Gut Microbiota-related Metabolites Research Articles

Investigating the Influence of Gut Microbiota-related Metabolites in Gastrointestinal Cancer.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets.

Polysaccharides of Aspergillus cristatus attenuate obesity by regulating gut microbiota and gut microbiota-related metabolites

Golden-flower fungus, the only dominant microorganism determining the Fu-brick tea quality through fermentation and the important microbe in Liupao tea, is considered a potential probiotic fungus based on its anti-obesity effect. However, the classification of golden-flower fungi is still controversial; the anti-obesity effect of golden-flower fungus polysaccharides remains unknown. In this study, we identify a golden-flower strain as Aspergillus cristatus based on morphological characteristics and multigene phylogeny analysis, which resolves the controversy of classification. Moreover, we find A. cristatus polysaccharides (ACPS) attenuate obesity in rats. ACPS modulate gut bacterial composition, in which Akkermansia, Akkermansia muciniphila, Bacteroides, Romboutsia, Blautia, and Desulfovibrio are considered the core microbes regulated by ACPS. ACPS increase fecal total short-chain fatty acid content and serum, hepatic, and fecal total bile acid content. Furthermore, ACPS-induced gut microbiota alteration plays a causal role in the protection from obesity, according to a fecal transplantation experiment. Thus, ACPS ameliorate obesity by regulating gut microbiota and gut microbiota-related metabolites.

Association of Gut Microbiota-Related Metabolites and Type 2 Diabetes in Two Puerto Rican Cohorts.

(1) Aims: Gut microbiota metabolites may play integral roles in human metabolism and disease progression. However, evidence for associations between metabolites and cardiometabolic risk factors is sparse, especially in high-risk Hispanic populations. We aimed to evaluate the cross-sectional and longitudinal relationships between gut microbiota related metabolites and measures of glycemia, dyslipidemia, adiposity, and incident type 2 diabetes in two Hispanic observational cohorts. (2) Methods: We included data from 670 participants of the Boston Puerto Rican Health Study (BPRHS) and 999 participants of the San Juan Overweight Adult Longitudinal Study (SOALS). Questionnaires and clinical examinations were conducted over 3 years of follow-up for SOALS and 6 years of follow-up for BPRHS. Plasma metabolites, including L-carnitine, betaine, choline, and trimethylamine N-oxide (TMAO), were measured at baseline in both studies. We used multivariable linear models to evaluate the associations between metabolites and cardiometabolic risk factors and multivariable logistic and Poisson regressions to assess associations with prevalent and incident type 2 diabetes, adjusted for potential confounding factors. Cohort-specific analyses were combined using a fixed-effects meta-analysis. (3) Results: Higher plasma betaine was prospectively associated with lower fasting glucose [-0.97 mg/dL (95% CI: -1.59, -0.34), p = 0.002], lower HbA1c [-0.02% (95% CI: -0.04, -0.01), p = 0.01], lower HOMA-IR [-0.14 (95% CI: -0.23, -0.05), p = 0.003], and lower fasting insulin [-0.27 mcU/mL (95% CI: -0.51, -0.03), p = 0.02]. Betaine was also associated with a 22% lower incidence of type 2 diabetes (IRR: 0.78, 95% CI: 0.65, 0.95). L-carnitine was associated with lower fasting glucose [-0.68 mg/dL (95% CI: -1.29, -0.07), p = 0.03] and lower HbA1c at follow-up [-0.03% (95% CI: -0.05, -0.01), p < 0.001], while TMAO was associated with higher fasting glucose [0.83 mg/dL (95% CI: 0.22, 1.44), p = 0.01] and higher triglycerides [3.52 mg/dL (95% CI: 1.83, 5.20), p < 0.0001]. Neither choline nor TMAO were associated with incident type 2 diabetes. (4) Conclusions: Higher plasma betaine showed consistent associations with a lower risk of glycemia, insulinemia, and type 2 diabetes. However, TMAO, a metabolite of betaine, was associated with higher glucose and lipid concentrations. These observations demonstrate the importance of gut microbiota metabolites for human cardiometabolic health.

