence of recent wheeze was lower in children who consumed milk products daily (13.7%) than in those who did not (18.4%) and in children who consumed butter daily (7.7%) than in those who did not (15.4%). These effects remained in a logistic regression model including different foods and confounders (adjusted odds ratio (CI) for recent asthma: full cream milk daily v rarely 0.59 (0.40 to 0.88), butter daily v rarely 0.28 (0.09 to 0.88)). Daily consumption of brown bread was also associated with lower rates of asthma and wheeze, whereas no associations were observed with the consumption of fruits, vegetables, margarine, and fish.
In pre-school children, frequent consumption of products containing milk fat is associated with a reduced risk of asthma symptoms.
Breast-feeding is protective against respiratory infections in early life. Given the co-evolutionary adaptations of humans and cattle, bovine milk might exert similar anti-infective effects in human infants.
To study effects of consumption of raw and processed cow's milk on common infections in infants.
The PASTURE birth cohort followed 983 infants from rural areas in Austria, Finland, France, Germany, and Switzerland, for the first year of life, covering 37,306 person-weeks. Consumption of different types of cow's milk and occurrence of rhinitis, respiratory tract infections, otitis, and fever were assessed by weekly health diaries. C-reactive protein levels were assessed using blood samples taken at 12 months.
When contrasted with ultra-heat treated milk, raw milk consumption was inversely associated with occurrence of rhinitis (adjusted odds ratio from longitudinal models [95% CI]: 0.71 [0.54-0.94]), respiratory tract infections (0.77 [0.59-0.99]), otitis (0.14 [0.05-0.42]), and fever (0.69 [0.47-1.01]). Boiled farm milk showed similar but weaker associations. Industrially processed pasteurized milk was inversely associated with fever. Raw farm milk consumption was inversely associated with C-reactive protein levels at 12 months (geometric means ratio [95% CI]: 0.66 [0.45-0.98]).
Early life consumption of raw cow's milk reduced the risk of manifest respiratory infections and fever by about 30%. If the health hazards of raw milk could be overcome, the public health impact of minimally processed but pathogen-free milk might be enormous, given the high prevalence of respiratory infections in the first year of life and the associated direct and indirect costs.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E2 or of specific E prostanoid (EP) receptors is not known.
Here we tested the role of EP2 signaling in allergic asthma.
Wild-type (WT) and EP2(-/-) mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2(-/-) CD4 T cells was used to validate the importance of EP2 expression on T cells.
Compared with WT mice, EP2(-/-) mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2(-/-) mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2(-/-) mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE2 decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4(+) T cells. Coculture of flow cytometry-sorted splenic CD4(+) T cells and CD11c(+) dendritic cells from WT or EP2(-/-) mice suggested that the increased IL-13 production in EP2(-/-) mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4(+) EP2(-/-) T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4(+) T cells.
We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.
Several epidemiologic studies have shown that growing up in a farming environment is associated with a decreased risk of allergies. A factor that correlates strongly with this effect is the early ingestion of unheated cow's milk. Although, to date, no controlled studies on raw milk consumption have been performed to formally demonstrate this effect, several factors in bovine milk have been described that might explain how raw cow's milk consumption can decrease the risk of allergies. In addition, increasing knowledge on the immunologically active factors in breast milk have also contributed to our understanding of the effects of bovine milk in infants because many of the factors in bovine milk are expected to have functional effects in human subjects as well. Here we review these factors and their mechanisms of action and compare their presence in bovine milk and breast milk. A better understanding of these factors, as well as how to retain them, might ultimately lead to the development of mildly processed milk and infant nutrition products that could become a part of preventive strategies to reduce the incidence of allergic disease.
Multiple studies have shown that the prevalence of asthma and atopy is reduced in children raised on traditional dairy farms. This article discusses the temporal constraints for the protective farm effect, the components of a farming environment that are associated with protection, and novel mechanisms that may underlie protection from asthma and atopy in farming populations.
Protection from asthma and allergy is strongest when exposure occurs in utero or early in life, but the protective effects can persist into adulthood. Just three exposures (contact with cows and straw and consumption of unprocessed cow's milk) account for virtually all the protective farm effect for asthma but not atopy. Whey proteins appear to be critical for the protective effects of farm milk, whereas the high microbial diversity existing in a farm environment is strongly and inversely associated with asthma, but only weakly associated with atopy. Therefore, distinct mechanisms are likely to mediate protection from asthma and atopy. The biological significance of microbial diversity is still unclear, but multiple lines of evidence link the asthma-protective and allergy-protective effects of farming to immune responses and the microbiome. Work in mouse models is revealing novel cellular and molecular mechanisms through which the microbiota may modulate immune responses and allergic inflammation, and thus contribute to the farm effect. The role of the host's genetic makeup, on the contrary, remains poorly understood.
