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Synthetic surfactant food additives can cause intestinal barrier dysfunction
Abstract
In addition to genetic factors and antigen exposure, intestinal barrier dysfunction plays a key role in the pathogenesis of numerous allergic and autoimmune diseases. The hypothesis of this article is that synthetic surfactant food additives (also called emulsifiers) - which are applied in relatively high concentrations in even the most frequently consumed foods -cause increased intestinal permeability, hence they can play a significant role in the increasing incidence of numerous allergic and autoimmune diseases. In many cases the surfactants added to foods are exactly the same as the ones used in pharmaceutics as absorption enhancers. Numerous synthetic surfactant food additives have been shown to increase the intestinal permeability through paracellular and/or transcellular mechanisms and some of them were also shown to inhibit P-glycoprotein. Additionally, based on the general characteristics of surfactants it can be predicted that they decrease the hydrophobicity of the mucus layer, which has also been shown to associate with increased intestinal permeability.
... A GIT barrierfunkcióinak zavara számos allergiás, ill. autoimmun betegségben is szerepet játszik [37]. Számos környezeti és endogén hatás idézheti elő a GIT barrierfunkcióinak zavarát. ...
... előidézhetik azt egyes kórokozók [40], a cukorbetegség [41] és a dohányzás is [42] hajlamosíthat rá. Bizonyos mesterséges élelmiszer-adalékanyagok is előidézik a működészavart [37]. Egyes gyümölcsökben, zöldségekben található bioaktív anyagok, mint a ferulasav hatékony a GIT barrierfunkció-csökkenésének megelőzésében [43]. ...
A szerzők dolgozatukban rövid irodalmi áttekintést adnak a tejben megtalálható biológiailag aktív peptidekről, azok lehetséges szerepéről az egészség megőrzésében, egyes betegségek megelőzésében. A tehéntejben, ill. a kolosztrum-ban mintegy 514 féle, különböző biológiai hatású fehérjét azonosítottak: vannak baktérium-, vírus-és gombaellenes hatásúak, rendelkezhetnek antioxidáns vagy daganatellenes hatással, de akár szabályozó szerepük is lehet egyes anyag-csere-, ill. immunológiai folyamatokban, vagy a bél természetes barrierfunkciójának fenntartásában.
SUMMARY: Milk of mammals is a unique and complex food and has a high nutritive value. The most important nutrients in milk and their concentrations are well known. However, both colostrum and milk contain, or are the source of molecules that exert biological functions, such as bioactive peptides. 514 proteins have been identified in cow milk and colostrum, 352 of them in the cell fraction and 162 in the fluid phase. Many of these bioactive molecules possess antibacterial, antivi-ral, antifungal or antioxidant properties. Some regulate metabolic and immune processes. Others contribute to maintaining gut integrity, the barrier function of the gut. Opioid and antihypertensive peptides are also intensively researched and we have also identified peptides that can be used effectively in the prevention of certain tumours, thrombosis, caries or osteoporosis. Some peptides function as vasorelaxants, others may be antagonists of certain toxins. Due to the wide range of proposed beneficial effects on human health, milk proteins are considered as potential ingredients for the production of health-promoting functional foods. Although we know more and more about bioactive compounds and have described the mode of action of new bioactive molecules, most of the evidence for bioactive effects comes from in vitro studies, and there is need for further research to fully evaluate the true potential of milk-derived bioactive factors and to investigate allergenic and toxic properties and the stability of these molecules. Universal guidelines for the evaluation of BAPs in humans, such as adequately powered double blind randomised clinical trials are needed. In this review we give a short, scientifically founded review of bioactive peptides in milk and their proven effects that contribute to maintaining human health.
... Oral exposure is the major pathway of people exposed to PEs, and their absorption and transport in the gastrointestinal tract are influenced by multiple factors, including food matrix, the body's nutritional status, and the contaminants' physical property (Gao et al., 2019). Besides these factors, food emulsifiers (one kind of surfactant) could enhance the permeability of intestinal cells (Csaki, 2011). As the surfactant, food emulsifiers could diminish surface hydrophobicity, and are used in most frequently consumed foods with high concentrations, such as flour products and dairy products (Gao et al., 2018). ...
... Dietary intake is the main route of people exposure to contaminants and food emulsifiers. As reported, food emulsifiers could enhance the absorption of dietary pollutants, which might cause the increase of food safety risks (Csaki, 2011;Gao et al., 2016). ...
Objectives
This study was aimed to investigate the effect of widely used food emulsifier glycerin monostearate (GM) on testicular toxicity caused by the mixture of three commonly used PEs (MPEs) in rats, and further to explore the underlying mechanism.
Materials and Methods
Thirty male Sprague-Dawley rats were divided into three groups randomly. Rats were orally treated with 160 mg/kg/d MPEs in MPEs group; Rats were coinstantaneously treated with 160 mg/kg/d MPEs and 200 mg/kg/d GM in MPEs+GM group; Rats were treated with the excipient in control group. The intervention last for 5 weeks. Testis weight, epididymis weight, testicular histopathology and serum testosterone were detected for testicular toxicity evaluation. The testicular ultrastructure, the tight junction proteins zonula occluden (ZO)-1 and claudin were measured for the mechanism exploration.
Results
The body weight, epididymis, serum testosterone level, and anogenital distance in MPEs+GM group were significantly decreased comparing with control group (P<0.05); Testicular histopathological observation showed that shed spermatids were observed in MPEs+GM group. Ultrastructural observation of testicular cells showed that the cristae number was decreased in some mitochondrion in MPEs group, whereas the cristae was fused and disappeared in most mitochondrion in MPEs+GM group. The tight junctions were broken in MPEs+GM group, meanwhile, the expression of ZO-1 and claudin were altered in MPEs+GM group (P<0.01).
Conclusions
The results from this study indicated that GM aggravated MPEs’ testicular toxicity, which might relate to the injured mitochondrion and damaged tight junctions in testicular tissue.
... Xu et al. found that food emulsifier can increase the bioavailability of PAEs (Xu et al., 2016). Although some surfactants may affect the intestinal barrier and cause intestinal allergic diseases (Csáki, 2011;F. Csáki and Sebestyén, 2019), these studies did not provide sufficient evidences to elucidate the mechanism of emulsifier promoting the absorption of EDCs. ...
... These pathophysiological and cellular changes are considered to be the mechanism of promote intestinal absorption (McCartney et al., 2016). Csáki et al. proposed a hypothesis that some synthetic nonionic emulsifiers may affect the intestinal barrier and cause intestinal allergic diseases (Csáki, 2011). We reported that P80 could promote the absorption of DEHP in rats (Lu et al., 2014). ...
Di-2-ethylhexyl phosphate (DEHP) and its main toxic metabolite mono-2-ethylhexyl phthalate (MEHP) are the typical endocrine disrupting chemicals (EDCs) and widely affect human health. Our previous research reported that synthetic nonionic dietary emulsifier polysorbate 80 (P80, E433) had the promotional effect on the oral absorption of DEHP in rat. The aim of this study was to explore its mechanism of promoting oral absorption, focusing on the mucus barrier and mucosal barrier of the small intestine. A small molecule fluorescent probe 5-aminofluorescein-MEHP (MEHP-AF) was used as a tracker of MEHP in vivo and in vitro. First of all, we verified that P80 promoted the bioavailability of MEHP-AF in the long-term and low-dose exposure of MEHP-AF with P80 as a result of increasing the intestinal absorption of MEHP-AF. Afterwards, experimental results from Western blot, qPCR, immunohistochemistry, and immunofluorescence showed that P80 decreased the expression of proteins (mucus protein mucin-2, tight junction proteins claudin-1 and occludin) related to mucus barrier and mucosal barriers in the intestine, changed the integrity of intestinal epithelial cell, and increased the permeability of intestinal epithelial mucosa. These results indicated that P80 promoted the oral absorption of MEHP-AF by altering the intestinal mucus barrier and mucosal barrier. These findings are of great importance for assessing the safety risks of some food emulsifiers and clarifying the absorption mechanism of chemical pollutants in food, especially for EDCs.
... Liposomes have also been successfully used to enhance the bioavailability of chlorogenic acid [96]. We do not recommend solidliquid nanoparticles, nano-emulsions and nano-micelles since recent research identified that most of those nonionic surfactants present in such formulations significantly interfere with the human gut microbiome [97,98]. In short, oppositely charged cationic-anionic natural polyelectrolytes such as cationic chitosan and various anionic polysaccharides or proteins seem to be the most efficient compositions with the least human side effects. ...
Objectives: Many polyphenols such as EGCG from green tea, curcumin, apigenin, resveratrol or the alkaloid berberine show in-vitro activity that is much higher than FDA and EU approved drugs. And yet, while mice studies show excellent results, human clinical trials have so far been quite disappointing.
Methods: In this review paper we accordingly present data from scientific literature and publicly available databases that support further development of nanoformulations for enhanced natural antioxidants bioavailability and activity.
Results: Nanobubbles, and nanoparticles may enhance the polyphenols bioavailability and special coatings can be used to avoid liver fast inactivation. Zeolites have also been tested as carriers for bioactive compounds from the Mediterranean food. Other polyphenols can be used with nanoemulsions for synergistic antioxidants treatment. Finally, nanobubbles in the presence of ferric or copper ions at low pH as in human stomach or lysosomes can produce small amount of hydroxyl radicals, stimulating activation of Nrf2 transcription factor and detox enzymes.
Discussion: A number of nanoformulations, including nanobubbles loaded with natural antioxidants may be used with low carbs and protein diet as a support to chemotherapy or treatment of advanced tumors. Good results in animal studies of neurodegenerative diseases and type II diabetes were also observed.
KEY POLICY HIGHLIGHTS
Nanobubbles and nanoparticles may enhance the polyphenols’ bioavailability
Nanobubbles may stimulate the activation of Nrf2 and detox enzymes
Armoured oxygen nanobubbles may enhance radiotherapy or chemotherapy effects
... Research by Suez et al. (48) has substantiated that non-caloric artificial sweeteners can disrupt microbial metabolic pathways. Additionally, dietary emulsifiers, such as lecithin, fatty acid monoglycerides, and diglycerides, have been shown to enhance bacterial translocation across epithelial cells in vitro, promoting systemic inflammation (48,49). This phenomenon reduces the diversity of intestinal microorganisms, decreases the abundance of Bacteroides, and increases the abundance of mucin-degrading microorganisms (Akkermansia muciniphila) and Proteobacteria. ...
Design
Ultra-processed foods (UPFs) have become a pressing global health concern, prompting investigations into their potential association with low muscle mass in adults.
Methods
This cross-sectional study analyzed data from 10,255 adults aged 20−59 years who participated in the National Health and Nutritional Examination Survey (NHANES) during cycles spanning from 2011 to 2018. The primary outcome, low muscle mass, was assessed using the Foundation for the National Institutes of Health (FNIH) definition, employing restricted cubic splines and weighted multivariate regression for analysis. Sensitivity analysis incorporated three other prevalent definitions to explore optimal cut points for muscle quality in the context of sarcopenia.
Results
The weighted prevalence of low muscle mass was 7.65%. Comparing the percentage of UPFs calories intake between individuals with normal and low muscle mass, the values were found to be similar (55.70 vs. 54.62%). Significantly linear associations were observed between UPFs consumption and low muscle mass (P for non-linear = 0.7915, P for total = 0.0117). Upon full adjustment for potential confounding factors, participants with the highest UPFs intake exhibited a 60% increased risk of low muscle mass (OR = 1.60, 95% CI: 1.13 to 2.26, P for trend = 0.003) and a decrease in ALM/BMI (β = −0.0176, 95% CI: −0.0274 to −0.0077, P for trend = 0.003). Sensitivity analysis confirmed the consistency of these associations, except for the International Working Group on Sarcopenia (IWGS) definition, where the observed association between the highest quartiles of UPFs (%Kcal) and low muscle mass did not attain statistical significance (OR = 1.35, 95% CI: 0.97 to 1.87, P for trend = 0.082).
Conclusion
Our study underscores a significant linear association between higher UPFs consumption and an elevated risk of low muscle mass in adults. These findings emphasize the potential adverse impact of UPFs on muscle health and emphasize the need to address UPFs consumption as a modifiable risk factor in the context of sarcopenia.
... The common way to stabilize emulsion is by adding chemically synthesized surfactant. Even though synthetic surfactants can efficiently stabilized emulsion with relatively small droplet size, the use of these compounds raising some controversies in the food and pharmaceutical industries due to the reported side effects to human health (Csáki, 2011). For that reason, the use of food derived particles to stabilized emulsion is proposed as an innovative alternative to the synthetic surfactant. ...