Strategy for Comprehensive Detection and Annotation of Gut Microbiota-Related Metabolites Based on Liquid Chromatography-High-Resolution Mass Spectrometry.

Gut microbiota, widely populating the mammalian gastrointestinal tract, plays an important role in regulating diverse pathophysiological processes by producing bioactive molecules. Extensive detection of these molecules contributes to probing microbiota function but is limited by insufficient identification of existing analytical methods. In this study, a systematic strategy was proposed to detect and annotate gut microbiota-related metabolites on a large scale. A pentafluorophenyl (PFP) column-based liquid chromatography-high-resolution mass spectrometry (LC-HRMS) method was first developed for high-coverage analysis of gut microbiota-related metabolites, which was verified to be stable and robust with a wide linearity range, high sensitivity, satisfactory recovery, and repeatability. Then, an informative database integrating 968 knowledge-based microbiota-related metabolites and 282 sample-sourced ones defined by germ-free (GF)/antibiotic-treated (ABX) models was constructed and subsequently used for targeted extraction and annotation in biological samples. Using pooled feces, plasma, and urine of mice for demonstration application, 672 microbiota-related metabolites were annotated, including 21% neglected by routine nontargeted peak detection. This strategy serves as a useful tool for the comprehensive capture of the intestinal flora metabolome, contributing to our deeper understanding of microbe-host interactions.

Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with Toxoplasma gondii

BackgroundOral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism.ResultsThere were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus.ConclusionsThe present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection.5uvpHNDACknu2usY1bpcjuVideo

Butyrate alleviates renal fibrosis in CKD by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway

Chronic kidney disease (CKD) is a serious and irreversible disease primarily characterized by chronic inflammation and renal fibrosis. Recent studies have suggested that gut microbiota-related metabolites, particularly short-chain fatty acids (SCFAs) are significantly associated with kidney diseases. Notably, butyrate, a type of SCFAs, plays a crucial role in this correlation. However, the effect of butyrate on renal fibrosis in patients with CKD and its potential mechanisms remain unclear. In this study, we demonstrated that butyrate levels are reduced as CKD progresses using a CKD C57BL/6 mouse model established by a 0.2% adenine diet. Exogenous supplementation of butyrate effectively alleviated renal fibrosis and repressed the levels of proteins associated with NLRP3-mediated pyroptosis (NLRP3, IL-1β, caspase-1, and GSDMD). Additionally, we conducted an in vitro experiment using HK-2 cells, which also confirmed that the elevated levels of NLRP3-mediated pyroptosis proteins in TGF-β1-stimulated HK-2 cells are reversed by butyrate intervention. Further, butyrate mitigated the activity of the STING/NF-κB/p65 pathway, and STING overexpression impaired the protective function of butyrate in CKD. Hence, we suggest that butyrate may have a renoprotective role in CKD, alleviating renal fibrosis possibly by regulating NLRP3-mediated pyroptosis via the STING/NF-κB/p65 pathway.

Fermented soybean foods and diabetes.

The number of patients with type 2 diabetes mellitus is increasing, and its prevention and management are important. One of the factors contributing to the increased incidence of type 2 diabetes mellitus is the change in dietary habits, including a Westernized diet. Fermented foods are foods that are transformed by the action of microorganisms to produce beneficial effects in humans and have been consumed for thousands of years. The production and consumption of fermented soy foods, including natto, miso, douchi, cheonggukjang, doenjang, tempeh, and fermented soy milk, are widespread in Asian countries. This review focuses on fermented soybean foods and summarizes their effects on diabetes. Fermentation increases the content of ingredients originally contained in soybeans and adds new ingredients that are not present in the original soybeans. Recent studies have revealed that fermented soybean food modifies the gut microbiota-related metabolites by modifying dysbiosis. Furthermore, it has been reported that fermented soybean foods have antioxidant, anti-inflammatory, and anti-diabetic effects. In recent years, fermented foods, including fermented soybeans, have shown various beneficial effects. Therefore, it is necessary to continue focusing on the benefits and mechanisms of action of fermented foods.

