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An overview of the ways in which choline intake may cause disease. Abbreviations: GVB, gut vascular barrier; IBD, inflammatory bowel disease; MI, myocardial infarction; NASH, non-alcoholic steatohepatitis; TMAO, trimethylamine-N-oxide.
Source publication
Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which, upon absorption by the host is converted into trimethylamine-N-oxide (TMAO) in the liver. A high accumulation of both components is related to cardiovascular disease, inflammatory bowel disease,...
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Introduction: Gut microbiota is not only a taxonomic biologic ecosystem but is also involved in human intestinal and extra-intestinal functions such as immune system modulation, nutrient absorption and digestion, as well as metabolism regulation. The latter is strictly linked to non-alcoholic fatty liver disease (NAFLD) pathophysiology. Materials a...
Citations
... Choline, in its water-soluble form (mainly present in breast milk), is transported into the portal circulation from where it reaches the liver. On the other hand, choline in its lipid-soluble form (present in most foods) is part of chylomicrons, which are then absorbed and distributed through the lymphatic system [11]. ...
... Choline has several key functions that support the development and health of the human body. Its derivatives, PC and sphingomyelin, are essential for the following processes: cell division and growth, lipid transport, cell membrane synthesis, myelination of nerve cell axons, and cell signaling [11]. As a precursor of ACh, choline has a direct effect on cholinergic neurotransmission [12]. ...
The nutritional status of the mother-to-be has a key impact on the proper development of the fetus. Although all nutrients are important for the developing baby, recent research indicates the importance of adequate choline intake during the periconceptional period, pregnancy, and lactation. Choline plays a key role in the biosynthesis of cell membranes, supporting liver function, neurotransmission, brain development, and DNA and histone methylation. Choline participates in the formation of a child’s nervous system, supports its cognitive development, and reduces the risk of neural tube defects. The human body is incapable of producing sufficient choline to meet its needs; therefore, it must be obtained from the diet. Current data indicate that most women in their reproductive years do not achieve the recommended daily intake of choline. The presented narrative review indicates the importance of educating mothers-to-be and thereby increasing their awareness of the effects of choline on maternal and child health, which can lead to a more aware and healthy pregnancy and proper child development.
... Choline is a key component for the synthesis of acetylcholine; a neurotransmitter recognized for its role in memory and learning. While dietary choline has predominantly been attributed positive effects on cognition in early life [36], recent research suggests that depending on the composition and diversity of the gut microbiota, other pathways of choline metabolism may be activated as well, resulting in the synthesis of betaine, sphingomyelin and phosphatidylcholine (components of the cell membrane structure) or TMAO [37]. With dysbiosis of the gut, the probability of choline being metabolized into TMAO increases [36], which has previously been Plasma levels of TMAO and its precursors (in µmol/l) were natural log-transformed. ...
... While dietary choline has predominantly been attributed positive effects on cognition in early life [36], recent research suggests that depending on the composition and diversity of the gut microbiota, other pathways of choline metabolism may be activated as well, resulting in the synthesis of betaine, sphingomyelin and phosphatidylcholine (components of the cell membrane structure) or TMAO [37]. With dysbiosis of the gut, the probability of choline being metabolized into TMAO increases [36], which has previously been Plasma levels of TMAO and its precursors (in µmol/l) were natural log-transformed. The G-factor reflects the first component of the principal component analysis including the delayed recall score of the Stroop interference test, the letter-digit-substitution test, the verbal fluency task, the Purdue pegboard test and the 15-word learning test. ...
Background
The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain.
Methods
In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function.
Results
Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses.
Conclusions
Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.
... Choline metabolism occurs in the intestine and is affected by the disruption of the microbiota. In this case, triglycerides that cannot be removed from the liver may lead to fatty liver (81,82,83,84). ...
Our gastrointestinal system, often referred to as our "second brain," is grappling with the devastating effects of COVID-19, a disease that has
plagued recent years. Researchers are investigating how bacteria in the intestinal microflora may contribute to or mitigate liver damage caused by
COVID-19. Despite the limited number of studies, the fight against liver organ damage by the gastrointestinal system, which is our second brain
is important. All original articles published in English until March 01, 2020, were retrieved via a library-assisted literature search from
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inclusion. Effect size and 95% confidence interval were evaluated in this study. The randomized trials exhibit a noteworthy level of heterogeneity
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the weights of the studies are significantly to the right of the 2 vertical lines. The confidence interval of each study has significant weights.