Starch is a sustainable and cheap raw material claimed as a good emulsion stabilizer for edible products either in food or pharmaceutical industry. To produce an emulsion stabilized by food based edible stabilizer, this study focused on the non-chemical starch modification for oil in water (O/W) emulsion stabilization produced by ultrasonic emulsification. The results showed that the finest emulsion was obtained at power rate of 500 W for 7 mins of sonication. The stability of the emulsion was investigated by turbidity, centrifugal stability values and droplet size. Pre-gelatinized corn starch (PCS) stabilizer showed better emulsion stability compared to gelatinized corn starch (GCS) due to the different polysaccharide components of the two modified cornstarch. GCS mainly contained amylose while the PCS contained both amylose and amylopectin. The emulsion, stabilized by 6 wt.% of PCS and addition of 3 wt.% of tween-80 exhibited excellent storage stability, along the 30 days storage. The results showed the lowest turbidity of 1.01 cm-1 , centrifugal stability value of 36.85% and average droplet diameter of 14.27 µm.
... This enhances the permeability of the gut as well as harmful luminal component exposure (Lugea et al., 2000). It was hypothesized that emulsifiers can also interact with similar amphipathic phospholipid bilayers of cell membranes and lead to easier diffusion across cell membranes (Csáki, 2011;Csáki and Sebestyén, 2019). ...
... As reviewed by Raoul et al. (2022), lecithin and mono-and diglycerides of fatty acids (also present in sports nutrition supplements) could induce the loss of GM diversity and abundance associated with an alteration of the intestinal barrier, promoting chronic inflammation and abnormal immune response (Chassaing et al. 2015) mainly due to translocation of E. coli across the epithelium and into M cells in vitro, causing intestinal inflammation (Marion-Letellier et al. 2019). In summary, emulsifiers may induce alterations in GM composition associated with mucous layer impairment and a reduction in mucous layer thickness (Ilbäck et al. 2004;Kralova and Sjöblom 2009;Csáki 2011;Roberts et al. 2013;Chassaing et al. 2015). Indeed, it has been reported that they can provoke an inflammatory cascade in colonic epithelial cells with upregulation of TNF-α secretion (Martino et al. 2017). ...
To improve performance and recovery faster, athletes are advised to eat more often than usual and consume higher doses of simple carbohydrates, during and after exercise. Sports energetic supplements contain food additives, such as artificial sweeteners, emulsifiers, acidity regulators, preservatives, and salts, which could be harmful to the gut microbiota and impair the intestinal barrier function. The intestinal barrier plays a critical function in bidirectionally regulation of the selective transfer of nutrients, water, and electrolytes, while preventing at the same time, the entrance of harmful substances (selective permeability). The gut microbiota helps to the host to regulate intestinal homeostasis through metabolic, protective, and immune functions. Globally, the gut health is essential to maintain systemic homeostasis in athletes, and to ensure proper digestion, metabolization, and substrate absorption. Gastrointestinal complaints are an important cause of underperformance and dropout during endurance events. These complications are directly related to the loss of gut equilibrium, mainly linked to microbiota dysbiosis and leaky gut. In summary, athletes must be cautious with the elevated intake of ultra-processed foods and specifically those contained on sports nutrition supplements. This review points out the specific nutritional interventions that should be implemented and/or discontinued depending on individual gut functionality.
... Emulsifiers (i.e., lecithin, mono-and diglycerides of FA, guar gum, xanthan gum, carrageenan, celluloses, and polysorbates) that are common in bakery, dairy, beverages, ice cream, sauces, chocolate, and other foods are suspected to impair the diversity of gut microbiota (decrease in anti-inflammatory genera like Akkermansia and promotion of proinflammatory genera like Escherichia, Roseburia, Bradyrhizobium, and Turicibacter) [94]. In addition, emulsifiers may stimulate inflammatory pathways [95], impair the function of the mucus layer and the tight junctions [96]. High consumption of UPF is therefore suspected to play a causal role in several diseases associated with dysbiosis and impaired intestinal permeability, such as cardiovascular and microvascular diseases like chronic kidney disease, obesity, type 2 diabetes, and cancer [97][98][99]. ...
A high consumption of ultra-processed food (UPF) is a hallmark of Western diets that has been related to increased risk of non-communicable diseases. As an underlying mechanism, UPF may promote non-alcoholic fatty liver disease (NAFLD) which is a key driver of metabolic impairment with extra-hepatic manifestations like type 2 diabetes, cardiovascular disease, chronic kidney disease, and osteoporosis among others. The present review provides an overview of UPF properties that may promote NAFLD and are thus potential targets for reformulation of UPF. Such approaches should address improvements in the quality of carbohydrates and fat, changes in food texture that lower eating rate as well as ingredients that prevent excess caloric intake or avoid dysbiosis and leaky gut syndrome. Promising strategies are enrichment with fiber, prebiotics, phytochemicals, and protein with a concurrent reduction in glycemic load, energy density, saturated fatty acids (FA; SFA), emulsifiers, fructose, and non-caloric sweeteners. Future studies are needed to examine the interactive and protective effects of such modifications in the composition of UPF on prevention and treatment of NAFLD.
... The popularity of ultra-processed and fast foods is partly due to their inexpensive and easy to find nature. However, the high fat content, particularly the trans fatty acid content and the presence of additives or reaction products owed to processing [51][52][53][54] may be linked with the augmentation of FD symptoms. Similarly, the prevalence of FD in Asia has increased during the last decades due to the change towards a more Westernized diet, higher in fatand lower in carbohydrate-rich foods, whereas the spicy foods in Asian diets are associated with a higher risk of developing FD [55]. ...
Functional dyspepsia is a gastrointestinal disorder characterized by postprandial fullness, early satiation, epigastric pain, and epigastric burning. The pathophysiology of the disease is not fully elucidated and there is no permanent cure, although some therapies (drugs or herbal remedies) try to reduce the symptoms. Diet plays a critical role in either the reduction or the exacerbation of functional dyspepsia symptoms; therefore dietary management is considered to be of high importance. Several foods have been suggested to be associated with worsening functional dyspepsia, such as fatty and spicy foods, soft drinks, and others, and other foods are thought to alleviate symptoms, such as apples, rice, bread, olive oil, yogurt, and others. Although an association between functional dyspepsia and irregular eating habits (abnormal meal frequency, skipping meals, late-night snacking, dining out, etc.) has been established, not many dietary patterns have been reported as potential factors that influence the severity of functional dyspepsia. A higher adherence to Western diets and a lower adherence to FODMAPs diets and healthy patterns, such as the Mediterranean diet, can contribute to the worsening of symptoms. More research is needed on the role of specific foods, dietary patterns, or specific eating habits in the management of functional dyspepsia.
... A simple way to figure out the association of antibodies against S. cerevisiae in inflammatory and allergic conditions is the ability of the mannoprotein to act as an emulsifier [54]. Emulsifiers, also called surfactants, have been associated with the disruption of the intestinal mucous barrier, with may produce intestinal hyperpermeability [55], [56]. The disruption of the intestinal mucous layer impacts the gut microbiota and enhances the penetration of bacterial toxins, which is associated with colitis, metabolic syndrome, and food allergy [57], [58]. ...
Background: The presence of anti-Saccharomyces cerevisiae antibodies (ASCA) has been reported in the serum of patients with several immune-inflammatory diseases. Objective: To evaluate the presence of ASCA in patients with non-IgE-mediated hypersensitivity. Methods: A group of 222 patients with non-IgE-mediated hypersensitivity was divided into three groups according to dermatologic, gastrointestinal, and respiratory symptoms. Group D was composed of 163 patients with dermatologic symptoms diagnosed as intrinsic atopic dermatitis and/or non-IgE-mediated urticaria. Group G was composed of 23 patients diagnosed with non-IgE-mediated gastrointestinal food allergies. Group R was composed of 36 patients with respiratory symptoms diagnosed as non-IgE-mediated rhinitis and/or non-IgE-mediated asthma. Results: The Wilcoxon-Mann-Whitney U test comparing the precipitin’s titers of group G and group D showed a non-significant p-value of 0.83366. The Wilcoxon-Mann-Whitney U test comparing the precipitin’s titers of group R and group G showed a significant p-value of 0.00034. The Wilcoxon-Mann-Whitney U test comparing the precipitin’s titers of group R and group D showed a significant p-value < 0.0001. Conclusion: The patients with respiratory symptoms diagnosed as non-IgE-mediated rhinitis and/or asthma presented significantly less humoral immunoreactivity against S. cerevisiae than patients with non-IgE-mediated food allergy and patients with intrinsic atopic dermatitis and/or non-IgE-mediated urticaria. The elevation of ASCA titers may be an unspecific marker of intestinal hyperpermeability, and possibly may participate in Gell and Coomb’s types II and/or type III hypersensitivity reactions responsible for the patient’s dermatologic and gastrointestinal symptoms.
... Emulsifiers stimulate various inflammatory pathways, such as activating LPS-induced inflammation through Bcell lymphoma/leukaemia-10 (Bcl-10) pathway, and triggering NF-κB through TLR4 pathway, and increasing TNFα, IL-1β, IL-6, IL-8 pathway (Bancil et al., 2021). Emulsifiers can drop hydrophobicity of the mucus layer, reduce mucus thickness, and alter ZO-1 to allow bacteria translocation, which is associated with increasing intestinal permeability (Csáki, 2011). ...
Dysfunction of gut barrier is known as “leaky gut” or increased intestinal permeability. Numerous recent scientific evidences showed the association between gut dysfunction and multiple gastrointestinal tract (GI) and non‐GI diseases. Research also demonstrated that food plays a crucial role to cause or remedy gut dysfunction related to diseases. We reviewed recent articles from electronic databases, mainly PubMed. The data were based on animal models, cell models, and human research in vivo and in vitro models. In this comprehensive review, our aim focused on the relationship between dietary factors, intestinal permeability dysfunction, and related diseases. This review synthesizes currently available literature and is discussed in three parts: (a) the mechanism of gut barrier and function, (b) food and dietary supplements that may promote gut health, and food or medication that may alter gut function, and (c) a table that organizes the synthesized information by general mechanisms for diseases related to leaky gut/intestinal permeability and associated dietary influences. With future research, dietary intervention could be a new target for individualized disease prevention and management. This review summarizes current literature, mainly from PubMed, on the mechanisms of gut barrier and function, including food and dietary supplements or medications that promote or alter gut health. It also provides a comprehensive and clear table about basic mechanisms for disease‐related leaky gut/increased intestinal permeability with associated dietary influences.
... Very little data exist on the possible association of such non-macronutrient constituents with type 1 diabetes. However, surfactant food additives can increase intestinal permeability [40]. Increased intestinal permeability is known to precede the onset of type 1 diabetes and is thought to be causally related to it [41]. ...
... Drinking water contaminated by perfluoroalkyl substances may also be associated with IBD, possibly by disrupting the intestinal mucosa (22). A population-based study conducted in Ronneby, Sweden, reported an increased risk of IBD among those >10 years of age who exposed to these substances between 1985 and 1994 (HR 1.26, 95% CI 1.01-1.57); ...
Pediatric inflammatory bowel disease (IBD) is becoming increasingly common around the world, rapidly accelerating in regions undergoing rapid economic development. IBD is more common among those living in cities, and the association between the urban environment and IBD incidence is strongest in children. The 'urban exposome' is defined as the totality of environmental exposures associated with urban living: air pollution, water contamination, green and blue space, nighttime light, noise, and availability of pre-processed and packaged foods. Investigation of the role of the urban exposome and IBD is in its infancy. Existing research have reached heterogeneous conclusions, and most studies have focused specifically on adult-onset disease and environmental exposures in isolation rather than the interaction between exposures. By better understanding the impact of the urban exposome on pediatric IBD, we can work to minimize these exposures and decrease the future burden of IBD in children.
... Synthetic additives from the food industry used as emulsifiers (also known as surfactants or detergents) have a mucolytic activity or inhibit the Pglycoprotein, increasing intestinal permeability by dissolving the mucus layer [76]. The main food additives associated with this activity are carboxymethylcellulose, polysorbate, and fatty acid esters (E471, E473, and E475) [77]. They have been implicated in disrupting the protective mucus layer, increasing the microbiota encroachment, and leading to an inflammatory state [78]. ...
Food Allergy is a chronic systemic immuno-inflammatory condition that depends on several factors, but, above all, the gastrointestinal epithelial barrier. The rupture of this intestinal barrier results in a deleterious increase in intestinal permeability allowing the paracellular permeation of molecules greater than 150 Da into the bloodstream, producing an equivalent immune response, decreasing the immune tolerance. Intestinal Hyperpermeability has been linked not only to food allergy but also to Metabolic Syndrome and Non-Alcoholic Fat Liver Disease. Here we review the factors that contribute to producing Intestinal Hyperpermeability, as well the factors that contribute to the restoration of the epithelial barrier, improving the clinical outcome of food-allergic patients. The main factors that increase the Intestinal Hyperpermeability are A) Immune-Inflammatory (food allergy itself and autoimmune conditions); B) Iatrogenic (steroids, non-steroidal anti-inflammatories, antacids, antibiotics, and gastric-bypass surgeries); C) Infectious (rotavirus, HIV, SARS-CO2, Helicobacter pylori, Candida albicans, etc.); and D) Lifestyle-related (alcoholic beverages, food addiction, food overconsumption, consumption of industrialized food with high-fructose content and emulsifiers). The main factors that restore the intestinal barrier and immune tolerances are the intestinal microbiota and functional nutrients such as Vitamin A and vegetal fibers. Mucoprotectants agents, such as gelatin tannate and xyloglucan, are in study to become part of the medical arsenal to treat Intestinal Hyperpermeability conditions.