Gut microbiota related response of Oryzias melastigma to combined exposure of polystyrene microplastics and tetracycline

The co-existence of microplastics (MPs) and antibiotics in the coastal environment poses a combined ecological risk. Single toxic effects of MPs or antibiotics on aquatic organisms have been verified, however, the exploration of their combined toxic effects remains limited. Here, foodborne polystyrene microplastics (PS-MPs, 10 μm, 0.1 % w/w in food) and waterborne tetracyclines (TC, 50 μg/L) were used to expose an estuarine fish Oryzias melastigma for four weeks. We found that the aqueous availability of TC was not significantly altered coexisting with MPs. The fish body weight gain was significantly slower in TC alone or combined groups than the control group, consistent with the lower lipid content in livers. The body length gain was significantly inhibited by the combined presence compared to the single exposure. Both exposures led to a shift of gut microbiota composition and diversity. TC and the combined group possessed similar gut microbiota which is distinct from PS-MPs and the control group. The Firmicutes/Bacteroidetes (F/B) ratio in the TC and combined groups were significantly lower compared to the control, while the PS-MPs group showed no significant impact. Metabolomic analysis of the fish liver confirmed the shift of metabolites in specific pathways after different exposures. More, a number of gut microbiota-related metabolites on lipid metabolism was perturbed, which were annotated in arachidonic acid metabolism and linoleic acid metabolism. In all, TC modulates bacterial composition in the fish gut and disturbs their liver metabolites via the gut-liver axis, which led to the slower growth of O. melastigma. More, the adverse impact was aggravated by the co-exposure to foodborne PS-MPs.

Aromatic Amino Acids and Their Interactions with Gut Microbiota-Related Metabolites for Risk of Gestational Diabetes: A Prospective Nested Case-Control Study in a Chinese Cohort

Introduction: The aim of this study was to explore associations of aromatic amino acids (AAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high AAA and gut microbiota-related metabolites had interactive effects on GDM risk. Methods: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women from 2010 to 2012. According to the International Association of Diabetes and Pregnancy Study Group’s criteria, 243 women were diagnosed with GDM. Binary conditional logistic regression was performed to examine associations of AAA with GDM risk. Interactions between AAA and gut microbiota-related metabolites for GDM were examined using additive interaction measures. Results: High phenylalanine and tryptophan were associated with increased GDM risk (OR: 1.72, 95% CI: 1.07–2.78 and 1.66, 1.02–2.71). The presence of high trimethylamine (TMA) markedly increased the OR of high phenylalanine alone up to 7.95 (2.79–22.71), while the presence of low glycoursodeoxycholic acid (GUDCA) markedly increased the OR of high tryptophan alone up to 22.88 (5.28–99.26), both with significant additive interactions. Furthermore, high lysophosphatidylcholines (LPC18:0) mediated both interactive effects. Conclusions: High phenylalanine may have an additive interaction with high TMA, while high tryptophan may have an additive interaction with low GUDCA toward increased risk of GDM, both being mediated via LPC18:0.

Polysaccharides from Fu brick tea ameliorate obesity by modulating gut microbiota and gut microbiota-related short chain fatty acid and amino acid metabolism

Fu brick tea (FBT) is a traditional tea manufactured by solid-state fermentation of tea leaves (Camellia sinensis). Although anti-obesity effects have been reported for FBT, the associated role of FBT polysaccharides (PSs) and the underlying mechanisms remain unknown. In this study, we found that FBTPSs inhibited obesity, hyperlipidemia, and inflammation; improved intestinal barrier function; and alleviated gut microbiota dysbiosis in high-fat diet-fed rats. Akkermansia muciniphila, Bacteroides, Parasutterella, Desulfovibrio, and Blautia were the core microbes regulated by FBTPSs. FBTPSs regulated the production of gut microbiota-related metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids, and aromatic amino acids throughout the development of obesity, and regulated the SCFA-GPR signaling pathway. FBTPS-treated fecal microbiota transplant ameliorated obesity, alleviated gut microbiota dysbiosis, and improved gut microbiota-associated metabolites, suggesting that the anti-obesity effect of FBTPSs was gut microbiota-dependent. FBTPSs may serve as novel prebiotic agents for the treatment of obesity and dysbiosis of gut microbiota.