The discovery of the central role played by microbial diversity in the asthma-protective and allergy-protective effects of farming warrants metagenomic studies that concertedly and longitudinally investigate the microbiome, the genome, and the immune system of farmers and the farms they live on.
Studies on the association of farm environments with asthma and atopy have repeatedly observed a protective effect of farming. However, no single specific farm-related exposure explaining this protective farm effect has consistently been identified.
We sought to determine distinct farm exposures that account for the protective effect of farming on asthma and atopy.
In rural regions of Austria, Germany, and Switzerland, 79,888 school-aged children answered a recruiting questionnaire (phase I). In phase II a stratified random subsample of 8,419 children answered a detailed questionnaire on farming environment. Blood samples and specific IgE levels were available for 7,682 of these children. A broad asthma definition was used, comprising symptoms, diagnosis, or treatment ever.
Children living on a farm were at significantly reduced risk of asthma (adjusted odds ratio [aOR], 0.68; 95% CI, 0.59-0.78; P< .001), hay fever (aOR, 0.43; 95% CI, 0.36-0.52; P< .001), atopic dermatitis (aOR, 0.80; 95% CI, 0.69-0.93; P= .004), and atopic sensitization (aOR, 0.54; 95% CI, 0.48-0.61; P< .001) compared with nonfarm children. Whereas this overall farm effect could be explained by specific exposures to cows, straw, and farm milk for asthma and exposure to fodder storage rooms and manure for atopic dermatitis, the farm effect on hay fever and atopic sensitization could not be completely explained by the questionnaire items themselves or their diversity.
A specific type of farm typical for traditional farming (ie, with cows and cultivation) was protective against asthma, hay fever, and atopy. However, whereas the farm effect on asthma could be explained by specific farm characteristics, there is a link still missing for hay fever and atopy.
Farm milk consumption has been identified as an exposure that might contribute to the protective effect of farm life on childhood asthma and allergies. The mechanism of action and the role of particular constituents of farm milk, however, are not yet clear.
We sought to investigate the farm milk effect and determine responsible milk constituents.
In rural regions of Germany, Austria, and Switzerland, a comprehensive questionnaire about farm milk consumption and other farm-related exposures was completed by parents of 8334 school-aged children, and 7606 of them provided serum samples to assess specific IgE levels. In 800 cow's milk samples collected at the participants' homes, viable bacterial counts, whey protein levels, and total fat content were analyzed. Asthma, atopy, and hay fever were associated to reported milk consumption and for the first time to objectively measured milk constituents by using multiple regression analyses.
Reported raw milk consumption was inversely associated to asthma (adjusted odds ratio [aOR], 0.59; 95% CI, 0.46-0.74), atopy (aOR, 0.74; 95% CI, 0.61-0.90), and hay fever (aOR, 0.51; 95% CI, 0.37-0.69) independent of other farm exposures. Boiled farm milk did not show a protective effect. Total viable bacterial counts and total fat content of milk were not significantly related to asthma or atopy. Increased levels of the whey proteins BSA (aOR for highest vs lowest levels and asthma, 0.53; 95% CI, 0.30-0.97), α-lactalbumin (aOR for interquartile range and asthma, 0.71; 95% CI, 0.52-0.97), and β-lactoglobulin (aOR for interquartile range and asthma, 0.62; 95% CI, 0.39-0.97), however, were inversely associated with asthma but not with atopy.
The findings suggest that the protective effect of raw milk consumption on asthma might be associated with the whey protein fraction of milk.
Numerous epidemiological studies have shown that children who grow up on traditional farms are protected from asthma, hay fever and allergic sensitization. Early-life contact with livestock and their fodder, and consumption of unprocessed cow's milk have been identified as the most effective protective exposures. Studies of the immunobiology of farm living point to activation and modulation of innate and adaptive immune responses by intense microbial exposures and possibly xenogeneic signals delivered before or soon after birth.