... 5 Especially, small synthetic surfactant food additives have been associated with an increased incidence of numerous allergic and autoimmune diseases caused by intestinal barrier dysfunction. 6 To avoid any potential toxicity associated with these surfactants, some researchers have investigated the minimal concentrations of them with high stability of emulsion system or explored natural ingredients such as polysaccharide-based materials (starch, cellulose, and chitin), protein-based materials (soy protein, whey protein, and gelatin), or their complex materials as substitutes for synthetic surfactants. [7][8][9][10][11] Whey proteins, derived from cow's milk, are composed of ⊍-lactalbumin, ⊎-lactoglobulin, and bovine serum albumin. ...
BACKGROUND
To overcome the limitations in the use of protein as an emulsifier, soy lecithin, a natural surfactant, was used along with whey protein isolate (WPI) to produce o/w emulsions containing cholecalciferol and α‐tocopherol. The physical stability of the emulsions prepared with WPI and varying concentrations of lecithin (0, 1, 2, and 3% w/w) was measured in different heat, pH, and ionic‐strength food environmental conditions.
RESULTS
All emulsions were shown to be less than 250 nm in size and less than 0.3 in polydispersity index (PDI). The morphology of the emulsions was spherical, and the droplets of the emulsion containing lecithin were thicker and larger than those of the emulsion without lecithin (WPI_L0). After autoclaving, WPI_L0 increased in size from 197.8 ± 1.7 nm to 528.5 ± 28.4 nm, and the retention of cholecalciferol and α‐tocopherol decreased to 40.83 ± 0.63% and 49.68 ± 1.84%, respectively. At pH 5.5, near the isoelectric point of WPI, WPI_L0 increased in size due to aggregation, but emulsions containing lecithin remained stable at a PDI under 0.3. Turbiscan stability index of the emulsion prepared with WPI and 3% lecithin was the lowest, indicating good storage stability. In addition, it was confirmed that the higher the lecithin content, the higher the viscosity, and the higher the amount of free fatty acids released in the in vitro digestion model.
CONCLUSION
This study can provide theoretical evidence for enhancing the physical stability of protein emulsions by co‐stabilization with lecithin, promoting their application in various foods. © 2022 Society of Chemical Industry.
... The surfactant properties of emulsifiers are generally predicted to decrease the hydrophobicity of the GI mucus layer, which can cause damage to the integrity of the epithelial barrier [89,91]. Furthermore, there is evidence that through impairing the GI barrier and altering the GI microbiota composition, emulsifiers could contribute to chronic low-grade inflammation and incidence of IBD and metabolic syndrome [92]. ...
Chronic inflammatory disease of the gastrointestinal (GI) tract is defined by several pathophysiological characteristics, such as dysbiosis of the microbiota, epithelial barrier hyperpermeability, systemic dissemination of endotoxins and chronic inflammation. In addition to well-reported environmental factors in non-communicable disease, such as smoking, diet, and exercise, humans are frequently exposed to myriads more environmental factors, from pesticides to food additives. Such factors are ubiquitous across both our diet and indoor/outdoor environments. A major route of human exposure to these factors is ingestion, which frequently occurs due to their intentional addition (intentional food additives) and/or unintentional contamination (unintentional food contaminants) of food products—often linked to environmental pollution. Understanding how this persistent, diverse exposure impacts GI health is of paramount importance, as deterioration of the GI barrier is proposed to be the first step towards systemic inflammation and chronic disease. Therefore, we aim to evaluate the impact of ingestion of environmental factors on inflammatory processes in the GI tract. In this review, we highlight human exposure to intentional food additives (e.g. emulsifiers, bulking agents) and unintentional food contaminants (e.g. persistent organic pollutants, pesticides, microplastics), then present evidence for their association with chronic disease, modification of the GI microbiota, increased permeability of the GI barrier, systemic dissemination of endotoxins, local (and distal) pro-inflammatory signalling, and induction of oxidative stress and/or endoplasmic reticulum stress. We also propose a link to NLRP3-inflammasome activation. These findings highlight the contribution of common environmental factors towards deterioration of GI health and the induction of pathophysiology associated with onset and maintenance of chronic inflammation in the GI tract.
... EDCs could increase the permeability of the small intestine, increasing the likelihood that bacterial pathogens will enter the body's circulation and target other organs (166). Food additives, such as artificial sweeteners (167,168), and contaminants such as pesticide residues (169) can interfere with the gut microbiota and gut barrier function which could lead to intestinal, metabolic, and autoimmune disorders. Notably, obesity and T2D were found to be associated with intestinal dysbiosis (170) and gut barrier disruption (171). ...
Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess and insufficient levels of physical activity leads to obesity is a commonly accepted answer for unwanted weight gain. This paradigm offers an inconclusive explanation as the world continually moves towards an unhealthier and heavier existence irrespective of energy balance. Endocrine disrupting chemicals (EDCs) are chemicals that resemble natural hormones and disrupt endocrine function by interfering with the body’s endogenous hormones. A subset of EDCs called obesogens have been found to cause metabolic disruptions such as increased fat storage, in vivo. Obesogens act on the metabolic system through multiple avenues and have been found to affect the homeostasis of a variety of systems such as the gut microbiome and adipose tissue functioning. Obesogenic compounds have been shown to cause metabolic disturbances later in life that can even pass into multiple future generations, post exposure. The rising rates of obesity and related metabolic disease are demanding increasing attention on chemical screening efforts and worldwide preventative strategies to keep the public and future generations safe. This review addresses the most current findings on known obesogens and their effects on the metabolic system, the mechanisms of action through which they act upon, and the screening efforts through which they were identified with. The interplay between obesogens, brown adipose tissue, and the gut microbiome are major topics that will be covered.
... Furthermore, mucous production could be another candidate which have been contributed to the discrepancies. Intestinal surface is covered by mucous layers [35,36] that is influenced by the ingested food [37,38]. Mucous layers can affect the host response towards intestinal environment which is evidently shown by the fact that mucin 2 (Muc2)-deficient mice can develop spontaneous colitis and intestinal tumor [39][40][41]. ...
Daikenchuto (TU-100) is herbal medicine which predominantly contains ginger, Japanese pepper, and ginseng. We investigated whether TU-100 can affect the composition of gut flora and intestinal tumor development using ApcMin/+ mice, a murine model of intestinal tumor. Bacterial 16S rRNA sequencing and short-chain fatty acid analysis were performed on faecal samples. Tumor number and size were analysed. Any change in gene expression of the tumor tissues was assessed by real-time PCR. Principal coordinate analysis (PCoA) showed that the faecal microbiota cluster of TU-100-fed mice was different from the microbiota of control mice. However, no significant difference was observed in the concentration of short-chain fatty acids, tumor number, and gene expression levels between the two groups. Our data showed that TU-100 can affect the intestinal environment; however, it does not contribute in tumor progression or inhibition in our setting.
... However, consumers' preferences for healthy, sustainable and natural lifestyle habits have increased worldwide. Moreover, some studies have reported intestinal dysfunctions caused by synthetic emulsifiers [4,5]. In this context, natural emulsifiers have emerged as great alternatives to replace their conventional counterparts, namely proteins [6], polysaccharides [7], phospholipids [8] and saponins [9]. ...
The food industry depends on using different additives, which increases the search for effective natural or natural-derived solutions, to the detriment of the synthetic counterparts, a priority in a biobased and circular economy scenario. In this context, different natural emulsifiers are being studied to create a new generation of emulsion-based products. Among them, phospholipids, saponins, proteins, polysaccharides, biosurfactants (e.g., compounds derived from microbial fermentation), and organic-based solid particles (Pickering stabilizers) are being used or start to gather interest from the food industry. This chapter includes the basic theoretical fundamentals of emulsions technology, stabilization mechanisms, and stability. The preparation of oil-in-water (O/W) and water-in-oil (W/O) emulsions, the potential of double emulsions, and the re-emerging Pickering emulsions are discussed. Moreover, the most relevant natural-derived emulsifier families (e.g., origin, stabilization mechanism, and applications) focusing food applications are presented. The document is grounded in a bibliographic review mainly centered on the last 10-years, and bibliometric data was rationalized and used to better establish the hot topics in the proposed thematic.
... • Because of human gut microbiome dynamics, static genetic sampling misses important short-and long-term microbiomerelated changes to host health, so future studies should be powered to account for inter-and interindividual variation and should use repeated measures within individuals. genetic origin, there are others that have a different cause, are those produced by the additives used in the production of foods that we have mentioned previously [23][24][25]. ...
... • Because of human gut microbiome dynamics, static genetic sampling misses important short-and long-term microbiomerelated changes to host health, so future studies should be powered to account for inter-and interindividual variation and should use repeated measures within individuals. genetic origin, there are others that have a different cause, are those produced by the additives used in the production of foods that we have mentioned previously [23][24][25]. ...
In this work we analyze the current interpretations based on the studies of Nutrigenomic and Microbiomics, according to which, at the base of many pathological and dysmetabolic manifestations, there would be or variations of single nucleotide polymorphisms (Snps), in the Nutrigenomic vision, or changes of the normal gut microbiota, in the Microbiomic conception. In particular, we analyze critically, the singular pathogenic coincidence, which for the same pathologies calls into question or Snps mutations or the presence of specific modifications of the Microbiota. Other possible causes of observed diseases are thus neglected. On the basis of the literature examined, we present a different interpretation of pathogenic causes.
... 5 In addition to pharmaceutical products, many foods contain excipients as additives. 6,7 Although excipients are traditionally recognized as pharmacologically inert, growing evidence has shown that many excipients are active in modulating the activities of biological targets including the transporters. 5,8 Therefore, it is important to evaluate the potential drug−excipient interactions thoroughly when designing formulations of the generic drugs, which require assessment of bioequivalence and clinical multidrug applications. ...
Newborns’ eyes and brains are prone to oxidative stress. Lutein has antioxidant properties and is the main component of macular pigment essential for protecting the retina, but has low bioavailability, thereby limiting its potential as a nutritional supplement. Oil-in-water emulsions have been used as lutein delivery systems. In particular, octenylsuccinated (OS) starch is a biopolymer-derived emulsifier safe to use in infant foods, while exhibiting superior emulsifying capacity. This study determined the effects of an OS starch-stabilized lutein emulsion on lutein bioavailability in Sprague-Dawley neonatal rats. In an acute study, 10-day-old pups received a single oral dose of free lutein or lutein emulsion, with subsequent blood sampling over 24 h to analyze pharmacokinetics. The lutein emulsion group had a 2.12- and 1.91-fold higher maximum serum lutein concentration and area under the curve, respectively, compared to the free lutein group. In two daily dosing studies, oral lutein was given from postnatal day 5 to 18. Blood and tissue lutein concentrations were measured. The results indicated that the daily intake of lutein emulsion led to a higher lutein concentration in circulation and key tissues compared to free lutein. The OS starch-stabilized emulsion could be an effective and safe lutein delivery system for newborns.
Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting.
Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mis-match for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.
Naringenin (NAR) has several potential benefits as a bioactive nutrient, but its low water solubility and poor bioavailability have limited its application. Here, a soy protein isolate-naringenin complex (NAR@SPI) was prepared for NAR delivery. Furthermore, to improve the encapsulation capacity of SPI for hydrophobic bioactive nutrients and their complex physiochemical properties, dipotassium glycyrrhizinate (DG) was used to modify SPI with a simple stirring process to obtain the SPI-DG complex, and then this complex was used to load the NAR. The final obtained nanocomplex was named NAR@SPI-DG. This novel NAR@SPI-DG has shown higher encapsulation efficiency (93.20 ± 0.27% versus 62.09 ± 3.20%) and loading capacity (8.53 ± 0.02% versus 5.89 ± 0.30%) for NAR as compared to the NAR@SPI. Spectral evaluations and molecular simulations revealed that the SPI’s and DG’s interaction in SPI-DG involved the combination of a spontaneous exothermic reaction, and the mechanisms of interaction were dominated by a hydrogen bond and van der Waals forces. NAR@SPI-DG has demonstrated significant improvements in solubility, in vitro antioxidant activity, in vitro anti-diabetes activity, and in vitro bioaccessibility as compared with bare NAR and NAR@SPI. Consequently, the use of DG is promising in the modification of SPI protein to construct a nano-delivery system for hydrophobic bioactive nutrients, such as NAR, in functional foods.