Cord serum metabolic signatures of future progression to immune-mediated diseases.

Previous prospective studies suggest that progression to autoimmune diseases is preceded by metabolic dysregulation, but it is not clear which metabolic changes are disease-specific and which are common across multiple immune-mediated diseases. Here we investigated metabolic profiles in cord serum in a general population cohort (All Babies In Southeast Sweden; ABIS), comprising infants who progressed to one or more immune-mediated diseases later in life: type 1 diabetes (n= 12), celiac disease (n= 28), juvenile idiopathic arthritis (n= 9), inflammatory bowel disease (n= 7), and hypothyroidism (n= 6); and matched controls (n= 270). We observed elevated levels of multiple triacylglycerols (TGs) an alteration in several gut microbiota related metabolites in the autoimmune groups. The most distinct differences were observed in those infants who later developed HT. The specific similarities observed in metabolic profiles across autoimmune diseases suggest that they share specific common metabolic phenotypes at birth that contrast with those of healthy controls.

Abstract MP23: Circulating Gut Microbiota-Related Metabolites and Risk of Coronary Heart Disease: A Prospective, Multiethnic, Metabolomic Study

Introduction: Despite the importance of gut microbiota in human cardiometabolic health, the associations between circulating levels of gut microbiota-related metabolites and incident coronary heart disease (CHD) remain largely unexplored. Hypothesis: Certain circulating microbial metabolites are associated with incident CHD. Methods: This is a multi-stage and multiethnic metabolomics study. We first conducted a global, semi-quantitative assay for discovery among 900 incident CHD cases and 900 age-/sex-/race-matched controls (300 pairs of Black Americans, White Americans, and Chinese adults, respectively) selected from the Southern Community Cohort Study and Shanghai Men’s and Women’s Health Studies. We focused on 226 metabolites that were potentially related to gut microbiota and applied conditional logistic regression to estimate odds ratios (ORs) of CHD associated with a 1-SD increase of log-transformed metabolites adjusting for traditional CHD risk factors. Then, an in-silico validation was conducted using existing metabolites data of 9,264 participants from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study. Results: In the discovery stage, we identified 73 named microbial metabolites related to incident CHD risk with a false discovery rate&lt;0.10 or nominal p &lt;0.05 and a large effect size (ORs &gt;1.5 or &lt;0.5). These metabolites were from super pathways of amino acids (n=28), lipids (n=24), nucleotides (n=6), carbohydrates (n=4), energy (n=4), xenobiotics (n=4), and cofactors/vitamins (n=3). Of them, 61 metabolites were available for the in-silico validation, and 30 showed a significant association ( p &lt;0.05) with the same direction as the discovery results. After further adjustments for established CHD risk factors (e.g., glucose and LDL-cholesterol), 25 metabolites remained significant. A 14%-48% increased risk was observed for N-acetylglutamate (OR=1.48), sphingomyelin (1.42), imidazole propionate (1.37), hypoxanthine (1.29), guaiacol sulfate (1.28), glutamate (1.22), 2-hydroxyphenylacetate (1.20), 3-hydroxybutyrate (1.19), 3-hydroxy-2-ethylpropionate (1.17), 1-methyl-4-imidazoleacetate (1.16), urea (1.16), urate (1.16), 4-hydroxyphenylacetate (1.15), choline (1.15), isoleucine (1.14), and glycerol (1.14). Meanwhile, a significant inverse association was found for taurine (OR=0.64), asparagine (0.75), serotonin (0.78), histidine (0.79), threonine (0.81), glutamine (0.83), glycine (0.84), oxalate (0.85), and N-methylproline (0.89). Conclusions: Among ethnically and geographically diverse populations, we identified and validated some circulating gut microbiota-related metabolites as potential novel biomarkers for incident CHD. Targeted quantitative assays to confirm these results are ongoing, which are essential to inform potential clinical utility.