During the last decade, the contribution of omega-3 and -6 long chain-polyunsaturated fatty acids (LC-PUFA) and conjugated linoleic acids (CLA) to the prevention and development of many inflammatory and cardiovascular diseases has been of growing interest. In order to investigate the etiology of these diseases, rapid, combined and comparable methods are invaluable for monitoring both the intake and the incorporation of these fatty acids (FA).
The fatty acid methyl esters (FAME) were analyzed using a gas chromatography/flame ionization detector (GC-FID) system and quantified with an internal standard (C18:0 iso).
An effective and rapid protocol for sample preparation and the analysis of FAME was developed and validated. The comparison of different extraction methods showed that the Hara and Radin method gave the best results for serum and erythrocyte membranes. Excellent mean within-day and day-to-day precisions for serum, erythrocytes and cow's milk LC-PUFAs demonstrated the high reproducibility of the method. Recovery rates for FAMEs in serum and milk were close to 100%. In addition, high mean method linearity (R(2)) (>0.99) was shown for serum, erythrocytes and cow's milk. The sensitivity for FA achieved by GC analysis was acceptable.
With the newly adapted protocols, combined and rapid analyses of up to 46 FAMEs, including CLAs and omega-3/-6 LC-PUFAs, can be conducted with high reliability and reproducibility using serum, erythrocyte membranes or cow's milk. This provides a novel tool that can be easily implemented in epidemiological studies or clinical diagnostics.
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA) are precursors of potent lipid mediators, termed eicosanoids, which play an important role in the regulation of inflammation. Eicosanoids derived from n-6 PUFAs (e.g., arachidonic acid) have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFAs [e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have anti-inflammatory properties, traditionally attributed to their ability to inhibit the formation of n-6 PUFA-derived eicosanoids. While the typical Western diet has a much greater ratio of n-6 PUFAs compared with n-3 PUFAs, research has shown that by increasing the ratio of n-3 to n-6 fatty acids in the diet, and consequently favoring the production of EPA in the body, or by increasing the dietary intake of EPA and DHA through consumption of fatty fish or fish-oil supplements, reductions may be achieved in the incidence of many chronic diseases that involve inflammatory processes; most notably, these include cardiovascular diseases, inflammatory bowel disease (IBD), cancer, and rheumatoid arthritis, but psychiatric and neurodegenerative illnesses are other examples.
Traditional farming represents a unique model situation to investigate the relationship of early-life farm-related exposure and allergy protection.
To investigate associations between maternal farm exposures and cytokine production in cord blood (CB) mononuclear cells in a prospective multinational birth cohort of 299 farm and 326 nonfarm children and their families.
Supernatants from phorbol 12-myristate 13-acetate/ionomycin-stimulated CB mononuclear cells were assessed for the production of IFN-gamma, TNF-alpha, IL-5, IL-10, and IL-12.
Significantly higher levels of IFN-gamma and TNF-alpha in farm compared with nonfarm children were found, whereas IL-5, IL-10, and IL-12 levels did not differ between study groups. Maternal contact with different farm animal species and barns and consumption of farm-produced butter during pregnancy enhanced the production of proinflammatory CB cytokines, whereas maternal consumption of farm-produced yogurt resulted in significant lower levels of IFN-gamma and TNF-alpha in umbilical blood.
Maternal exposure to farming activities and farm dairy products during pregnancy modulated cytokine production patterns of offspring at birth.
Evidence from observational studies, prospective cohort studies and randomized clinical intervention studies indicate that moderate doses of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) significantly decrease risk of fatal coronary heart disease (CHD). Higher doses and longer duration of intervention may also protect from non-fatal CHD events. The exact mechanisms through which LC n-3 PUFA has an effect on CHD are not well established but may include a decrease in fasting and postprandial triacylglycerol levels, a decrease in arrhythmias, modulation of platelet aggregation and decreased synthesis of pro-inflammatory agents. The mechanistic relation between LC n-3 PUFA and inflammation has attracted great interest, and in vitro studies have revealed that these fatty acids decrease endothelial activation, affect eicosanoid metabolism (including epoxygenation pathways) and induce inflammatory resolution. However, the effects of LC n-3 PUFA on established biomarkers of inflammation and endothelial activation in vivo are not strong. Consequently we need new and more sensitive and systemic biomarkers to reveal the effects of LC n-3 PUFA on localized inflammatory processes.
We investigated the anti-inflammatory potential of n-3 polyunsaturated fatty acids (PUFA) on specific bronchial inflammation. Allergic asthmatics were challenged using a low-dose allergen provocation model.