The terms discussed in this review—biosurfactants (BSs) and bioemulsifiers (BEs)—describe surface-active molecules of microbial origin which are popular chemical entities for many industries, including food. BSs are generally low-molecular-weight compounds with the ability to reduce surface tension noticeably, whereas BEs are high-molecular-weight molecules with efficient emulsifying abilities. Some other biomolecules, such as lecithin and egg yolk, are useful as natural BEs in food products. The high toxicity and severe ecological impact of many chemical-based surfactants have directed interest towards BSs/BEs. Interest in food surfactant formulations and consumer anticipation of “green label” additives over synthetic or chemical-based surfactants have been steadily increasing. BSs have an undeniable prospective for replacing chemical surfactants with vast significance to food formulations. However, the commercialization of BSs/BEs production has often been limited by several challenges, such as the optimization of fermentation parameters, high downstream costs, and low yields, which had an immense impact on their broader adoptions in different industries, including food. The foremost restriction regarding the access of BSs/BEs is not their lack of cost-effective industrial production methods, but a reluctance regarding their potential safety, as well as the probable microbial hazards that may be associated with them. Most research on BSs/BEs in food production has been restricted to demonstrations and lacks a comprehensive assessment of safety and risk analysis, which has limited their adoption for varied food-related applications. Furthermore, regulatory agencies require extensive exploration and analysis to secure endorsements for the inclusion of BSs/BEs as potential food additives. This review emphasizes the promising properties of BSs/BEs, trailed by an overview of their current use in food formulations, as well as risk and toxicity assessment. Finally, we assess their potential challenges and upcoming future in substituting chemical-based surfactants.
Nafion by-product 2 (Nafion BP2), an emerging fluorinated sulfonic acid commonly used in polymer electrolyte membrane technologies, has been detected in various environmental and human matrices. To date, however, few studies have explored its toxicity. In this study, zebrafish embryos were exposed to Nafion BP2 at concentrations of 20, 40, 60, 80, 100, 120, 140, and 160 mg/L from fertilization to 120 post-fertilization (hpf), and multiple developmental parameters (survival rate, hatching rate, and malformation rate) were then determined. Results showed that Nafion BP2 exposure led to a significant decrease in survival and hatching rates and an increase in malformations. The half maximal effective concentration (EC50) of Nafion BP2 for malformation at 120 hpf was 55 mg/L, which is higher than the globally important contaminant perfluorooctane sulfonate (PFOS, 6 mg/L). Furthermore, exposure to Nafion BP2 resulted in additional types of malformations compared to PFOS exposure. Pathologically, Nafion BP2 caused abnormal early foregut development, with exfoliation of intestinal mucosa, damage to lamina propria, and aberrant proliferation of lamina propria cells. Nitric oxide content also decreased markedly. In addition, embryos showed an inflammatory response following Nafion BP2 exposure, with significantly increased levels of pro-inflammatory factors C4 and IL-6. Acidic mucin in the hindgut increased more than two-fold. 16 S rRNA sequencing revealed a marked increase in the pathogen Pseudomonas otitidis. Furthermore, pathways involved in intestinal protein digestion and absorption, inflammatory response, and immune response were significantly altered. Our findings suggest that the intestine is a crucial toxicity target of Nafion BP2 in zebrafish, thus highlighting the need to evaluate its health risks.
Although additives are regularly used in the food industry to improve the organoleptic properties or extend the shelf life of food products, some additives are known to be potentially hazardous if consumed in excess. Increasingly, consumers are avoiding these types of products, highlighting an overall trend toward developing a green and sustainable economy and the emergence of natural additives with equal or greater benefits than synthetic ones. This book is an introduction to the use of natural food additives. It includes eleven chapters that discuss emerging compounds used as food additives and active packaging, molecular gastronomy, enzyme production in the food industry, and much more.
Over the years, the food technology has emerged in tandem with changes in dietary trends. New technologies have arisen that not only improve the flavor and shelf life of food goods, but also contain effective additives that are same for customers’ health and provide nutraceutical benefits. As a result, the adoption of natural alternatives to replace synthetic additives is increasing in ongoing research. Biosurfactants have evolved as natural alternatives that can employed as an emulsifying agent in the food processing industry. Biosurfactants of the lipopeptide, glycolipid, glycoprotein, glycolipopeptide types can emulsify a wide range of vegetable oils and fats in food processing with high emulsification index. This biomolecule has a beneficial impact on texture profile analysis and sensory attributes such as color, aroma, and taste evolution in baked goods. The research in this field is still in the lab, and additional research is needed before this natural alternative, biosurfactants, may be used in large industrial sectors.
Biosurfactants are natural surface-active materials created by microorganisms. Biosurfactants can contribute several properties including antibacterial, antioxidant, emulsifying, and antiadhesive activities to the food in which they are incorporated. Biosurfactants have been employed in food formulations to enhance viscosity, extending the shelf life of the products, improving texture and flavor, as well as lowering the calorie value by substituting fat. This chapter summarizes the activities of biosurfactants as antioxidants in food, as well as the features of biosurfactants in boosting food quality and the variables impacting biosurfactant synthesis.
In the past decades, we have shown that the industrial food manufacturers increased to satisfy the needs of population and urbanization. An explosion of ready-to-eat foods manifests this increase. However, these foods contain synthetic surfactants that can produce diverse diseases and environmental problems. With the change of lifestyle and the citizen’s conception of consuming only healthy and sustainable thumbprints, the food industry started a race toward using biotechnology-based microbes combined with nanotechnology to produce nanobiosurfactant.
Nanobiosurfactant is an area of emerging interest in the food industry for replacing the chemically synthesized surfactants. As an ingredient that resists temperature rise, these microbial products allow preserving the properties of several ready-to-eat foods. It can be used with silver nanoparticles to improve the hygienic quality of packaging for increasing the shelf life of food and delay the deterioration of food intended for consumers. The nanobiosurfactant is an emulsifying agent carrying active components, maintaining the consistency and texture of food and improves solubilization aroma and dispersing properties. Finally, it also inhibits microbial contamination and protects food against several pathogens and food-borne outbreak. So, the nanobiosurfactant is a trends biotechnology that has high-potential application in food industries.
This study investigated Pickering emulsions stabilized by hydrophobically modified cellulose from oil palm frond (OPF). The Cellulose modification was performed in aqueous medium using benzoyl chloride as modifying agent. Characterizations showed that isolated native cellulose (NC) suffered no structural degradation while surface degradation and improved thermal properties was observed in the modified cellulose (CB-10). Proximate analysis revealed that oil palm frond is a good source of cellulose and hemicellulose. The x-ray diffraction (XRD) showed that the crystallinity index (CrI) of NC and CB-10 derivative are 71.98% and 61.64% respectively. Also, the Thermogravimetric analysis (TGA) revealed that modified cellulose is more thermally stable than unmodified cellulose. The Pickering emulsions stabilized by isolated native cellulose (NC) was unstable at all concentrations investigated while Pickering emulsions stabilized by modified cellulose (CB-10) are stable and this showed that modified cellulose derivative from oil palm frond is a promising material for food, drug delivery, encapsulation and biomedical applications.
Background
Previously, a novel oat-ready-to-use therapeutic food (o-RUTF) resulted in improved recovery from severe acute malnutrition (SAM) when compared to standard RUTF (s-RUTF). O-RUTF contained 18% oat, while s-RUTF has no cereal ingredients.
Objective
We determined the effect of o-RUTF on intestinal permeability, as measured by lactulose permeability, and the 16S rRNA fecal microbiome configuration of children with SAM.
Methods
This was a prospective, randomized, double-blinded, controlled clinical trial. Sierra Leonean children aged 6–59 months with SAM defined by mid-upper arm circumference < 11.5 cm were randomized to receive o-RUTF or s-RUTF. All children received 7 days amoxicillin per guidelines. Lactulose permeability testing and fecal 16S rRNA sequencing were performed at baseline and after 4 weeks of therapy. Change in lactulose permeability was the primary outcome while fecal 16S rRNA configuration at 4 weeks was a secondary outcome.
Results
Of 129 children enrolled, 100 completed baseline and 82 completed week 4 lactulose permeability testing. After 4 weeks of therapeutic feeding, there were no differences in lactulose permeability between children receiving o-RUTF vs. s-RUTF (P = 0.84), and over half of children had increased lactulose permeability (50% s-RUTF vs 58% o-RUTF, mean difference = -7.5%; 95% CI -29.2, 15.2; P = 0.50). After four weeks of feeding, there were no differences in the 16S rRNA configuration between children receiving o-RUTF vs. s-RUTF (Permanova 999 permutations, P = 0.648, pseudo-F = 0.581), nor were there differences in α- or β-diversity.
Conclusions
Despite remarkable different compositions of o-RUTF and s-RUTF, no differences were identified in lactulose permeability or the fecal 16S rRNA configuration among children with SAM receiving these foods. These results suggest that the o-RUTF exerts its beneficial effect through mechanisms other than reducing intestinal permeability or altering the fecal 16S configuration.
Clinical Trial Registry: The trial was registered at ClinicalTrials.gov (NCT04334538).
Members of the Ganodermataceae are used in traditional medicine in Asian
countries. In Vietnamese Traditional Medicine, these mushrooms are used to
treat several diseases since the 15th century. In this study, five new
Ganodermataceae specimens as Ganoderma multiplicatum, Ganoderma
sinense, 2 strains of Ganoderma lingzhi, and Amauroderma subresinosum
collecting from Kon Ka Kinh National Park, Vietnam, were classified by
morphology and 5.8S-ITS rDNA phylogenetic analysis. Colour photographs of
macro-micro features and a phylogenetic tree were provided and discussed. This
is the first report of new records of Ganoderma multiplicatum, Ganoderma
sinense, two strains of Ganoderma lingzhi, and Amauroderma subresinosum for
Vietnam. This research contributed to the distribution of new Vietnamese
Ganodermataceae in geography, morphological characteristics, and rDNA
sequences.
The ever-increasing attention on environmental problems and sustainability has highlighted several problems related to the use of conventional pesticides in the agricultural industry, e.g., toxic residues in the soil and hazards to the environment and human health. In the search for natural antimicrobial and insecticide alternatives, essential oils (EOs) and their active components have emerged as promising candidates, but they suffer from some drawbacks related to their physical properties. We exploited cocrystallization with isonicotinamide, pyrazine, 2,3,5,6-tetramethylpyrazine, and 2,3-dimethylquinoxaline as a workaround to extend the applicability of carvacrol and thymol as natural pesticides, improving their ambient delivery profile. The cocrystals were prepared mechanochemically in a green solvent-free manner, and their purity, structure, and stability were investigated via powder and single-crystal X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and density functional theory (DFT) calculations. Moreover, each cocrystal was also tested in terms of EO release by headspace–gas chromatography–mass spectrometry (GC–MS) analysis over 14 days. We also report the conversion of a cocrystal to a new structure with different stoichiometry, which seems to afford a delayed boost of EO release that could be very interesting for food preservation applications.
Food additives in general, and emulsifiers in particular, are considered to be important dietary components with a potential to harm the intestine, in part by promoting intestinal inflammation. There is inadequate objective information about the specific nature and the magnitude of the problem.
The Food and Drug Administration (FDA) has recognized approximately 450 items added to our foods as being generally regarded as safe and has placed them on a generally regarded as safe (GRAS) list. Additionally, it has also approved approximately 3000 “food additives.” There is a general lack of transparency as to how either of these selections were and continue to be made. Once items are officially designated by the FDA as “food additives” or placed on the GRAS list, there is no regulatory mechanism for the ongoing monitoring of their safety.
The most widely used emulsifier is “lecithin,” which is biochemically identified as phosphatidylcholine (PC). Regulatory guidelines allow manufacturers to use the label “lecithin” to be applied to emulsifiers that contain PC plus other phospholipids in a variety of unspecified concentrations. The PC used in experiments cited in the literature, is unlikely to be the same thing as the “lecithin” in our diets.
The objective of this introduction to emulsifiers is to raise awareness of the current state of food additives in the USA and to encourage thoughtful approaches to the study of all additives found in our diets. The overriding goal should be to assure the safety of what we eat. As examples we discuss eight widely distributed food additives; six emulsifiers that are classified as GRAS as well as an additional emulsifier-associated food additive that is also on the GRAS list, and a synthetic emulsifying agent that is FDA approved as a “food additive.”