Abstract MP24: Atherogenic Gut Microbial Metabolite Scores and Risk of Coronary Heart Disease Among Women in the Nurses’ Health Study

Introduction: Recent evidence suggests that dietary proteins modulate the microbial composition and metabolite production to influence host physiology. Gut-microbiota-related metabolites, such as trimethylamine N-oxide (TMAO) and its precursors, phenylacetylglutamine (PAGln) and p-tolyl (cresol) sulfate, have been recently implicated as atherogenic metabolites derived from the microbial metabolism of protein foods (such as red meat) and amino acids. Hypothesis: We tested a hypothesis that combined effects of atherogenic gut microbiota-related metabolites may be strongly related to the risk of incident coronary heart disease (CHD) among women. Methods: We conducted a prospective nested case-control study of 762 incident cases of CHD (fatal CHD and nonfatal myocardial infarction) and 762 matched controls identified over 10-14 years of follow-up. Plasma metabolites (TMAO, N,N,N-trimethyllysine, PAGln, and p-tolyl (cresol) sulfate) were measured at baseline. We regressed the CHD outcome against metabolites using conditional logistic regression and then calculated an atherogenic microbial metabolite score (AMMS) of CHD by summing the β effects of metabolites. Results: Every 1 SD increment of AMMS was associated with a matching factor-adjusted RR of 1.28 (95% CI: 1.15, 1.44) and a multivariable-adjusted RR of 1.26 (1.12, 1.42) for CHD controlling for demographic, dietary, and lifestyle factors, postmenopausal hormone use, and body mass index. Dose-response analysis showed a linear relation between AMMS and the risk of CHD ( P &lt;0.001). In addition, there was a 1.20 (1.06, 1.36) times increased risk of CHD per 1 SD of AMMS after adjusting for common metabolic comorbidities (diabetes, hypertension, and dyslipidemia). The highest quintile (Q5) group had an adjusted RR of 1.60 (1.08, 2.37) for CHD, as compared to the lowest quintile (Q1) ( Fig ). Conclusions: Atherogenic gut microbiota-related metabolite scores were significantly associated with risk of incident CHD among women without prior CHD.

Maternal Betaine Supplementation Mitigates Maternal High Fat Diet-Induced NAFLD in Offspring Mice through Gut Microbiota

Maternal betaine supplementation has been proven to alleviate non-alcoholic fatty liver disease (NAFLD) in offspring caused by maternal high-fat diet (MHFD). The gut-liver axis plays an important role in NAFLD pathogenesis. However, whether maternal betaine supplementation can alleviate NAFLD in offspring by the gut-liver axis is unknown. C57BL/6J mice were fed with high-fat diet for 4 weeks before mating, and supplemented with 1% betaine during pregnancy and lactation. After weaning, offspring mice were fed with standard diet to 10 weeks. Maternal betaine supplementation reduced hepatic triglyceride content and alleviated hepatic steatosis in offspring mice exposed to MHFD. Furthermore, the mRNA expression of PPARα, CPT1α and FATP2 was increased and TNFα was reduced by maternal betaine supplementation. Maternal betaine intake decreased the relative abundances of Proteobateria, Desulfovibrio and Ruminococcus, but increased the relative abundances of Bacteroides and Parabacteroides. Moreover, maternal betaine intake increased the concentrations of short-chain fatty acids (SCFAs), including acetic acid, butyric acid and valeric acid, in the feces. Gut microbiota and SCFAs were significantly correlated with hepatic triglyceride content and expression of the above genes. Maternal betaine intake had no effect on other gut microbiota-related metabolites (bile acid and trimethylamine-n-oxide). Altogether, maternal betaine supplementation ameliorated MHFD-induced NAFLD possibly through regulating gut microbiota and SCFAs in offspring mice.