Our parallel double-blinded study randomly assigned 23 house dust mite-allergic asthmatics (aged 22-29 years; 13 females, 10 males) to dietary supplementation with either an n-3 PUFA-enriched fat blend (0.69 g/day) or placebo for 5 weeks. After 3 weeks, the patients were challenged daily with low doses of mite allergen for 2 weeks. Primary outcome parameters were effects on lung function (forced expiratory volume in 1 s, FEV(1)) and exhaled nitric oxide (eNO) as a marker of bronchial inflammation.
Even before the bronchial challenge, eNO was significantly lower in the n-3 PUFA group (p=0.014). Levels of eNO increased during allergen exposure in both groups, but differences in means were significantly lower in the n-3 PUFA group (p=0.022). During the low-dose allergen challenge, there were no differences between the groups with regard to symptoms, FEV(1) or the allergen dose required to induce deterioration of lung function (PD(20)). Numbers of sputum eosinophils did not differ significantly, while serum eosinophils (10.1+/-0.1.84 vs. 5.79+/-0.69%) as well as changes in eosinophilic cationic protein (20.5+/-9.93 vs. -1.68+/-4.36 ng/ml) and in vitro cysteinyl leukotriene release (2,889+/-872 vs. 1,120+/-173 ng/ml) were significantly lower in the n-3 PUFA group (p<0.05 each).
Our results provide evidence that dietary supplementation with n-3 PUFA is able to reduce bronchial inflammation even after low-dose allergen challenge.
In some studies, the prevalence of hay fever and asthma has been found to be lower in children from rural areas than in children from an urban environment. We hypothesized that living on a farm might be protective against development of allergic sensitization and allergic diseases.
In a cross-sectional survey, parents of 2283 children aged 8-10 years from a mostly rural area in Austria answered a standardized questionnaire on allergic diseases and environmental factors. 1137 children performed a skin prick test to seven local allergens.
The prevalence of hay fever (3.1 vs 10.3%, P = 0.0002), asthma (1.1 vs 3.9%, P = 0.017) and a positive skin prick reactivity to at least one of the common local allergens (18.8 vs 32.7%, P = 0. 001) was significantly lower in children living on a farm than in children from a non-farming environment. In a multivariate logistic regression model, adjusting for genetic background, parent education, living and housing conditions and dietary factors did not change the odds ratio for the association of farming and allergic sensitization. Only after including 'regular contact with livestock and poultry' into the model did the odds ratio change significantly (cOR 0.48 95% CI 0.30-0.75 to aOR 0.75 95% CI 0.37-1.52) indicating an association between regular contact with farm animals and reduced risk of atopic sensitization.
Possible explanations for the lower prevalence of hay fever, asthma and allergic sensitization in children living on a farm might be the development of immunotolerance or the stimulation of TH1 cells and suppression of TH2 cells by increased exposure of farm children to microbial antigens in the stables or farmhouses.
A farming environment protects against development of asthma, hay fever, and atopic sensitisation in children. We aimed to establish whether increased exposure to microbial compounds has to occur early in life to affect maturation of the immune system and thereby reduces risk for development of allergic diseases.
We did a cross-sectional survey in rural areas of Austria, Germany, and Switzerland. 2618 (75%) of 3504 parents of 6-13-year-old children completed a standardised questionnaire on asthma, hay fever, and atopic eczema. Children from farming families, and a random sample of non-farmers' children, who gave consent for blood samples to be obtained for measurements of specific serum IgE antibodies to common allergens were invited to participate (n=901).
Exposure of children younger than 1 year, compared with those aged 1-5 years, to stables and consumption of farm milk was associated with lower frequencies of asthma (1% [3/218] vs 11% [15/138]), hay fever (3% [7] vs 13% [18]), and atopic sensitisation (12% [27] vs 29% [40]). Protection against development of asthma was independent from effect on atopic sensitisation. Continual long-term exposure to stables until age 5 years was associated with the lowest frequencies of asthma (0.8% [1/122]), hay fever (0.8% [1]), and atopic sensitisation (8.2% [10]).
Long-term and early-life exposure to stables and farm milk induces a strong protective effect against development of asthma, hay fever, and atopic sensitisation.