Scope: Certain food emulsifiers may interfere with gut barrier function in ways correlating to increased exposure to allergens. Understanding the consequences of interactions between these food ingredients and the intestinal epithelium is important for evaluating allergen dose exposure characteristics. Methods and Results: Wechallenged Caco-2 cell monolayers, an in vitromodel of human intestinal epithelial tight junctions with synthetic polysorbate-80 or natural lecithin alone, or in combination with known allergens (egg proteins: ovalbumin, ovomucoid, and ovotransferrin; and a synthetic form of galactose-alpha-1,3-galactose (alpha-gal), an allergen of increasing concern). For most doses of individual emulsifiers and allergens, >90% cell viability and <15% cytotoxicity wasobserved; however, toxicity increased at a 0.5% concentration of emulsifiers. At low cytotoxic concentration (0.2%), only polysorbate-80 treatment reduced monolayer integrity (∼20%) with increased lucifer yellow passage. Dose-related differences in expression of tight junction genes and occludin proteins wereobserved with emulsifier treatments. The transport of all tested allergens across the cell monolayers, excluding ovotransferrin, nearly doubled in the presence of 0.2% polysorbate-80 compared to lecithin and untreated control. Conclusion: By modulating paracellular permeability, polysorbate-80 may enhance absorption of allergens in a size-dependent manner.
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Surfactants such as lecithin and egg yolk have been known for decades for their usefulness in the food systems. High toxicity and environmental influence of various surfactants have led to attention in other, natural surface-active agents such as microbial surfactants. The rising demand for surfactants in the food system also upsurges the consumer expectancy of non-toxic “green label” molecules over chemical surfactants. Sophorolipids and other established biosurfactants from Generally Regarded as Safe organisms have huge potential in the food system with an advantage of no acute toxicity. The major bottleneck is not the establishment of the cost-effective process but the apprehension about their safety and possible microbial hazards. Most of the research about biosurfactants in the food system are only limited to the applications, without doing an assessment of safety and risk analysis, and it is one of the undermined reasons behind the adoption of biosurfactants for food application. It should be consider for the appropriate applications such as biosurfactants with high HLB value must be used as food emulsifiers whereas, antimicrobial potential can be achieved at low concentrations and synergies with other conventional food preservatives. The efficacy of surfactin, rhamnolipids, and sophorolipids is evidenced to be utilized in bakery products with improved texture, properties, and food quality. The present book chapter emphases the most promising properties of biosurfactants, current use in food formulations, risk, and toxicity assessment, and forthcoming biosurfactants to substitute the currently used surfactants will be assessed.
Objectives: This study aimed to investigate the effect of the widely used food emulsifier glycerin monostearate (GM) on testicular toxicity caused by the mixture of three commonly used phthalate esters (MPEs) in rats, and further to explore the underlying mechanism. Materials and Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups. Rats were orally treated with 160 mg/kg/d MPEs in the MPEs group; coinstantaneously treated with 160 mg/kg/d MPEs and 200 mg/kg/d GM in the MPEs + GM group; and treated with the excipient in the control group. The intervention lasted for 5 weeks. Testis weight, epididymis weight, testicular histopathology, and serum testosterone were detected for testicular toxicity evaluation. The testicular ultrastructure, the tight junction proteins zonula occluden (ZO)-1, and claudin were measured for the mechanism exploration. Results: The body weight, epididymis, serum testosterone level, and anogenital distance in the MPEs + GM group were significantly decreased compared with control group (P < 0.05); Testicular histopathological observation showed that shed spermatids were observed in the MPEs + GM group. Ultrastructural observation of testicular cells showed that the cristae number was decreased in some mitochondria in the MPEs group, whereas the cristae were fused and disappeared in most mitochondria in the MPEs + GM group. The tight junctions were broken in the MPEs + GM group; meanwhile, the expression of ZO-1 and claudin were altered in the MPEs + GM group (P < 0.01). Conclusions: The results from this study indicated that GM aggravated MPEs' testicular toxicity, which might relate to the injured mitochondria and damaged tight junctions in testicular tissue.
In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the “leaky gut” may contribute to immune-inflammatory response in this disorder.
Soluble amphiphiles, or detergents, are known to produce a number of structural and dynamic effects on membranes, even at concentrations below those causing membrane solubilization (i.e. in the so-called stage I of detergent-membrane interaction). The main subsolubilizing detergent effects on membranes are transmembrane lipid motion (flip-flop), breakdown of the membrane permeability barrier (leakage), and vesicle lysis/reassembly. For a proper understanding of membrane solubilization by detergents, it is important to assess whether the various effects seen at subsolubilizing surfactant concentrations occur independently from each other or are interconnected by cause-effect relationships so that they can be interpreted as necessary steps in the overall process of solubilization. To answer this question, we have explored the three above-mentioned effects (i.e., flip-flop, leakage, and lysis/reassembly) apart from solubilization in model (large unilamellar vesicles) and cell (erythrocyte) membranes. Five structurally different surfactants, namely, chlorpromazine, imipramine, Triton X-100, sodium dodecylsulfate, and sodium deoxycholate have been used. Each of them behaves in a unique way. Our results reveal that lipid flip-flop, vesicle leakage, and vesicle lysis/reassembly occur independently between them and with respect to bilayer solubilization so that they cannot be considered to be necessary parts of a higher-order unified process of membrane solubilization by detergents.
The effect of the microenvironment on the Laurdan fluorescence was employed to study the solubilization mechanism of Dipalimtoyl-sn-glycero-3-phosphocholine (DPPC) small unilamellar vesicles with several sucrose monoesters. The saturation and the solubilization concentrations (C-sal and C-sol), the ester-DPPC molar ratio (R-c) and the bilayer/aqueous partition coefficients (K) were measured by monitoring changes in laurdan generalized polarization for four different alkyl esters of sucrose. All critical concentrations showed linear dependence with DPPC liposomes concentration. The saturation and the solubilization capacity of this type of surfactant do not show a direct dependence with the length of its alkyl chain. For the studied series the lauryl sucrose derivative is the Compound which presents the higher capacity to saturate and solubilize the DPPC vesicles, while the capacity of the esters with shorter and longer alkyl chains worsen. When the results obtained for DPPC liposomes are compared with previously obtained data for DODAC a different structuration of sucrose moieties in the bilayer can be postulated. This work was supported by funds from Fondecyt 1040573.
Increased exposure to enteric microbes as a result of intestinal barrier disruption is thought to contribute to the development of several intestinal inflammatory diseases; however, it less clear whether such exposure modulates the development of extra-intestinal inflammatory and autoimmune diseases. The goal of this study was to examine the potential role of pathogenic enteric microbes and intestinal barrier dysfunction in the pathogenesis of type 1 diabetes.
Using NOD mice, we assessed: (1) intrinsic barrier function in mice at different ages by measuring serum levels of FITC-labelled dextran; and (2) the impact on insulitis development of infection by strains of an enteric bacterial pathogen (Citrobacter rodentium) either capable (wild-type) or incapable (lacking Escherichia coli secreted protein F virulence factor owing to deletion of the gene [DeltaespF]) of causing intestinal epithelial barrier disruption.
Here we demonstrate that prediabetic (12-week-old) NOD mice display increased intestinal permeability compared with non-obese diabetes-resistant and C57BL/6 mice. We also found that young (4-week-old) NOD mice infected with wild-type C. rodentium exhibited accelerated development of insulitis in concert with infection-induced barrier disruption. In contrast, insulitis development was not altered in NOD mice infected with the non-barrier-disrupting DeltaespF strain. Moreover, C. rodentium-infected NOD mice demonstrated increased activation and proliferation of pancreatic-draining lymph node T cells, including diabetogenic CD8(+) T cells, compared with uninfected NOD mice.
This is the first demonstration that a loss of intestinal barrier integrity caused by an enteric bacterial pathogen results in the activation of diabetogenic CD8(+) T cells and modulates insulitis.
The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness.The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.
The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study.
Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively).
Two polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk.
During the last few years significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A genetic susceptibility to Crohn's disease has been proven by identification of variations as risk factor NOD2/CARD15. Functional data on NOD2/CARD15 and NF-kappaB activation indicate that an inflammatory reaction of the intestinal mucosa, as an immediate response of the innate immune system, may be necessary for the maintenance of gut homeostasis. Crohn's disease is now also discussed as an impaired and inadequate immune reaction and no longer only as a hyper-responsiveness of the mucosal immune system. Data on NOD2/CARD15 expression suggest that macrophages and epithelial cells could be the locus of the primary pathophysiological defect and that T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as backup mechanism to insufficient innate immunity. In addition to NOD2/CARD15 there are more "innate" pathways by which commensal and pathogenic bacteria can directly be hindered to invade the human body (such as interaction with Toll like receptors, TLRs and defensins). The "germ-concept" and the "genetic concept" of IBD pathophysiology are converging. However, more time is needed until these important insights in IBD pathogenesis will make their way into routine diagnostic procedures and treatment of patients with IBD.
The incidence of Type 1 diabetes has increased 2.5 times during the time period from 1966 to 2000 in Finland-a general trend seen in almost all developed countries that can only be explained by environmental factors. The aim of this study was to test the possible effect of a changing environment on distribution of genotypes associated with disease susceptibility.
HLA DRB1-DQA1-DQB1 genes and two diabetes-associated polymorphisms at IDDM2 and IDDM12 were analyzed. The frequencies of genotypes were compared between cases diagnosed with childhood-onset Type 1 diabetes during the period of 1939-1965 (n=367) and those diagnosed between 1990 and 2001 (n=736). Chi-square statistics or the Fisher's Exact test were used for the comparison of frequencies of analyzed haplotypes and genotypes in the two groups.
The frequencies of (DR3) -DQA1*05-DQB1*02 and (DR4) -DQB1*0302 risk haplotypes and the high risk (DR3) -DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 genotype were higher while proportion of patients carrying protective haplotypes-(DR15) -DQB1*0602 and (DR1301) -DQB1*0603-or protective genotypes was lower in patients diagnosed before 1965 as compared to those who developed disease after 1990. No temporal variation was found in the frequencies of genotypes at IDDM2 and IDDM12.
Our data suggest that the need for genetic susceptibility to develop Type 1 diabetes has decreased over time due to an increasing environmental pressure and this results in a higher disease progression rate especially in subjects with protective HLA genotypes.
Mechanisms by which the intestinal epithelium resists invasion by food-borne pathogens such as Listeria monocytogenes are an evolving area of research. Intestinal P glycoprotein is well known to limit the absorption of xenobiotics and is believed
to act as a cytotoxic defense mechanism. The aim of this study was to determine if intestinal P glycoprotein is involved in
host defense against L. monocytogenes. Caco-2 cells and a P-glycoprotein-overexpressing subclone (Caco-2/MDR) were employed in addition to mdr1a−/− mice and wild-type controls. In vitro invasion assays and in vivo experiments were employed to measure bacterial invasion
and dissemination. In addition, L. monocytogenes proteins were labeled with [35S]methionine, and the transepithelial transport across Caco-2 monolayers was characterized in both directions. Overexpression
of P glycoprotein in Caco-2/MDR cells led to increased resistance to L. monocytogenes invasion, whereas P-glycoprotein inhibition led to increased invasion. Flux of [35S]methionine-labeled L. monocytogenes proteins was significantly greater in the basolateral-to-apical direction than in the apical-to-basolateral direction, indicating
dependence on an apically located efflux transporter. Moreover, inhibiting P glycoprotein reduced the basolateral-to-apical
flux of the proteins. Early dissemination of L. monocytogenes from the gastrointestinal tract was significantly greater in the mdr1a−/− mice than in wild-type controls. Expression and function of intestinal P glycoprotein is an important determinant in resistance
to early invasion of L. monocytogenes.
We examined the hypothesis of an anti-inflammatory effect of phosphatidylcholine in ulcerative colitis.
A phase IIA, double blind, randomised, placebo controlled study was performed in 60 patients with chronic active, non steroid dependent, ulcerative colitis, with a clinical activity index (CAI) of > or = 4. Retarded release phosphatidylcholine rich phospholipids and placebo were administered at a dose of 6 g daily over three months. The primary end point was a change in CAI towards clinical remission (CAI < or = 3) or CAI improvement by > or = 50%. Secondary end points included > or = 50% changes in endoscopic activity index (EAI), histology, and quality of life scores.
Induction of clinical remission (CAI < or = 3) as the primary outcome variable was attained by 16 (53%) patients in the phosphatidylcholine treated group compared with three (10%) in the placebo group (p<0.00001). The rate of clinical remission and CAI improvement was 90% in the phosphatidylcholine group and only 10% in the placebo group. A median drop of seven points in the CAI score (70% improvement) was recorded in the phosphatidylcholine group compared with no change in the placebo group. Secondary end point analysis revealed concomitant drops in EAI and histology scores (p = 0.00016 and p = 0.0067 compared with placebo, respectively). Improvement in quality of life was reported by 16 of 29 evaluated patients in the phosphatidylcholine group compared with two of 30 in the placebo group (p = 0.00005).
Retarded release oral phosphatidylcholine is effective in alleviating inflammatory activity caused by ulcerative colitis.
The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This review is timely given the increased interest in the role of a 'leaky gut' in the pathogenesis of gastrointestinal diseases and the advent of novel treatment strategies, such as the use of probiotics.