According to the study findings, the interaction of the intestinal flora and the immune system showed us that there is an area that we need to
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... However, when dietary choline challenges were introduced, most recent investigations did not report significant increases in chronic TMAO concentrations in the plasma [33]. Given the likely individual variability in TMAO production, which depends on various factors, including one's gut microbiome profile [34], particularly the abundance of the phyla Firmicutes and Proteobacteria [35], as well as liver FMO3 [36], the rate of plasma clearance linked to kidney function [37], and the direct dietary source of TMAO [38], it is essential to consider these multiple determinants. ...
Background
Choline, an indispensable nutrient, plays a pivotal role in various physiological processes. The available evidence regarding the nexus between dietary choline intake and health outcomes, encompassing cardiovascular disease (CVD), cancer, and all-cause mortality, is limited and inconclusive. This study aimed to comprehensively explore the relationship between dietary choline intake and the aforementioned health outcomes in adults aged > 20 years in the U.S.
Methods
This study utilized data from the National Health and Nutrition Examination Survey between 2011 and 2018. Dietary choline intake was evaluated using two 24-h dietary recall interviews. CVD and cancer status were determined through a combination of standardized medical status questionnaires and self-reported physician diagnoses. Mortality data were gathered from publicly available longitudinal Medicare and mortality records. The study utilized survey-weighted logistic and Cox regression analyses to explore the associations between choline consumption and health outcomes. Restricted cubic spline (RCS) analysis was used for dose‒response estimation and for testing for nonlinear associations.
Results
In our study of 14,289 participants (mean age 48.08 years, 47.71% male), compared with those in the lowest quintile (Q1), the adjusted odds ratios (ORs) of CVD risk in the fourth (Q4) and fifth (Q5) quintiles of choline intake were 0.70 (95% CI 0.52, 0.95) and 0.65 (95% CI 0.47, 0.90), respectively (p for trend = 0.017). Each 100 mg increase in choline intake was associated with a 9% reduced risk of CVD. RCS analysis revealed a linear correlation between choline intake and CVD risk. Moderate choline intake (Q3) was associated with a reduced risk of mortality, with an HR of 0.75 (95% CI 0.60–0.94) compared with Q1. RCS analysis demonstrated a significant nonlinear association between choline intake and all-cause mortality (P for nonlinearity = 0.025). The overall cancer prevalence association was nonsignificant, except for colon cancer, where each 100 mg increase in choline intake indicated a 23% reduced risk.
Conclusion
Elevated choline intake demonstrates an inverse association with CVD and colon cancer, while moderate consumption exhibits a correlated reduction in mortality. Additional comprehensive investigations are warranted to elucidate the broader health implications of choline.
... Apart from the Mediterranean diet, probiotics, prebiotics, and their combination synbiotics might play a unique role in this context. The administration of probiotics, especially next-generation probiotics (NGP), such as Akkermansia muciniphila, has already been suggested to offer beneficial effects [73][74][75]. In particular, Akkermansia muciniphila has been documented to decrease the formation of abdominal aortic aneurysm, when administered in a mouse model. ...
Purpose of Review
Choline is an essential nutrient for human health and cellular homeostasis as it is necessary for the synthesis of lipid cell membranes, lipoproteins, and the synthesis of the neurotransmitter acetylcholine. The aim of this review is to analyze the beneficial effects of choline and its significance in cellular metabolism and various inflammatory pathways, such as the inflammasome. We will discuss the significance of dietary choline in cardiometabolic disorders, such as non-alcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), and chronic kidney disease (CKD) as well as in cognitive function and associated neuropsychiatric disorders.
Recent Findings
Choline deficiency has been related to the development of NAFLD and cognitive disability in the offspring as well as in adulthood. In sharp contrast, excess dietary intake of choline mediated via the increased production of trimethylamine by the gut microbiota and increased trimethylamine-N-oxide (TMAO) levels has been related to atherosclerosis in most studies. In this context, CVD and CKD through the accumulation of TMAO, p-Cresyl-sulfate (pCS), and indoxyl-sulfate (IS) in serum may be the result of the interplay between excess dietary choline, the increased production of TMAO by the gut microbiota, and the resulting activation of inflammatory responses and fibrosis.
Summary
A balanced diet, with no excess nor any deficiency in dietary choline, is of outmost importance regarding the prevention of cardiometabolic disorders as well as cognitive function. Large-scale studies with the use of next-generation probiotics, especially Akkermansia muciniphila and Faecalibacterium prausnitzii, should further examine their therapeutic potential in this context.