Although widely adopted by the chemical and pharmaceutical industries in recent years, little published data is available regarding possible applications of high pressure homogenisation for dairy products. The objective of this work was to compare the effects of conventional (18 MPa, two-stage) and single or two-stage high pressure homogenisation (HPH) at 50-200 MPa on some properties of raw whole bovine milk (approximately 4% fat). Fat globule size decreased as HPH pressure increased and, under certain conditions of temperature and pressure, HPH yielded significantly smaller fat globules than conventional homogenisation. Fat globule size was also affected by milk inlet temperature. The pH of all homogenised milk samples decreased during 24 h refrigerated storage. Total bacterial counts of milk were decreased significantly (P < 0.05) for milk samples HPH-treated at 150 or 200 MPa. Whiteness and rennet coagulation properties of milk were unaffected or enhanced, respectively, as homogenisation pressure was increased. Average casein micelle size decreased slightly when skim milk was homogenised at 200 MPa. Thus, HPH treatment has several, potentially significant, effects on milk properties.
There is growing interest in the potential role of anti-inflammatory n-3 polyunsaturated fatty acids (n-3 PUFAs) in the prevention of allergic disease.
We sought to determine whether maternal dietary supplementation with n-3 PUFAs during pregnancy could modify immune responses in infants.
In a randomized, controlled trial 98 atopic, pregnant women received fish oil (3.7 g n-3 PUFAs per day) or placebo from 20 weeks' gestation until delivery. Neonatal PUFA levels and immunologic response to allergens were measured at birth.
Eighty-three women completed the study. Fish oil supplementation (n = 40) achieved significantly higher proportions of n-3 PUFAs in neonatal erythrocyte membranes (mean +/- SD, 17.75% +/- 1.85% as a percentage of total fatty acids) compared with the control group (n = 43, 13.69% +/- 1.22%, P <.001). All neonatal cytokine (IL-5, IL-13, IL-10, and IFN-gamma) responses (to all allergens) tended to be lower in the fish oil group (statistically significant only for IL-10 in response to cat). Although this study was not designed to examine clinical effects, we noted that infants in the fish oil group were 3 times less likely to have a positive skin prick test to egg at 1 year of age (odds ratio, 0.34; 95% confidence interval, 0.11 to 1.02; P =.055). Although there was no difference in the frequency of atopic dermatitis at 1 year of age, infants in the fish oil group also had significantly less severe disease (odds ratio, 0.09; 95% confidence interval, 0.01 to 0.94; P =.045).
These data suggest a potential reduction in subsequent infant allergy after maternal PUFA supplementation. More detailed follow-up studies are required in larger cohorts to establish the robustness of these findings and to ascertain their significance in relation to longer-term modification of allergic disease in children.
The influence of grass-only diets either from rye-grass-dominated lowland pastures (400 m above sea level) or botanically
diverse alpine pastures (2000 m) on the FA profile of milk was investigated using three groups of six Brown Swiss cows each.
Two groups were fed grass-only on pasture (P) or freshly harvested in barn (B), both for two experimental periods in the lowlands
and, consecutively, two periods on the alp. Group C served as the control, receiving a silage-concentrate diet and permanently
staying in the lowlands. Effects of vegetation stage or pasture vs. barn feeding on milk fat composition were negligible.
Compared with the control, α-linoleic acid (18∶3n−3) consumption was elevated in groups P and B (79%, P
n-3 PUFA influence immune functioning and may affect the cytokine phenotype during development. To examine whether maternal fish oil supplementation during lactation could modify later immune responses in children, 122 lactating Danish mothers with a fish intake below the population median were randomized to groups supplemented for the first 4 mon of lactation with 4.5 g/d of fish oil (equivalent to 1.5 g/d of n-3 long-chain PUFA) or olive oil. Fifty-three mothers with a fish intake in the highest quartile of the population were also included. The FA composition of erythrocyte membranes was measured at 4 mon and at 2 1/2 yr. Plasma immunoglobulin E (IgE) levels and cytokine production in lipopolysaccharide-stimulated whole-blood cultures were determined at 2 1/2 yr. Erythrocyte n-3 PUFA at 4 mon were higher in infants from the fish oil group compared with the olive oil group (P < 0.001) but were no longer different at 2 1/2 yr. The median production of lipopolysaccharide-induced interferon gamma (IFN-gamma) in the fish oil group was fourfold higher than that in the olive oil group (P = 0.034), whereas interleukin-10 (IL-10) production was similar. The IFN-gamma/IL-10 ratio was twofold higher in the fish oil group (P = 0.019) and was positively correlated with 20:5n-3/20:4n-6 in erythrocytes at 4 mon (P = 0.050). The percentages of atopic children and plasma IgE were not different in the two groups, but the study was not designed to look at atopy. Cytokine responses and erythrocyte FA composition in children of mothers with a high fish intake were intermediate in comparison with those in the randomized groups. Fish oil supplementation during lactation resulted in increased in vitro IFN-gamma production in the children 2 yr after the supplementation was given, which may reflect a faster maturation of the immune system.