The autoimmune cascade that culminates in diabetes initiates within pancreatic lymph nodes (PLNs). Here, we show that developmentally controlled lymphogenesis establishes a preferential trafficking route from the gut to the PLN, where T cells can be activated by antigens drained from the peritoneum and the gastrointestinal tract. Furthermore, intestinal stress modifies the presentation of pancreatic self-antigens in PLNs. The convergence of endocrine and intestinal contents within PLNs has significant implications for type 1 diabetes and may help to explain the link between autoimmune pathogenesis and environmental provocation.
• autoimmunity
• diabetes
• peritoneal lymphatics
• enteropathy
The goal of this review is to describe barrier function of the intestine, the structure of the tight junction, methods to evaluate intestinal permeability, and most importantly the relevance of abnormal permeability to disease. In this context, we will also present an emerging paradigm regarding the genesis of autoimmune diseases and describe the data that supports this from the perspective of both human disease and animal models. While this is a complicated area there are several points worth remembering:
From the lower oesophageal sphincter to the anus, the gastrointestinal tract has a single contiguous layer of cells that separates the inside of the body from the external environment. Separation is important as there are a wide variety of environmental agents in the lumen of the bowel that can initiate or perpetuate mucosal inflammation if they cross the epithelial barrier. While the epithelial lining of the intestine plays a critical role in preventing access of these agents, it is not the only component of what is termed barrier function. Also important are secreted products such as immunoglobulin, mucous, defensins, and other antimicrobial products.
The importance of epithelial barrier function in normal homeostasis can be appreciated from experiments performed in the early 1990s where cell wall extracts from luminal bacteria were injected into the colonic wall of rats.1 This simple manoeuvre of bypassing the epithelial barrier and placing luminal compounds directly into the colonic wall initiated an …
The present report describes a young woman with no previous gastrointestinal complaints who was initially diagnosed with postinfective irritable bowel syndrome (IBS) after a confirmed case of
Campylobacter jejuni
enteritis. However, because of persistent diarrhea, new-onset bloating and the development of iron and vitamin deficiencies, serological markers for celiac disease (CD) were evaluated. A positive tissue transglutaminase immunoglobulin A antibody test and repeat endoscopy with duodenal biopsy showing a Marsh IIIa lesion confirmed the diagnosis of CD. Infectious gastroenteritis is a well-established risk factor for the development of IBS, and there is recent evidence that it could play a role in the initiation and exacerbation of inflammatory bowel disease. The present case suggests that the clinical expression of CD can be unmasked by an acute gastrointestinal infection and supports the hypothesis that environmental factors other than gliadin may play a role in the clinical onset of CD in a genetically susceptible host. The increasing availability of serological testing and upper endoscopy has led to increasingly frequent diagnoses of CD and recognition that it may mimic IBS. The present case findings suggest that CD should be considered in the differential diagnosis of persistent IBS-like symptoms after an episode of infectious gastroenteritis.
Providing a significant cross-fertilization of ideas across several disciplines, Enhancement in Drug Delivery offers a unique comprehensive review of both theoretical and practical aspects of enhancement agents and techniques used for problematic administration routes. It presents an integrated evaluation of absorption enhancers and modes for promoting absorption that is especially valuable to those involved with the development of pharmaceutical, cosmetic, bioengineered, and medical products, as well as graduate students looking to study this intriguing field and those professionals involved with patents and regulatory issues. Organized by routes of administration, the book is divided into eight major sections: oral, rectal, buccal/sublingual, dermal/transdermal, nasal, vaginal/uterine, ocular, and brain. It offers fundamental as well specialized information including current findings on- •Surfactant use to accelerate macromolecule input •Targeted gastrointestinal delivery and enhanced absorption of lipophilic drugs •Permeation issues in rectal absorption •Chemical means of enhancement •Carriers for enhanced delivery to and across the skin •Methods associated with breaching the skin •Promoted buccal and sublingual absorption •Emerging ocular, nasal, vaginal, and uterine delivery systems •Carriers for overcoming the blood brain barrier Those investigators primarily involved with one specific route of delivery will be able to learn of helpful concepts and find additional stimulation from reading the approaches others have used within and outside their own spheres of activity. Readers are likely to find the same enhancer tested for various administration routes and in diverse experimental models. By understanding the properties and behavior of the enhancers operating within such systems, they may well find the inspiration needed to develop appropriate enhancing delivery methods for new applications.
Food emulsions have existed since long before people began to process foods for distribution and consumption. Milk, for example, is a natural emulsion/colloid in which a nutritional fat is stabilized by a milk-fat-globule membrane. Early processed foods were developed when people began to explore the art of cuisine. Butter and gravies were early foods used to enhance flavors and aid in cooking. By contrast, food emulsifiers have only recently been recognized for their abil ity to stabilize foods during processing and distribution. As economies of scale emerged, pressures for higher quality and extension of shelf life prodded the de velopment of food emulsifiers and their adjunct technologies. Natural emulsifiers, such as egg and milk proteins and phospholipids, were the first to be generally utilized. Development of technologies for processing oils, such as refining, bleaching, and hydrogenation, led to the design of synthetic food emulsifiers. Formulation of food emulsions has, until recently, been practiced more as an art than a science. The complexity offood systems has been the barrier to funda mental understanding. Scientists have long studied emulsions using pure water, hydrocarbon, and surfactant, but food systems, by contrast, are typically a com plex mixture of carbohydrate, lipid, protein, salts, and acid. Other surface-active ingredients, such as proteins and phospholipids, can demonstrate either syner- XV xvi Preface gistic or deleterious functionality during processing or in the finished food.
Chapter 1 presents a general history of the development of modern surfactants, their role in many modern processes and products, and their ever increasing economic importance. Included is information on the real and potential environmental impact of surfactants, basic information on the biological and structural features of their removal from the environment and some ideas related to the use of petroleum vs. “renewable” raw materials for their elaboration. The final part of the chapter provides a glossary that defines some of the key terms encountered in surfactant related discussions.
Thoroughly revised and updated, the second edition of Food Emulsifiers and their Applications integrates theoretical background with practical orientation and serves as the definitive reference on subject. It offers practitioners an overview of the manufacture, analysis, physical properties, interactions and applications of emulsifiers used in processed food. Written for food technologists as well as R & D and product development personnel, begins with the design and preparation of emulsifiers (including interactions with other food ingredients), which leads in to product categories, including dairy, infant nutrition, bakery, confectionery, and margarine, followed by nutrition improvement and processing techniques. Gerard L. Hasenhuettl is a consultant in Port Saint Lucie, Florida. Richard W. Hartel is a Professor of Food Engineering in the Department of Food Science at the University of Wisconsin, Madison, Wisconsin. © 2008 Springer Science+Business Media, LLC. All rights reserved.
Approximately 1% of the population is intolerant to the immunogenic food antigen gluten, which results in the chronic illness celiac disease (CD). In genetically predisposed individuals, gluten evokes a T-cell response resulting in disease development. The only treatment of CD is a gluten-free diet (GFD), which is demanding for CD patients, and prevention of the disease would be desirable. Prevention is usually defined as any activity which reduces the burden of mortality or morbidity from disease, and which takes place at the primary, secondary or tertiary level. Adherence to the GFD reduces the complications of CD, and may be considered as a tertiary preventive measurement. Early diagnosis and treatment of CD represents secondary prevention. Primary prevention is based on avoiding disease development. The possibilities for primary prevention of CD are based on the modulation of environmental factors involved in the disease and in the development of tolerance to gluten.
The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates.
Surfactant Science and Technology gives readers an illustrated tour of how chemistry developed. Integrating the contents of his two earlier books, A Chemical History Tour and The Art of Chemistry, the author has included over 350 high-quality reproductions of figures from rare books spanning 400 years of chemical publications in his rare-book collection. The illuminating and entertaining essays that accompany each illustration explain the imagery's meaning and significance in the context of both historical scientific beliefs and modern chemical science. Several essays are new to this edition.
In the past decade, literature has increasingly pointed to a proximal intestinal barrier dysfunction and inappropriate paracellular permeability increase that precedes and correlates with inflammatory markers and/or disease expression in inflammatory bowel disease, celiac disease and irritable bowel syndrome. Exogenous and endogenous stimuli are known to induce paracellular permeability and disrupt barrier function. Recent identification of regulatory pathways that induce cytoskeletal reorganization, tight junction disassembly and paracellular permeability provide targets for therapeutic intervention in celiac disease. Here we review the identity, function and regulation of these pathways and propose various approaches to therapeutic intervention in celiac disease with the aim of inhibiting intestinal barrier dysfunction.
The primary functions of the gastrointestinal (GI) tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the GI tract however suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. The intestinal epithelial barrier controls the equilibrium between tolerance and immunity to non-self-antigens by regulating antigen trafficking both through the transcellular and paracellular pathways. When the finely tuned trafficking of macromolecules is deregulated in genetically susceptible individuals, autoimmune disorders can occur. Celiac disease is characterized by loss of intestinal barrier functions, and evidence is now accumulating suggesting a role of increased intestinal permeability in the early steps of the disease pathogenesis. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the celiac disease autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of celiac disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This chapter reviews the recent advance in intestinal mucosal biology involved in gliadin trafficking and possible alternative therapeutic approaches to correct the barrier defect typical of celiac disease.
The immune system provides protection against infections and repairs tissue damage induced by physical trauma. Autoimmune disease occurs when the immune response inadvertently inflicts damage to tissues in the body. Similar features between autoimmune diseases suggest that common pathogenic mechanisms could lead to the development of autoimmune disease in genetically susceptible individuals. Activation of specific innate immune pathways is a characteristic of many autoimmune diseases. Innate immune cell activation directs antigen‐specific autoimmune T and B cells to cause tissue pathology under the influence of sex hormones. Thus, most autoimmune diseases occur predominantly in one sex or the other such as type I diabetes, Crohn's disease and myocarditis in men vs. thyroiditis, rheumatoid arthritis and lupus in women. Importantly, at least 80% of all autoimmune diseases occur in women. Current research targets these common immune mechanisms in an effort to develop better therapies and to prevent autoimmune disease.
Key Concepts
Genes and the environment contribute to the development of autoimmune diseases.
Nearly 80% of autoimmune diseases occur in women.
Sex hormones regulate inflammation and alter autoimmune disease in animal models.
Estrogens increase auto‐antibodies, which are key diagnostic criteria for most autoimmune diseases.
Many theories exist for how infections and chemicals could cause autoimmune diseases.
Microbial and/or chemical activation of innate immunity must occur at the same time as damage to self‐tissues in order for autoimmune disease to develop.
Dysregulation of peripheral immunoregulatory mechanisms is a key characteristic of autoimmune diseases.
Successful treatment of autoimmune diseases might require the targeting of multiple effector pathways.
It is not uncommon for peptides and structurally-similar non-peptides to have poor intestinal permeability and low oral bioavailability. One possible way to solve a permeability problem is to formulate the compound with membrane permeation-enhancing excipients. Important criteria for success of this approach are: (1) achieving reproducible intestinal permeation, (2) doing so without causing toxicity, and (3) understanding the mechanisms of permeation enhancement. Some effective and potentially safe permeation enhancers are fatty acids, glycerides, surfactants, acyl carnitines, and bile salts. The literature on permeation enhancement with these agents is briefly reviewed. We evaluated permeation enhancement approaches to increase the oral bioavailability of a non-metabolized, cyclic peptide fibrinogen antagonist, DMP 728. Sodium caprate (15 mM) increased the in vitro intestinal permeation rate 3-fold. Oral absorption in dogs was also increased approximately 3-fold using a formulation containing 150 mg sodium caprate. Inter-animal variability in absorption was considerable, though. A diacidic, non-peptide angiotensin II antagonist, DuP 532, presented another case of a poorly membrane permeable lead compound. Sodium caprate did not affect DuP 532 oral bioavailability in rats. However, oral bioavailability of DuP 532 in rats and dogs was increased approximately 3-fold using glyceride vehicles. These excipients have the advantage of already being used in marketed products. As with DMP 728, there was substantial inter-animal variability of DuP 532 oral bioavailability, and optimization of the formulation would be required to improve reproducibility. These examples demonstrate the possibilities of significantly improving oral bioavailability of poorly permeable drugs using seemingly acceptable excipients.