... Elevated production of TMA and its subsequent conversion to TMAO is associated with the potential to accumulate in various tissues, exerting effects on multiple organs and systems within the body. This phenomenon, notably affecting the cardiovascular system and the liver, demonstrates an adverse correlation with gut dysbiosis (185,186). Prior research found an association between TMAO levels and the severity of depressive symptoms in both males and females. Overall, further study is needed to understand how the gut microbiota contributes to the neurocognitive advantages of TMA/TMAO in people with MDD. ...
Depression is considered a multifaceted and intricate mental disorder of growing concern due to its significant impact on global health issues. The human gut microbiota, also known as the “second brain,” has an important role in the CNS by regulating it through chemical, immunological, hormonal, and neurological processes. Various studies have found a significant bidirectional link between the brain and the gut, emphasizing the onset of depression therapies. The biological and molecular processes underlying depression and microbiota are required, as the bidirectional association may represent a novel study. However, profound insights into the stratification and diversity of the gut microbiota are still uncommon. This article investigates the emerging evidence of a bacterial relationship between the gut and the brain’s neurological system and its potential pathogenicity and relevance. The interplay of microbiota, immune system, nervous system neurotransmitter synthesis, and neuroplasticity transitions is also widely studied. The consequences of stress, dietary fibers, probiotics, prebiotics, and antibiotics on the GB axis are being studied. Multiple studies revealed the processes underlying this axis and led to the development of effective microbiota-based drugs for both prevention and treatment. Therefore, the results support the hypothesis that gut microbiota influences depression and provide a promising area of research for an improved knowledge of the etiology of the disease and future therapies.
... It is produced from foods rich in phosphatidylcholine and L-carnitine by the effect of intestinal microbial enzymes to produce trimethylamine (TMA), which is subsequently oxidized in the liver by flavin monooxygenase (FMO). 67 Currently, studies have shown that TMAO promotes atherosclerosis and there is a positive dose-dependent association between circulating TMAO levels and increased risk of diabetes. 68,69 TMAO can also promote the release of pro-inflammatory factors such as IL-6 and TNF-α in vivo by activating NF-κB, increasing the possibility of vascular r-associated inflammation. ...
Purpose of Review
The aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM.
Recent Findings
T2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized.
Summary
Dysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.
... The presence of high bacterial diversity in atherosclerotic plaques and the connection between microbiota and plaque stability have been confirmed. The development of atherosclerosis involves an initial damage to the endothelial cells, subsequent accumulation of lipids, and adherence of macrophages and other immune cells to the artery walls [134,135]. Atherosclerosis encompasses metabolic and inflammatory elements, both potentially affected by changes in the IM. The connection between IM and atherosclerosis was initially recognized through the detection of various bacterial DNA types within atherosclerotic plaques [134]. ...
... Atherosclerosis encompasses metabolic and inflammatory elements, both potentially affected by changes in the IM. The connection between IM and atherosclerosis was initially recognized through the detection of various bacterial DNA types within atherosclerotic plaques [134]. The Chryseomonas genus was present in all examined human atherosclerotic plaques, and Streptococcus was present in most samples. ...
Metabolic syndrome (MetS) is a combination of metabolic disorders that concurrently act as factors promoting systemic pathologies such as atherosclerosis or diabetes mellitus. It is now believed to encompass six main interacting conditions: visceral fat, imbalance of lipids (dyslipidemia), hypertension, insulin resistance (with or without impairing both glucose tolerance and fasting blood sugar), and inflammation. In the last 10 years, there has been a progressive interest through scientific research investigations conducted in the field of metabolomics, confirming a trend to evaluate the role of the metabolome, particularly the intestinal one. The intestinal microbiota (IM) is crucial due to the diversity of microorganisms and their abundance. Consequently, IM dysbiosis and its derivate toxic metabolites have been correlated with MetS. By intervening in these two factors (dysbiosis and consequently the metabolome), we can potentially prevent or slow down the clinical effects of the MetS process. This, in turn, may mitigate dysregulations of intestinal microbiota axes, such as the lung axis, thereby potentially alleviating the negative impact on respiratory pathology, such as the chronic obstructive pulmonary disease. However, the biomolecular mechanisms through which the IM influences the host's metabolism via a dysbiosis metabolome in both normal and pathological conditions are still unclear. In this study, we seek to provide a description of the knowledge to date of the IM and its metabolome and the factors that influence it. Furthermore, we analyze the interactions between the functions of the IM and the pathophysiology of major metabolic diseases via local and systemic metabolome's relate endotoxemia.