Since January 2002, the European Commission is funding a large project, 'Protection against Allergy--Study in Rural Environments' (PASTURE; contract no. QLK4-2001-00250), under the Fifth Framework Program in the field of epidemiology of allergic diseases. The aim of this paper was to describe the background and design as well as the aims of the project. Asthma and allergic disorders are a major public health problem in many Western countries. The aetiology of asthma and allergic disease remains poorly understood despite considerable research. Epidemiology has the potential to add greatly to the understanding by elucidating the risk factors for asthma and allergic disease and thereby suggesting productive avenues for research into causation and prevention. Several risk factors for the development of asthma and atopic disease in children such as passive smoke exposure during pregnancy and infancy, low birth weight or high body mass index later in life have been described. Furthermore, there is consistent evidence that the prevalence of atopy increases with higher socio-economic status. Levels of air pollution such as ozone, NO2, SO2 and particles are likely to provoke acute exacerbations of pre-existent respiratory disease. Their role in the inception of asthma and allergies remains to be clarified. Allergen exposure has been linked to the development of atopic sensitization to that particular allergen in children as well as in adults with occupational exposures. Exposure to house dust mite or cat allergen is, however, unlikely to contribute to the development of childhood asthma. In turn, pet keeping in the first year of life, particularly, dog keeping, has been inversely related to the development of wheeze and atopic illnesses. Several prospective birth cohort studies found a decreased prevalence of atopic disease in children having daily contact to pets, in particular to cats and dogs, during early infancy. The protective effect might be attributable to allergen or other exposures associated with pet ownership, but may also in part be because of the removal of pets in families with sensitized or symptomatic children or in families with a positive history for atopy at the time the child was born.
Studies in Europe have reported a reduced prevalence of allergy in farmers' children. We aimed to determine if there is a similar reduction in allergy among New Zealand farm children.
Two hundred and ninety-three children participated (60%) aged 7-10 years, from selected schools in small towns and the surrounding rural area. Skin prick tests (SPT) to eight common allergens were performed. Parents completed questionnaires about allergic and infectious diseases, place of residence, exposure to animals, and diet, and they provided dust from the living-room floor. Endotoxin was measured using an Limulus amoebocyte lysate (LAL) assay and Der p 1 using enzyme-linked immunoassay (ELISA).
Current farm abode was found to increase the risk of having symptoms associated with allergy, but not SPT positivity. Independent inverse associations were found for early-life exposures: at least weekly consumption of yoghurt with hayfever (odds ratio (OR) = 0.3, 95% confidence intervals (CI) 0.1-0.7) and allergic rhinitis (OR = 0.3, 95% CI 0.2-0.7); any unpasteurized milk consumption with atopic eczema/dermatitis syndrome (AEDS) (OR = 0.2, 95% CI 0.1-0.8); cats inside or outside with hayfever (OR = 0.4, 95% CI 0.1-1.0) and AEDS (OR = 0.4, 95% CI 0.2-0.8); dogs inside or outside with asthma (OR = 0.4, 95% CI 0.2-0.8); and pigs with SPT positivity (OR = 0.2, 95% CI 0.1-0.9).
Despite finding a protective effect of early-life animal exposures, we found a greater prevalence of allergic disease on farms.
Farmers' children have a reduced prevalence of allergic disorders. The specific protective environmental factors responsible are not yet identified.
We sought to determine whether farmers' children in the rural county of Shropshire, England, have a reduced risk of atopy and, if so, to identify the factors responsible.
The Study of Asthma and Allergy in Shropshire was a 2-stage cross-sectional study. In stage 1 a questionnaire to elicit allergic status, diet, and farming exposure was completed by the parents of 4767 children. In stage 2 a stratified subsample of 879 children underwent skin prick testing and measurement of domestic endotoxin.