The epithelial and endothelial barriers of the human body are major obstacles for drug delivery to the systemic circulation and to organs with unique environment and homeostasis, like the central nervous system. Several transport routes exist in these barriers, which potentially can be exploited for enhancing drug permeability. Beside the transcellular pathways via transporters, adsorptive and receptor-mediated transcytosis, the paracellular flux for cells and molecules is very limited. While lipophilic molecules can diffuse across the cellular plasma membranes, the junctional complexes restrict or completely block the free passage of hydrophilic molecules through the paracellular clefts. Absorption or permeability enhancers developed in the last 40 years for modifying intercellular junctions and paracellular permeability have unspecific mode of action and the effective and toxic doses are very close. Recent advances in barrier research led to the discovery of an increasing number of integral membrane, adaptor, regulator and signalling proteins in tight and adherens junctions. New tight junction modulators are under development, which can directly target tight or adherens junction proteins, the signalling pathways regulating junctional function, or tight junction associated lipid raft microdomains. Modulators acting directly on tight junctions include peptides derived from zonula occludens toxin, or Clostridium perfringens enterotoxin, peptides selected by phage display that bind to integral membrane tight junction proteins, and lipid modulators. They can reversibly increase paracellular transport and drug delivery with less toxicity than previous absorption enhancers, and have a potential to be used as pharmaceutical excipients to improve drug delivery across epithelial barriers and the blood–brain barrier.
The purpose of this study was to analyze the effects of two common monoglyceride components of lipid excipients, 1-monoolein and 1-monostearin, on the activity and expression of P-glycoprotein (P-gp) in Caco-2 cells. Non-cytotoxic concentrations of 1-monoolein and 1-monostearin were determined by assessing membrane permeability and mitochondrial activity in Caco-2 cells, a human colon adenocarcinoma cell line. Concentrations of 500 and 100 microM were used to evaluate P-gp activity through Rh123 accumulation and bifunctional transport studies. The P-gp protein expression levels were quantified through the use of immunoblots. The changes in cell membrane fluidity and nuclear membrane integrity upon the addition of monoglycerides were analyzed by fluorescence anisotropy using DPH and TMA-DPH as the fluorescent labels and by using increasing salt concentrations to release the nuclear contents, respectively. The absorptive flux (apical to basolateral) in the bifunctional transport studies was not found to be statistically significant for the non-cytotoxic concentrations of 1-monoolein and 1-monostearin. However, treatments of 500 and 100 microM of 1-monoolein or 1-monostearin displayed statistically lowered efflux (basolaterial to apical, P < 0.05) compared to the controls (7.9 +/- 0.8, 12.9 +/- 2.6 x 10 (6) cm/s for 1-monoolein or 11.1 +/- 2.0, 11.4 +/- 2.3 x 10 (6) cm/s for 1-monostearin, respectively, compared to the untreated control, 21.1 +/- 2.9 x 10 (6) cm/s, n = 5). Rh123 accumulation was also found to be enhanced upon 24 h incubation with both concentrations of the monoglycerides; however, only concentrations of 500 muM of the monoglycerides were shown to significantly reduce the P-gp protein expression. The results from this study suggest that these two monoglycerides, common components in various lipid excipients, are inhibitors of P-gp.
The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.
Phospholipids are essential for the normal function of the intestinal mucus barrier. The objective of this study was to systematically investigate phospholipids in the intestinal mucus of humans suffering from inflammatory bowel diseases, where a barrier defect is strongly supposed to be pathogenetic.
Optimal mucus recovery was first validated in healthy mice and the method was then transferred to the endoscopic acquisition of ileal and colonic mucus from 21 patients with ulcerative colitis (UC), 10 patients with Crohn's disease (CD), and 29 healthy controls. Nano-electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to determine phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and sphingomyelin (SM) in lipid extracts of mucus specimens.
Human and rodent mucus contained very similar phospholipid species. In the ileal and colonic mucus from patients suffering from UC, the concentration of PC was highly significantly lower (607 +/- 147 pmol/100 microg protein and 745 +/- 148 pmol/100 microg protein) compared to that of patients with CD (3223 +/- 1519 pmol/100 microg protein and 2450 +/- 431 pmol/100 microg protein) and to controls (3870 +/- 760 pmol/100 microg protein and 2790 +/- 354 pmol/100 microg protein); overall, P = 0.0002 for ileal specimens and P < 0.0001 for colonic specimens. Independent of disease activity, patients suffering from UC showed an increased saturation grade of PC fatty acid residues and a higher LPC-to-PC ratio.
The intestinal mucus barrier of patients with UC is significantly altered concerning its phospholipid concentration and species composition. These alterations may be very important for the pathogenesis of this disease and underline new therapeutic strategies.
The present study was aimed to investigate the effects of polyoxyethylene (40) stearate (PS), a non-ionic surfactant, on the activity of P-glycoprotein (P-gp) and six major cytochrome P450 (CYP) isoforms. An in vitro diffusion chamber system was utilized to estimate the effects of PS concentration on the transport characteristics of Rhodamine 123 (R123) and Rhodamine 110 (R110), a standard P-gp substrate and nonsubstrate, respectively, across the excised intestinal segments of rat. Caco-2 cells were cultured to investigate the mechanisms by estimating the effects of PS on intracellular ATP levels, P-gp ATPase activity and membrane fluidity. The obtained results showed that PS inhibited P-gp mediated efflux in a concentration-dependent manner mainly by modulating substrate-stimulated P-gp ATPase activity. On the other hand, human liver microsomes were utilized to examine the inhibitive potential of PS on six major CYP isoforms. Inhibitive potential on two of these CYP2C9 and CYP2C19 was found to be clinically significant. In conclusion, PS is potentially useful as a pharmaceutical ingredient to improve the oral bioavailability of coadministered P-gp substrates and substrates for certain CYP isoforms.
The historical prevalence and long-term outcome of undiagnosed celiac disease (CD) are unknown. We investigated the long-term outcome of undiagnosed CD and whether the prevalence of undiagnosed CD has changed during the past 50 years.
This study included 9133 healthy young adults at Warren Air Force Base (sera were collected between 1948 and 1954) and 12,768 gender-matched subjects from 2 recent cohorts from Olmsted County, Minnesota, with either similar years of birth (n = 5558) or age at sampling (n = 7210) to that of the Air Force cohort. Sera were tested for tissue transglutaminase and, if abnormal, for endomysial antibodies. Survival was measured during a follow-up period of 45 years in the Air Force cohort. The prevalence of undiagnosed CD between the Air Force cohort and recent cohorts was compared.
Of 9133 persons from the Air Force cohort, 14 (0.2%) had undiagnosed CD. In this cohort, during 45 years of follow-up, all-cause mortality was greater in persons with undiagnosed CD than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2.0-7.5; P < .001). Undiagnosed CD was found in 68 (0.9%) persons with similar age at sampling and 46 (0.8%) persons with similar years of birth. The rate of undiagnosed CD was 4.5-fold and 4-fold greater in the recent cohorts, respectively, than in the Air Force cohort (both P < or = .0001).
During 45 years of follow-up, undiagnosed CD was associated with a nearly 4-fold increased risk of death. The prevalence of undiagnosed CD seems to have increased dramatically in the United States during the past 50 years.
The influence of two surface-active food additives on the integrity and permeability of rat ileal mucosa has been studied. We determined the activity of N-acetyl-beta-glucosaminidase, a lysosomal enzyme, in the rat intestinal lumen after deposition of polyoxyethylene (20) sorbitan monostearate (polysorbate 60; Tween 60) or polyoxyethylene (20) sorbitan monooleate (polysorbate 80; Tween 80) in a section of ligated, cannulated gut. We also determined the activities of N-acetyl-beta-glucosaminidase, alkaline phosphatase, 5'-nucleotidase and phospholipase A2 in mixtures of isolated mucosal cells and polysorbate 60 or polysorbate 80. The activity of N-acetyl-beta-glucosaminidase was increased in the luminal contents of the cannulated gut 15 min after deposition of either polysorbate 60 or polysorbate 80 (10 mg/ml fluid instilled into gut). It was also increased in mixtures of mucosal cells and polysorbate 60 or polysorbate 80 (0.1-10 mg/ml). In contrast, the activities of alkaline phosphatase and 5'-nucleotidase were unaffected and that of phospholipase A2 was decreased by the presence of either polysorbate. These findings indicated that polysorbate 60 and polysorbate 80 released lysosomal enzymes from the intestinal mucosal cells and that these agents might damage the intestinal mucosa and increase its permeability. We therefore determined the intestinal permeability to sodium fluorescein in the absence and presence of polysorbate 60 or 80 and found that the permeability was slightly increased in the presence of either of the compounds at concentrations of 10 mg/ml fluid instilled into gut. It is possible therefore that surface-active food additives might impair the function of the mucosal barrier and increase the permeability of the gut to potentially toxic and pathogenic molecules.
Surfactants are one of the most frequently used adjuvants in oral pharmaceutical preparations, used primarily as solubilizers, stabilizers, emulsifiers, and wetting agents. However, surfactants can disrupt normal membrane structure. In this study, lactate dehydrogenase (LDH) and mucus were evaluated as potential markers of intestinal damage in a single-pass in situ perfusion model in the rat. The release of LDH and mucus into the intestinal lumen of the rat following perfusion of the nonionic surfactants Tween 80 and Triton X-100 was determined. The release rate of LDH increased in the order saline < Tween 80 < Triton X-100 in both jejunum and colon. LDH release rate was approximately three times lower in the colon than in the jejunum, but relative effects of nonionic surfactants were comparable between regions. In addition, the rate of LDH release in the jejunum increased with decreasing perfusion rates for both saline and Tween groups and with increasing Tween 80 concentrations. At each flow rate studied, mucus release rate was greater in the presence of Tween 80 and Triton X-100 than saline, but there was no significant difference between the effect of Tween 80 and Triton X-100 on mucus release rate. When perfusion of Triton X-100 was followed by saline, rates of both mucus and LDH release returned to baseline values, suggesting damage is reversible. Histological damage agreed with trends observed in LDH and mucus release rates. This model allows for early evaluation of intestinal damage due to both excipients and active ingredients and simultaneous measurement of drug absorption.
An understanding of the action of many drugs requires a knowledge of how the drug reaches the site of action in a cell. A detailed knowledge of the structure and function of cell membranes is often required to understand the transport of drugs across the plasma membrane. To obtain this information proteins must be isolated. The isolation and characterisation of cell membrane proteins usually requires the solubilisation of the membrane and a method of separation of the various membrane proteins and glycoproteins. The starting point for such an investigation is the choice of a suitable surfactant (detergent) to solubilise the membrane. This review considers the range of surfactants that are available for membrane solubilisation, how surfactants interact with membranes, the part they play in the separation of integral membrane proteins and in the reconstitution of membrane proteins for functional studies. The solubilisation of specific membrane proteins and glycoproteins including the human erythrocyte anion transporter, mitochondrial porin, sarcoplasmic reticulum Ca(2+)-ATPase, the ATPase-active multidrug transporter P-glycoprotein, bacteriorhodopsin and rhodopsin are also discussed.
Mucosal surface hydrophobicity is a key factor of the gastric acid defence barrier. In the colon, surface hydrophobicity is high but its biological function remains unexplored.
To investigate the functional changes of the barrier due to removal of the surface active phospholipid layer by a detergent, or to reinforcement of the surface active phospholipid by local application of a suspension of lipids.
Surface hydrophobicity (contact angle measurement), colonic permeability (lumen to blood clearance of mannitol and dextran), and mucosal resistance against luminal aggression (distal colitis induced by dextran sodium sulphate, DSS) were investigated in three study groups: (a) rats pretreated with a detergent (Brij 35) known to remove surfactant lipids; (b) rats pretreated with a suspension of surface active lipids (tripalmitin and dipalmitoyl-phosphatidylcholine); and (c) control rats pretreated with the corresponding vehicles.
In controls, surface hydrophobicity was low on the caecal mucosa and high in colon and rectum. Detergent treatment reduced surface hydrophobicity, and increased colonic permeability to mannitol and dextran. Conversely, treatment with lipids increased surface hydrophobicity, and reduced colonic permeability. Administration of DSS induced a progressive loss of colonic surface hydrophobicity, and an increase in permeability to mannitol and dextran. Detergent treatment increased susceptibility to epithelial damage and mucosal inflammation by DSS. Treatment with lipids reduced susceptibility to DSS colitis.
Colonic surface hydrophobicity modulates permeability to hydrophilic molecules and protects against toxins.
This review addresses the field of improving oral bioavailability through the use of excipients that increase intestinal membrane permeability. The critical issues to consider in evaluating these approaches are 1) the extent of bioavailability enhancement achieved, 2) the influence of formulation and physiological variables, 3) toxicity associated with permeation enhancement, and 4) the mechanism of permeation enhancement. The categories of permeation enhancers discussed are surfactants, fatty acids, medium chain glycerides, steroidal detergents, acyl carnitine and alkanoylcholines, N-acetylated alpha-amino acids and N-acetylated non-alpha-amino acids, and chitosans and other mucoadhesive polymers. Some of these approaches have been developed to the stage of initial clinical trials. Several seem to have potential to improve oral bioavailabilities of poorly absorbed compounds without causing significant intestinal damage. In addition, the possible use of excipients that inhibit secretory transport is reviewed.