... Unfortunately, Griffin et al. [51] reported that a six-month Mediterranean-style dietary intervention was insufficient to reduce TMAO levels in a healthy population, and the authors recommended that interrupting the dietary conversion of TMA to TMAO should be considered. However, some scholars have proposed that species differences affecting gut microbiota composition may explain the findings [52]. Moreover, the short-term interventions presented in animal models are insufficient to induce remodeling of the gut microbiota formed by years of habituation; instead, dysbiosis occurs and increases TMAO levels [52,53]. ...
... However, some scholars have proposed that species differences affecting gut microbiota composition may explain the findings [52]. Moreover, the short-term interventions presented in animal models are insufficient to induce remodeling of the gut microbiota formed by years of habituation; instead, dysbiosis occurs and increases TMAO levels [52,53]. Interestingly, probiotic/prebiotic applications performed in human clinical and animal models effectively enhanced the abundance of probiotics in the intestines and significantly reduced TMA and TMAO metabolism, accompanied by other benefits such as decreased body weight, lipids, and cholesterol marker levels [52,54,55]. ...
... Moreover, the short-term interventions presented in animal models are insufficient to induce remodeling of the gut microbiota formed by years of habituation; instead, dysbiosis occurs and increases TMAO levels [52,53]. Interestingly, probiotic/prebiotic applications performed in human clinical and animal models effectively enhanced the abundance of probiotics in the intestines and significantly reduced TMA and TMAO metabolism, accompanied by other benefits such as decreased body weight, lipids, and cholesterol marker levels [52,54,55]. Probiotic supplementation alone completes the regulation of the gut microbiota, with improved lipid profiles and reduced inflammation [56][57][58][59]. ...
Resveratrol (RSV), obtained from dietary sources, has been shown to reduce trimethylamine oxide (TMAO) levels in humans, and much research indicates that TMAO is recognized as a risk factor for cardiovascular disease. Therefore, this study investigated the effects of RSV and RSV-butyrate esters (RBE) on the proliferation of co-cultured bacteria and HepG2 cell lines, respectively, and also investigated the changes in trimethylamine (TMA) and TMOA content in the medium and flavin-containing monooxygenase-3 (FMO3) gene expression. This study revealed that 50 µg/mL of RBE could increase the population percentage of Bifidobacterium longum at a rate of 53%, while the rate was 48% for Clostridium asparagiforme. In contrast, co-cultivation of the two bacterial strains effectively reduced TMA levels from 561 ppm to 449 ppm. In addition, regarding TMA-induced HepG2 cell lines, treatment with 50 μM each of RBE, 3,4′-di-O-butanoylresveratrol (ED2), and 3-O-butanoylresveratrol (ED4) significantly reduced FMO3 gene expression from 2.13 to 0.40–1.40, which would also contribute to the reduction of TMAO content. This study demonstrated the potential of RBE, ED2, and ED4 for regulating TMA metabolism in microbial co-cultures and cell line cultures, which also suggests that the resveratrol derivative might be a daily dietary supplement that will be beneficial for health promotion in the future.
... Most studies have suggested that a higher intake or higher plasma levels of carnitine, betaine, and choline may improve fatty liver and liver damage, including NAFLD [25,26]. However, intake of carnitine, betaine, and choline can elevate TMAO levels, which increases the risks of developing associated diseases [27]. Our results suggest that the elevated levels of TMAO and its precursors in the serum are associated with the progression of ALD. ...
Without early detection and treatment, chronic and excessive alcohol consumption can lead to the development of alcoholic liver disease (ALD). With this in mind, we exploit the recent concept of the liver–gut axis and analyze the serum profile of ALD patients for identification of microbiome-derived metabolites that can be used as diagnostic biomarkers for onset of ALD. 1H-NMR was used to analyze serum metabolites of 38 ALD patients that were grouped according to their Child–Turcotte–Pugh scores (CTP): class A (CTP-A; 19), class B(CTP-B; 10), and class C (CTP-C; 9). A partial least squares-discriminant analysis (PLS-DA) and a variable importance of projection (VIP) score were used to identify significant metabolites. A receiver operating characteristic (ROC) curve and correlation heatmap were used to evaluate the predictability of identified metabolites as ALD biomarkers. Among 42 identified metabolites, 6 were significantly correlated to exacerbation of ALD. As ALD progressed in CTP-C, the levels of trimethylamine N-oxide (TMAO), malate, tyrosine, and 2-hydroxyisovalerate increased, while isobutyrate and isocitrate decreased. Out of six metabolites, elevated levels of TMAO and its precursors (carnitine, betaine, choline) were associated with severity of ALD. This indicates that TMAO can be used as an effective biomarker for the diagnosis of ALD progression.