Compared with rural nonfarming children, farmers' children had significantly less current asthma symptoms (adjusted odds ratio (OR), 0.67; 95% CI, 0.49-0.91; P = .01) and current seasonal allergic rhinitis (adjusted OR, 0.50; 95% CI, 0.33-0.77; P = .002) but not current eczema symptoms (adjusted OR, 0.91; 95% CI, 0.68-1.21; P = .53) or atopy (adjusted OR, 0.68; 95% CI, 0.40-1.16; P = .15). In contrast, current unpasteurized milk consumption was associated with significantly less current eczema symptoms (adjusted OR, 0.59; 95% CI, 0.40-0.87; P = .008) and a greater reduction in atopy (adjusted OR, 0.24; 95% CI, 0.10-0.53; P = .001). The effect was seen in all children, independent of farming status. Unpasteurized milk consumption was associated with a 59% reduction in total IgE levels (P < .001) and higher production of whole blood stimulated IFN-gamma (P = .02).
Unpasteurized milk consumption was the exposure mediating the protective effect on skin prick test positivity. The effect was independent of farming status and present with consumption of infrequent amounts of unpasteurized milk.
Unpasteurized milk might be a modifiable influence on allergic sensitization in children.
Early life exposures may be important in the development of asthma and allergic disease.
To test house dust mite (HDM) avoidance and dietary fatty acid modification, implemented throughout the first 5 years of life, as interventions to prevent asthma and allergic disease.
We recruited newborns with a family history of asthma antenatally and randomized them, separately, to HDM avoidance or control and to dietary modification or control. At age 5 years, they were assessed for asthma and eczema and had skin prick tests for atopy.
Of 616 children randomized, 516 (84%) were evaluated at age 5 years. The HDM avoidance intervention resulted in a 61% reduction in HDM allergen concentrations (microg/g dust) in the child's bed but no difference in the prevalence of asthma, wheeze, or atopy (P > .1). The prevalence of eczema was higher in the active HDM avoidance group (26% vs 19%; P = .06). The ratio of omega-6 to omega-3 fatty acids in plasma was lower in the active diet group (5.8 vs 7.4; P < .0001). However, the prevalence of asthma, wheezing, eczema, or atopy did not differ between the diet groups (P > .1).
Further research is required to establish whether other interventions can be recommended for the prevention of asthma and allergic disease.
House dust mite avoidance measures and dietary fatty acid modification, as implemented in this trial during infancy and early childhood, did not prevent the onset of asthma, eczema, or atopy in high-risk children.
In this study fish oil was incorporated into commercial homogenized milk using different homogenization temperatures and pressures. The main aim was to understand the significance of homogenization temperature and pressure on the oxidative stability of the resulting milks. Increasing homogenization temperature from 50 to 72 degrees C decreased droplet size only slightly, whereas a pressure increase from 5 to 22.5 MPa decreased droplet size significantly. Surprisingly, emulsions having small droplets, and therefore large interfacial area, were less oxidized than emulsions having bigger droplets. Emulsions with similar droplet size distributions, but resulting from different homogenization conditions, had significantly different oxidative stabilities, indicating that properties of significance to oxidation other than droplet size itself were affected by the different treatments. In general, homogenization at 72 degrees C appeared to induce protective effects against oxidation as compared to homogenization at 50 degrees C. The results thus indicated that the actual composition of the oil-water interface is more important than total surface area itself.
In recent years, studies have shown a protective effect of being raised in a farm environment on the development of hay fever and atopic sensitization. Inconsistent data on the relation of farming to asthma and wheeze have raised some doubt about a true protective effect.
We sought to study the differential effects of farm-associated exposures on specific asthma-related health outcomes.
The cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle study included 8263 school-age children from rural areas in 5 European countries. Information on farm-related exposures and health outcomes was obtained by using questionnaires. In subsamples allergen-specific IgE and RNA expression of CD14 and Toll-like receptor genes were measured, and dust from children's mattresses was evaluated for microbial components.
Inverse relations with a diagnosis of asthma were found for pig keeping (odds ratio [OR], 0.57; 95% CI, 0.38-0.86), farm milk consumption (OR, 0.77; 95% CI, 0.60-0.99), frequent stay in animal sheds (OR, 0.71; 95% CI, 0.54-0.95), child's involvement in haying (OR, 0.56; 95% CI, 0.38-0.81), and use of silage (OR, 0.55; 95% CI, 0.31-0.98; for nonatopic asthma) and in Germany for agriculture (OR, 0.34; 95% CI, 0.22-0.53). Protective factors were related with higher expression levels of genes of the innate immunity. Potential risk factors for asthma and wheeze were also identified in the farm milieu. Levels of endotoxin and extracellular polysaccharides were related to the health outcomes independently of the farm exposures.
