Maternal regulation of biliary disease in neonates via gut microbial metabolites.
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ABSTRACT:
SUBMITTER: Jee JJ
PROVIDER: S-EPMC8748778 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:<p>Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn’s susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.</p>
2022-01-11 | MTBLS2171 | MetaboLights
Project description:The gut microbiome plays major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens1-3, including enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea, and acute renal failure (hemolytic uremic syndrome)4,5. Although gut microbes can provide colonization resistance by outcompeting some pathogens or modulating host defense provided by the gut barrier and intestinal immune cells, this phenomenon remains poorly understood. Emerging evidence suggests that small-molecule metabolites produced by the gut microbiota may mediate this process6. Here, we show that tryptophan (Trp)-derived metabolites produced by the gut bacteria protect the host against Citrobacter rodentium, a murine AE pathogen widely used as a model for EHEC infection7,8, by activation of the host neurotransmitter dopamine receptor D2 (DRD2) within the intestinal epithelium. We further find that these Trp metabolites act through DRD2 to decrease expression of a host actin regulatory protein involved in C. rodentium and EHEC attachment to the gut epithelium via formation of actin pedestals. Previously identified mechanisms of colonization resistance either directly affect the pathogen by competitive exclusion or indirectly by modulation of host defense mechanisms9,10, so our results delineate a noncanonical colonization resistance pathway against AE pathogens featuring an unconventional role for DRD2 outside the nervous system in controlling actin cytoskeletal organization within the gut epithelium. Our findings may inspire prophylactic and therapeutic approaches for improving gut health and treating gastrointestinal infections, which afflict millions globally.
| S-EPMC10055168 | biostudies-literature
Project description:Background and aimsBiliary atresia is the most common cause of liver disease and liver transplantation in children. The accumulation of bile acids in hepatocytes and the stimulation of the intestinal microbiome can aggravate the disease progression. This study investigated changes in the composition of the gut microbiota and its metabolites in biliary atresia and the possible effects of these changes on disease progression.MethodsStool samples of biliary atresia at different disease stages and matched control individuals were collected (early stage: 16 patients, 16 controls; later stage: 16 patients, 10 controls). Metagenomic sequencing was performed to evaluate the gut microbiota structure. Untargeted metabolomics was performed to detect and analyze the metabolites and bile acid composition.ResultsA disturbed gut microbiota structure occurred in the early and later stages of biliary atresia. Klebsiella, Streptococcus, Veillonella, and Enterococcus have always been dominant. The abundance of V. atypica displayed significant changes between the early and later stages of biliary atresia. Combined with clinical indicators, Spearman's analysis showed that Klebsiella and Veillonella atypica strongly correlated with liver enzymes. Enterococcus faecium had an enormously positive relationship with lithocholic acid derivatives. Metabolites involved in tryptophan metabolism were changed in the patients with biliary atresia, which had a significant association with stool V. atypica and blood total bilirubin (p < 0.05).ConclusionsThe liver damage of biliary atresia was directly or indirectly exacerbated by the interaction of enriched Klebsiella (K. pneumoniae), Veillonella (V. atypica), and Enterococcus (E. faecium) with dysmetabolism of tryptophan and bile acid.
| S-EPMC8495239 | biostudies-literature
Project description:Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites-indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde-which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.
| S-EPMC7431026 | biostudies-literature
Project description:Over the past two decades, non-alcoholic fatty liver disease (NAFLD) has become a leading burden of hepatocellular carcinoma and liver transplantation. Although the exact pathogenesis of NAFLD has not been fully elucidated, recent hypotheses placed more emphasis on the crucial role of the gut microbiome and its derivatives. Reportedly, microbial metabolites such as short-chain fatty acids, amino acid metabolites (indole and its derivatives), bile acids (BAs), trimethylamine N-oxide (TMAO), and endogenous ethanol exhibit sophisticated bioactive properties. These molecules regulate host lipid, glucose, and BAs metabolic homeostasis via modulating nutrient absorption, energy expenditure, inflammation, and the neuroendocrine axis. Consequently, a broad range of research has studied the therapeutic effects of microbiota-derived metabolites. In this review, we explore the interaction of microbial products and NAFLD. We also discuss the regulatory role of existing NAFLD therapies on metabolite levels and investigate the potential of targeting those metabolites to relieve NAFLD.