Purpose:
To gain some mechanistic understanding of surfactant-induced membrane permeabilization and identify a surfactant physical property that can be used as a predictor for intestinal membrane permeability enhancement.
Methods:
The maximum surface pressures (piCMC) of series of anionic and non-ionic surfactants as indicators of surface activity were determined using a bubble surface tensiometer, and related to in vivo intestinal membrane permeability and acute damage data of the same surfactants from a previous work. Phospholipid bilayers with constant surface pressures and monolayers with different surface pressures were used as model membranes to systematically study membrane permeability enhancement and membrane penetration of surfactants at different concentrations.
Results:
Surfactants that did not permeabilize or acutely damage the intestinal wall generally exhibited a piCMC < 25 dyne/cm. Permeability enhancement and acute damage increased as piCMC increased beyond 25 dyne/cm. This critical threshold value at around 25 dynes/cm was also observed with in vitro experiments using phospholipid vesicles and monolayers. Data support the hypothesis that the threshold phenomenon originates from the interfacial tension at the membrane/water interface, which controls the surface adsorption process of surfactant molecules onto the membrane.
Conclusions:
For a surfactant to permeabilize and acutely damage the intestinal wall, it must exhibit a surface pressure of greater than 25 dynes/cm. This threshold value is related to an intrinsic property, surface pressure, of the phospholipid membranes. Since the surfactant surface pressure is a property of the surfactant monomer, partition of the surfactant monomer, not the micelle, into the membrane is an obligate step in membrane permeabilization. Above the surfactant critical micelle concentration, CMC, micelles may act as a depot to continuously replace aqueous surfactant monomers taken up by the membrane. For some surfactants above CMC, sufficient number of monomers can partition into the membrane to cause solubilization of membrane lipids in surfactant micelles.
The challenges encountered in the peroral route for protein and peptide drug delivery were discussed. The chemical approaches which enhanced PP drug delivery included prodrug development, pegylation and small molecular complex-forming agents. Approaches based on modulation of gastrointestinal absorption barrier properties were useful provided their toxic manifestations were overcome. The approaches were effectively combined with other strategies for providing maximum protection from degradation and achieving drug-delivery at the preferred site of absorption.
Food additives are responsible for certain allergic types of symptoms. Here Caco-2 cell monolayers were used as a model of the intestinal epithelium for the study of the effect of a food grade surfactant. We determined whether or not the presence of a surfactant enhances the transportation of food allergens across human intestinal epithelial Caco-2 cells.
This study investigated sucrose monoester fatty acids, which are a food grade surfactant. As an in vitro model of human epithelial cells, Caco-2 cells were grown in monolayers and exposed to different doses of the surfactant in conjunction with ovomucoid, a major egg white allergen. The integrity of the monolayer was assessed by measuring transepithelial electrical resistance (TEER). The permeability of tight junctions and transport of the antigen were studied.
TEER correlated with the permeability of tight junctions. TEER significantly decreased upon exposure to a surfactant, indicating an increase in ovomucoid permeability without degradation. The surfactant induced shortening in microvilli, actin disbandment and structural separation of tight junctions. The results indicate that food grade surfactants can increase the paracellular uptake of food allergens.
The effect of diacetyltartaric acid esters of mono and diglycerides (DATEM) on fusion of respiratory syncytial virus (RSV) with HEp-2 cells was studied using the R18 fluorescence dequenching fusion assay. At DATEM concentrations less than 2.0 microg/ml, the inhibition of fusion increased with the concentration of DATEM. At 2 microg/ml of DATEM, the fusion was suppressed by 80-90%. Studies examining possible mechanism of fusion-inhibition indicated that DATEM was likely adsorbed onto lipid membranes of both viral envelope and target cell membranes. Quantitative measurements of DATEM adsorption onto membranes were also performed using lipid monolayers and vesicles. The surface pressure of lipid monolayer formed at the air/aqueous interface increased as the concentration of DATEM in the monolayer subphase increased, suggesting that DATEM was inserted into the monolayer. As the concentration of DATEM in vesicle suspensions increased, electrophoretic mobility of initially uncharged lipid vesicles also increased, reflective of increased negative charge at vesicle surfaces. These results strongly suggest that the insertion of DATEM onto membranes inhibited viral fusion. DATEM may prove to be effective in limiting the infectivity of RSV by interference with the fusion of the viral envelope with target cell membranes.
P-Glycoprotein (P-gp) is a transmembrane protein, playing significant roles in the process of drug discovery and development and in pest resistance to pesticides. P-gp affects absorption, disposition, and elimination of different compounds and is mainly expressed in intestines, liver, kidneys, heart, colon, and placenta. The expression of P-gp in the blood-brain barrier (BBB) has been associated with the restricted access of many compounds to the central nervous system. Generated knockout mice by disruption of mdr 1a gene, encoding for P-gp, showed that this protein was expressed in the BBB. The absence or the low levels of P-gp elevated drug concentrations in tissues and decreased drug elimination. P-gp is responsible for resistance of cells to agents, particularly the anticancer drugs, by removing these drugs from cells. Increased expression of P-gp is implicated in decreased HIV drug availability at certain intracellular sites. The role of P-gp in affecting efficacy and toxicity of environmental toxicants such as pesticides and heavy metals has not been adequately investigated. Studies showed that P-gp contributes to resistance to pesticides in certain pest species, and to decrease toxicity by removing compounds from cells in mammals. Placental drug-transporting P-gp plays a significant role in limiting the transport of toxicants such as potential teratogens to the fetus. Several in vitro or in vivo assays, including using P-gp knockout or naturally deficient mice, were described for testing P-gp modulators. The role of P-gp following concurrent exposure to more multiple compounds needs further research. P-gp modulators should be carefully used, since some modulators that reverse P-gp efflux action in vitro may lead to alterations of tissue function and increase toxicity of xenobiotics in normal tissues. Recent reports from the pharmaceutical studies on the significance of P-gp as transporters in altering the efficacy and toxicity clearly highlight the need for further research in interaction with environmental toxicants.
The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates.
The incidence of many common diseases has increased during the last decades. High fat intake is a risk factor for many diseases. We propose that some of the negative effects of fat are caused by lipid-induced damage of the gastrointestinal epithelium, thus compromising the epithelial function as a barrier for passage of toxic substances and allergenic agents to the circulatory system. Monoglycerides (MGs), phospholipids and fatty acids (FAs) are surface-active molecules that in pharmaceutical studies act as permeability enhancers for hydrophilic drugs with low absorption. Three possible mechanisms were proposed: (a) lipid-induced alterations in intracellular events may cause destabilization of tight junctions between the GI epithelial cells, (b) lipids may destabilize cell membranes, (c) lipids cause intestinal cell damage, which increase the permeability of the GI epithelium. These "side effects" of lipids may partly explain the association between fat intake and disease observed in epidemiological studies.
There is a spectrum of distinct disease states that have in common their effect of breaking down epithelial and/or endothelial barrier function. Fluid compartmentalization goes awry, with profound implications for epithelial and stromal homeostasis, fluid and/or electrolyte balance, generation of inflammatory states, and even tumor microenvironment. Specific effects on the tight junction are found to be integral to bacterial invasion and tumor progression.
In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
To understand better the wide-spread pharmaceutical use of non-ionic surfactant Tween 80 (TW), the colloidal properties of the surfactant alone and in combinations with the common phospholipid, phosphatidylcholine (PC), were studied. Static and dynamic light scattering revealed that TW solubilises PC at TW/PC approximately 2.75/1 mol/mol and that TW micelle disintegration occurs on time-scale of 2.5 min, independent of amphipath concentration. This is up to nearly 300-times faster than the TW caused dissolution of PC containing unilamellar vesicles. The apparent dissolution time of TW/PC mixed aggregates, in contrast, decelerates from >700 min to <5 min upon increasing starting total amphipath concentration, with thermal activation energy > or =24 (< or =80) kJ mol(-1). The aggregate dissolution rate in highly concentrated TW/PC suspensions reflects the dissolved polysorbate-aggregate exchange rate (approximately 6.7 x 10(-3)s(-1)) rather than TW flip-flop rate across a bilayer (>0.2 min(-1)). PC solubilisation proceeds linearly with the square-root of time, and is kinetically governed by the speed of surfactant diffusion through the bulk (D approximately 2.8 x 10(-11)m2 s(-1)). Creation of small Tween-phosphatidylcholine mixed micelles is typically preceded by pre-solubilisation structures, first in the form of deformable, strongly fluctuating, bilayer vesicles and then of elongated, presumably thread-like, mixed micelles. TW/PC mixed micelles become smaller with growing surfactant/lipid molar ratio, whereas TW/PC mixed vesicles become more and more leaky with increasing surfactant concentration. Our results highlight the molecular and kinetic aspects of polysorbate-membrane interactions and provide a rationale for the popularity of Tween surfactants in pharmaceutical products: such surfactants can solubilise fatty molecules and bilayer membranes but need quite a long time for this, which is available in pharmaceutical preparations but normally not in vivo; this makes Tweens relatively efficient and safe. Furthermore, our data could help design better ultra-deformable mixed lipid-surfactant vesicles for the non-invasive transdermal drug delivery across the skin.
The effect of co-administration of a mucolytic agent with a penetration enhancer was assessed on the intestinal absorption of poorly absorbed hydrophilic compounds. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4 kDa (FD-4) was used as a model compound, and N-acetylcysteine (NAC) was used as a mucolytic agent. Sodium caprate (C10), tartaric acid (TA), sodium taurodeoxycholate (TDC), sodium dodecyl sulfate (SDS), p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as penetration enhancers with different mechanisms of action. Various dosing solutions containing a penetration enhancer in the absence or in the presence of NAC were directly administered into the exposed rat jejunum, and the bioavailability of FD-4 up to 2 h was determined. The extent of improvement by co-administration was highly dependent on the penetration enhancer species applied. The observed enhancement was thought to result from the mucolytic activity of NAC, which can reduce the mucus viscosity and facilitate the penetration of FD-4 to mucosal membrane. Among the combinations tested, the simultaneous administration of NAC and TX-100 provided the highest enhancement (22.5-fold) of intestinal FD-4 absorption compared to the control. Although the detailed mechanism for the observed drastic improvement is unclear, one possible reason was thought to be due to the improved diffusivity of TX-100 micellar system in the mucus layer. All these results suggest that the combination of a mucolytic agent and a non-ionic surfactant may have potential as an enhancing system for peroral delivery of poorly absorbed hydrophilic compounds like protein and peptide drugs.
Transport molecules can significantly affect the pharmacodynamics and pharmacokinetics of drugs. An important transport molecule, the 170 kDa P-glycoprotein (Pgp), is constitutively expressed at several organ sites in the human body. Pgp is expressed at the blood-brain barrier, in the kidneys, liver, intestines and in certain T cells. Other transporters such as the multidrug resistance protein 1 (MRP1) and MRP2 also contribute to drug distribution in the human body, although to a lesser extent than Pgp. These three transporters, and especially Pgp, are often targets of drugs. Pgp can be an intentional or unintentional target. It is directly targeted when one wants to block its function by a modifier drug so that another drug, also a substrate of Pgp, can penetrate the cell membrane, which would otherwise be impermeable. Unintentional targeting occurs when several drugs are administered to a patient and as a consequence, the physiological function of Pgp is blocked at different organ sites. Like Pgp, MRP1 also has the capacity to mediate transport of many drugs and other compounds. MRP1 has a protective role in preventing accumulation of toxic compounds and drugs in epithelial tissue covering the choroid plexus/cerebrospinal fluid compartment, oral epithelium, sertoli cells, intesticular tubules and urinary collecting duct cells. MRP2 primarily transports weakly basic drugs and bilirubin from the liver to bile. Most compounds that efficiently block Pgp have only low affinity for MRP1 and MRP2. There are only a few effective and specific MRP inhibitors available. Drug targeting of these transporters may play a role in cancer chemotherapy and in the pharmacokinetics of substrate drugs.
Some of the non-ionic surfactants used in pharmaceutical formulations inhibit P-glycoprotein (P-gp), the multi-drug transporter. The effect of such food emulsifiers as polyglycerol esters (PGE) and sugar esters (SE) of fatty acids on the P-gp activity was studied by using human intestinal Caco-2 cells. The cellular accumulation of [(3)H]-daunomycin, a P-gp substrate, was markedly enhanced by PGE and SE. This accumulation-enhancing activity varied among the emulsifiers, but was correlated with their surface activity. The uptake of soluble nutrients such as amino acids was only slightly reduced by PGE and SE. These results suggest that these emulsifiers specifically inhibited P-gp. When the basal-to-apical transport of daunomycin across the Caco-2 monolayers was measured, however, the emulsifiers did not decrease the efflux of daunomycin to the apical chamber. The enhanced accumulation of daunomycin would therefore not have been due to P-gp inhibition, but instead to the increased daunomycin permeability of cell membranes caused by the emulsifiers.