The protective effect of being raised in a farm environment was ascribed to distinct exposures.
The development of atopic sensitization and atopic and nonatopic asthma is most likely determined by different environmental factors, possibly reflecting distinct pathomechanisms.
Dietary interventions as a means for atopy prevention attract great interest. Some studies in rural environments claimed an inverse association between consumption of farm-produced dairy products and the prevalence of allergic diseases, but current evidence is controversial.
To investigate whether consumption of farm-produced products is associated with a lower prevalence of asthma and allergy when compared with shop-purchased products.
Cross sectional multi-centre study (PARSIFAL) including 14,893 children aged 5-13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children). A detailed questionnaire including a dietary component was completed and allergen-specific IgE was measured in serum.
Farm milk consumption ever in life showed a statistically significant inverse association with asthma: covariate adjusted odds ratio (aOR) 0.74 [95% confidence interval (CI) 0.61-0.88], rhinoconjunctivitis: aOR 0.56 (0.43-0.73) and sensitization to pollen and the food mix fx5 (cut-off level of >or=3.5 kU/L): aOR 0.67 (0.47-0.96) and aOR 0.42 (0.19-0.92), respectively, and sensitization to horse dander: aOR 0.50 (95% CI 0.28-0.87). The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome.
Our results indicate that consumption of farm milk may offer protection against asthma and allergy. A deepened understanding of the relevant protective components of farm milk and a better insight into the biological mechanisms underlying this association are warranted as a basis for the development of a safe product for prevention.
Exposure to a farming environment protects individuals from respiratory allergy. The timing and duration of exposure seem to play critical roles. The largest reduction in risk of developing respiratory allergies is seen among those who are exposed prenatally and continuously thereafter. Contact with farm animals, at least in childhood, likely confers protection; other factors have not been completely identified. Also, the consumption of milk directly from the farm during childhood has been shown to be beneficial with respect to childhood asthma and allergies. Increased levels of microbial substances may contribute to the protective effects. The mechanisms by which such environmental exposures confer protection from respiratory allergies are not well understood. A number of gene-by-environment interactions have been observed with polymorphisms in genes of innate immunity receptors and exposure to farming environments. Increased levels of microbial exposures recognized by innate immune responses may affect adaptive immune responses resulting in decreased levels of atopic sensitization and asthma.
Free fatty acid (FFA) release and quantification and lipid oxidation extent of ultra-high-pressure homogenized (UHPH) milk samples were evaluated to assess the effect of UHPH on the susceptibility of milk lipids to lipolysis and oxidation. Milk was UHPH-treated at 200 and 300 MPa with inlet temperatures of 30 and 40 degrees C. UHPH-treated samples were compared to high-pasteurized milk (PA; 90 degrees C, 15 s). Results showed that all FFA increased significantly during storage only in 200 MPa samples. Lipid oxidation was measured as an accumulation of lipid hydroperoxides as the primary oxidation product and malondialdehyde and hexanal as the secondary oxidation products. Samples treated at 300 MPa presented higher malondialdehyde and hexanal content compared to 200 MPa treated-samples and to PA milk.
The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease
- Wlasiuk
Wlasiuk G, Vercelli D. The farm effect, or: when, what and how a farming
environment protects from asthma and allergic disease. Curr Opin Allergy Clin
Immunol 2012;12:461-6.
United States: United States Department of Agriculture
- Milks
Milks, fluid. United States: United States Department of Agriculture; 2001.
Available at: http://www.ams.usda.gov/sites/default/files/media/CID%20Milks%
2C%20Fluid.pdf. Accessed December 16, 2015.
Informationen liefert die Verpackung/das Etikett?: Bayerisches Staatsministerium f€ ur Umwelt und Verbraucherschutz
- Kennzeichnung Von Milch-Welche
Kennzeichnung von Milch-Welche Informationen liefert die Verpackung/das
Etikett?: Bayerisches Staatsministerium f€ ur Umwelt und Verbraucherschutz;
2013.] Available at: http://www.vis.bayern.de/ernaehrung/lebensmittelsicherheit/
kennzeichnung/milchkennzeichnung.htm. Accessed December 16, 2015.
Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids.
- Wall R.
- Ross R.P.
- Fitzgerald G.F.
- Stanton C.
Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the
anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev 2010;
68:280-9.
Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids
- Wall