Gut-Bile Acid-Immune Axis Regulates T Cell Homeostasis in the Pathogenesis of Immune Thrombocytopenia

Introduction Immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease characterized by isolated thrombocytopenia. In a previous study, we observed dysbiosis in the phylogenetic composition and function of the gut microbiome of patients with ITP [Sci China Life Sci, 2020]. It is suggested that impaired intestinal barrier as well as the gut microbiota-related metabolites may provide signaling molecules and facilitate communication between the intestinal tract and the immune system. For example, bile acids (BAs), which are synthesized in the liver and transformed into secondary BAs in the gut, have recently been considered to be important signaling metabolites for the immune system. The bile acid receptor FXR can also inhibit the TLR4/MAPK pathway and participate in the regulation of the immune response. Here, we provide evidence that the gut-bile acid-immune axis plays a role in the pathogenesis of ITP and that obeticholic acid (OCA) treatment can repair the gut barrier and restore the gut-bile acid balance to reduce the destruction of platelets. Methods After establishing an active ITP mouse model, pathological analyses of biopsies, 16S amplicon sequencing, targeted bile acid metabolomics and real-time fluorescent quantitative PCR were used to explore the changes in intestinal barrier function, gut microbiota composition, and bile acid metabolites in feces and plasma. OCA treatment of the ITP mouse model and bone marrow-derived dendritic cells was used to investigate the effect of OCA on gut bile acid metabolism and T cell differentiation. In a clinical sample study, 65 treatment-naïve ITP patients and 62 healthy controls were enrolled. Metagenomic sequencing, bile acid-targeted metabolomics and mass cytometry were used to explore the characteristics of the "gut-bile acid-immune” axis in the ITP patients. Results In the mouse model of ITP, the gut barrier was damaged, as shown by exfoliation of IECs according to H&E staining and greater FITC-dextran leakage from the intestinal mucosa into the peripheral circulation. RNA sequencing of the IEC transcriptome revealed that the expression of claudin-4 and claudin-8 was significantly diminished in ITP mice. As a result of the impaired gut barrier, plasma levels of LPS were elevated in ITP mice. Moreover, the Firmicutes:Bacteroidetes ratio was elevated in the gut microbiota according to 16S amplicon sequencing, and increased fecal levels of BAs were observed, which gave priority to primary BAs like β-MCA. The accumulation of β-MCA, which is an FXR antagonist, inhibited the activity of FXR in IECs, hepatocytes and immune cells such as DCs. After stimulation with LPS in vitro, murine bone marrow-derived DCs were observed to induce greater Th1 differentiation, which could be reversed by an FXR agonist (GW4064 or OCA). The secretion of IL-12 by DCs induced Th1 differentiation and was regulated by the TLR4/MAPK/p38 pathway, and this effect was inhibited by OCA through the activation of FXR. In vivo, OCA increased the expression of claudin-4 and claudin-8, and restored the balance of bile acid metabolism in the mice with ITP. After OCA treatment, the Th1/Th2 imbalance in the bone marrow of the mice with ITP was corrected, and reduced platelet destruction in the spleen and liver was observed with an in vivo imaging system. Clinical studies have shown that the gut microbiota in ITP patients is dysregulated, which showed an increased abundance of Firmicutes. Scanning electron microscopy showed that the gaps between IECs were increased in the ITP patients. The bile acid pool of the ITP patients was shown to have an increased proportion of primary BAs in the bone marrow. After in vitro treatment with OCA for 72 h, the proportion of human Th1 cells among human bone marrow mononuclear cells was significantly reduced, which suggested the therapeutic effect of OCA in ITP patients. Conclusions This study preliminarily revealed the characteristics of the "gut-bile acid-immune” axis in ITP patients and a mouse model. In vitro and in vivo studies confirmed that OCA could repair the intestinal barrier, correct gut microbiota dysbiosis and bile acid metabolism abnormalities, and decrease the proportion of peripheral Th1 cells via MAPK signaling in DCs, resulting in a decrease in the excessive destruction of platelets. This study provides a theoretical basis for targeting the gut microbiota in the clinical treatment of ITP.

Update on gut microbiota in cardiovascular diseases.

In recent years, due to the development and widespread utilization of metagenomic sequencing and metabolomics, the relationship between gut microbiota and human cardiovascular diseases (CVDs) has received extensive attention. A growing number of studies have shown a strong relationship between gut microbiota and CVDs, such as coronary atherosclerosis, hypertension (HTN) and heart failure (HF). It has also been revealed that intestinal flora-related metabolites, such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFA) and bile acids (BAs), are also related to the development, prevention, treatment and prognosis of CVDs. In this review, we presented and summarized the recent findings on the relationship between gut microbiota and CVDs, and concluded several currently known gut microbiota-related metabolites and the occurrence and development of CVDs.

Habitual intakes of sugar-sweetened beverages associated with gut microbiota-related metabolites and metabolic health outcomes in young Chinese adults

Background and aimsReducing consumption of sugar-sweetened beverages (SSBs) is a global public health priority because of their limited nutritional value and associations with increased risk of obesity and metabolic diseases. Gut microbiota-related metabolites emerged as quintessential effectors that may mediate impacts of dietary exposures on the modulation of host commensal microbiome and physiological status. Methods and resultsThis study assessed the associations among SSBs, circulating microbial metabolites, and gut microbiota–host co-metabolites, as well as metabolic health outcomes in young Chinese adults (n = 86), from the Carbohydrate Alternatives and Metabolic Phenotypes study in Shaanxi Province. Five principal component analysis-derived beverage drinking patterns were determined on self-reported SSB intakes, which were to a varying degree associated with 143 plasma levels of gut microbiota-related metabolites profiled by untargeted metabolomics. Moreover, carbonated beverages, fruit juice, energy drinks, and bubble tea exhibited positive associations with obesity-related markers and blood lipids, which were further validated in an independent cohort of 16,851 participants from the Regional Ethnic Cohort Study in Northwest China in Shaanxi Province. In contrast, presweetened coffee was negatively associated with the obesity-related traits. A total of 79 metabolites were associated with both SSBs and metabolic markers, particularly obesity markers. Pathway enrichment analysis identified the branched-chain amino acid catabolism and aminoacyl-tRNA biosynthesis as linking SSB intake with metabolic health outcomes. ConclusionOur findings demonstrate the associations between habitual intakes of SSBs and several metabolic markers relevant to noncommunicable diseases, and highlight the critical involvement of gut microbiota-related metabolites in mediating such associations.

Integrated 16S rRNA sequencing and metabolomics analysis to investigate the antidepressant role of Yang-Xin-Jie-Yu decoction on microbe-gut-metabolite in chronic unpredictable mild stress-induced depression rat model.

Objectives: Our goals were to evaluate the antidepressant efficacy of Yang-Xin-Jie-Yu Decoction (YXJYD) in Chronic Unpredictable Mild Stress (CUMS)-induced depression rat model and to investigate the underlying mechanisms. Design: We used CUMS-induced depression rat model to evaluate whether oral administration of YXJYD with different doses (2.1 g/kg, 1.05 g/kg and 0.525 g/kg, respectively) improve the depressive-like symptoms, and then performed UHPLC-Q-TOF-MS to explore the active ingredients of YXJYD. Subsequently, rat’s cecal contents, serum, and urine were collected from the control group, CUMS model group, and YXJYD high-dose (2.1 g/kg) treatment group. The 16S rRNA sequencing was performed on the cecal contents, based on Illumina MiSeq platform, and ANOVA analysis were used to analyze the composition variety and screen differential expression of gut bacteria in the three groups. 1H Nuclear Magnetic Resonance (NMR) analysis was used for analyzing the metabolites obtained from cecal contents, serum, and urine, and KEGG enrichment analysis was used to identify pathways of differential metabolites. An integrated 16S rRNA sequencing and metabolomic data were conducted to characterize the underlying mechanisms of YXJYD Results: The gut microbial communities, and serum, cecal content, urine metabolic compositions were significantly significantly altered in CUMS-induced depressive rats, while YXJYD effectively ameliorated the CUMS-associated gut microbiota dysbiosis, especially of Monoglobus, and alleviated the disturbance of serum, cecal content, urine metabolome and reversed the changes of key depressive and gut microbiota-related metabolites, such as succinic acid, taurine, hippuric acid, melatonin. With an integrated study of the gut microbiota and metabolomes, we identified the pathway of tricarboxylic acid cycle (TCA cycle) and propanoate metabolism as the regulated target of YXJYD on host-microbiome interaction. Conclusion: Our findings further confirmed the imbalance of metabolism and intestinal microbial is closely related to CUMS-induced depression. YXJYD regulates gut microbiome to affect body metabolomes and then produce antidepressant-like effect in CUMS-induced depressive rats while its molecular mechanism possibly be increased Monoglobus abundance in gut microbiota and regulated the TCA cycle pathway and propanoate metabolism in host.

Elucidation of Anti-Hypertensive Mechanism by a Novel Lactobacillus rhamnosus AC1 Fermented Soymilk in the Deoxycorticosterone Acetate-Salt Hypertensive Rats.

Dietary intake of fermented soymilk is associated with hypotensive effects, but the mechanisms involved have not been fully elucidated. We investigated the anti-hypertensive effects of soymilk fermented by L. rhamnosus AC1 on DOCA-salt hypertension from the point of view of oxidative stress, inflammatory response and alteration of the gut microbiome. The antioxidant assays in vitro indicated the ethanol extract (EE) of L. rhamnosus AC1 fermented soymilk showed better antioxidative effects than the water extract (WE). Those extracts displayed a hypotensive effect using a tail-cuff approach to measuring blood pressure and improved nitric oxide (NO), angiotensin II (Ang II), tumor necrosis factor-α (TNF-α) and interleukin factor-6 (IL-6) on DOCA-salt hypertensive rats. Furthermore, cardiac and renal fibrosis were attenuated by those extracts. The gut microbiota analysis revealed that they significantly reduced the abundance of phylum Proteobacteria, its family Enterobacteriaceae and genus Escherichia-Shigella. Moreover, metabolomic profiling revealed several potential gut microbiota-related metabolites which appeared to involve in the development and recovery of hypertension. In conclusion, fermented soymilk is a promising nutritional intervention strategy to improve hypertension via reducing inflammation and reverting dysbiotic microbiota.

Changes in Plasma Choline and the Betaine-to-Choline Ratio in Response to 6-Month Lifestyle Intervention Are Associated with the Changes of Lipid Profiles and Intestinal Microbiota: The ICAAN Study.

Trimethylamine N-oxide (TMAO) and its precursors, including choline, betaine, and L-carnitine, are gut microbiota-related metabolites associated with the risk of obesity. We aimed (1) to comprehensively examine whether the changes in plasma TMAO and its precursors induced by lifestyle intervention are associated with the improvements in plasma metabolic parameters; and (2) to identify the fecal microbiome profiles and nutrient intakes associated with these metabolites and metabolic index. Data from 40 participants (obese children and adolescents) having the plasma metabolites data related to the changes in BMI z-scores after 6-month lifestyle intervention were analyzed. In this study, we observed that choline and the betaine-to-choline ratio (B/C) showed different patterns depending on the changes in BMI z-scores by the response to lifestyle intervention. During the 6 months, an increase in choline and a decrease in B/C were observed in non-responders. We also found that changes in choline and B/C were associated with the improvements in plasma lipid levels. Individuals who showed reduced choline or increased B/C from the baseline to 6 months had a significant decrease in LDL-cholesterol over 6 months compared to those with increased choline or decreased B/C, respectively. In addition, the increase in choline or decrease in B/C was associated with the increase in plasma triglycerides. The distribution of gut microbiota belonging to the Firmicutes, such as Clostridia, Clostridiales, Peptostreptococcaceae, Romboutsia, and Romboutsia timonensis was altered to be lower during the 6 months both as choline decreased and B/C increased. Moreover, the decrease in choline and the increase in B/C were associated with reduced fat intake and increased fiber intake after the 6-month intervention. Finally, lower abundance of Romboutsia showed the association with lower LDL-cholesterol and higher intake of fiber. In summary, we demonstrated that reduced choline and increased B/C by lifestyle intervention were associated with the improvements of LDL-cholesterol and triglycerides, low-fat and high-fiber intakes, and low abundance of Firmicutes. These indicate that changes to circulating choline and B/C could predict individuals’ changes in metabolic compositions in response to the lifestyle intervention.