| S-EPMC9730013 | biostudies-literature
Project description:BackgroundThe intestinal tract undergoes a period of cellular maturation during early life, primarily characterized by the organization of epithelial cells into specialized crypt and villus structures. These processes are in part mediated by the acquisition of microbes. Infants delivered at term typically harbor a stable, low diversity microbiota characterized by an overrepresentation of various Bacilli spp., while pre-term infants are colonized by an assortment of bacteria during the first several weeks after delivery. However, the functional effects of these changes on intestinal epithelium homeostasis and maturation remain unclear. To study these effects, human neonate feces were obtained from term and pre-term infants. Fecal 16S rDNA sequencing and global untargeted LC-MS were performed to characterize microbial composition and metabolites from each population. Murine enteral organoids (enteroids) were cultured with 0.22 μm filtered stool supernatant pooled from term or pre-term infants.ResultsTerm and pre-term microbial communities differed significantly from each other by principle components analysis (PCoA, PERMANOVA p < 0.001), with the pre-term microbiome characterized by increased OTU diversity (Wilcox test p < 0.01). Term communities were less diverse and dominated by Bacilli (81.54%). Pre-term stools had an increased abundance of vitamins, amino acid derivatives and unconjugated bile acids. Pathway analysis revealed a significant increase in multiple metabolic pathways in pre-term samples mapped to E. coli using the KEGG database related to the fermentation of various amino acids and vitamin biosynthesis. Enteroids cultured with supernatant from pre-term stools proliferated at a higher rate than those cultured with supernatant from term stools (cell viability: 207% vs. 147.7%, p < 0.01), grew larger (area: 81,189μm2 vs. 41,777μm2, p < 0.001), and bud at a higher rate (6.5 vs. 4, p < 0.01). Additionally, genes involved in stem cell proliferation were upregulated in pre-term stool treated enteroid cultures (Lgr5, Ephb2, Ascl2 Sox9) but not term stool treated enteroids.ConclusionsOur findings indicate that microbial metabolites from the more diverse gut microbiome associated with pre-term infants facilitate stem cell proliferation. Therefore, perturbations of the pre-term microbiota may impair intestinal homeostasis.
| S-EPMC7353703 | biostudies-literature
Project description:Neonatal sepsis due to intestinal bacterial translocation is a major cause of morbidity and mortality. Understanding microbial colonisation of the gut in prematurity may predict risk of sepsis to guide future strategies to manipulate the microbiome.Prospective longitudinal study of premature infants. Stool samples were obtained weekly. DNA was extracted and the V6 hypervariable region of 16S rRNA was amplified followed by high throughput pyrosequencing, comparing subjects with and without sepsis.Six neonates were 24-27 weeks gestation at birth and had 18 samples analysed. Two subjects had no sepsis during the study period, two developed late-onset culture-positive sepsis and two had culture-negative systemic inflammation. 324 350 sequences were obtained. The meconium was not sterile and had predominance of Lactobacillus, Staphylococcus and Enterobacteriales. Overall, infants who developed sepsis began life with low microbial diversity, and acquired a predominance of Staphylococcus, while healthy infants had more diversity and predominance of Clostridium, Klebsiella and Veillonella.In very low birth weight infants, the authors found that meconium is not sterile and is less diverse from birth in infants who will develop late-onset sepsis. Empiric, prolonged antibiotics profoundly decrease microbial diversity and promote a microbiota that is associated not only with neonatal sepsis, but the predominant pathogen previously identified in the microbiome. Our data suggest that there may be a 'healthy microbiome' present in extremely premature neonates that may ameliorate risk of sepsis. More research is needed to determine whether altered antibiotics, probiotics or other novel therapies can re-establish a healthy microbiome in neonates.
| S-EPMC3724360 | biostudies-literature
Project description:Antibody production is a metabolically demanding process that is regulated by gut microbiota, but the microbial products supporting B cell responses remain incompletely identified. We report that short-chain fatty acids (SCFAs), produced by gut microbiota as fermentation products of dietary fiber, support host antibody responses. In B cells, SCFAs increase acetyl-CoA and regulate metabolic sensors to increase oxidative phosphorylation, glycolysis, and fatty acid synthesis, which produce energy and building blocks supporting antibody production. In parallel, SCFAs control gene expression to express molecules necessary for plasma B cell differentiation. Mice with low SCFA production due to reduced dietary fiber consumption or microbial insufficiency are defective in homeostatic and pathogen-specific antibody responses, resulting in greater pathogen susceptibility. However, SCFA or dietary fiber intake restores this immune deficiency. This B cell-helping function of SCFAs is detected from the intestines to systemic tissues and conserved among mouse and human B cells, highlighting its importance.
| S-EPMC4982788 | biostudies-literature
Project description:Trillions of microbes inhabiting the gut modulate the metabolism of the host. Cross-sectional studies have reported associations between physical performance and the gut microbiota (GM). Physical activity seems to increase GM diversity and the abundance of certain health-beneficial microbes. We reviewed the evidence from longitudinal studies on the connection between physically active lifestyle or long-term exercise interventions and the GM. We made literature searches using databases of Web of Science and PubMed Medline to collect human studies showing or not the associations between the GM and exercise. Many controversies exist in the studies. However, the longitudinal studies show that frequently, medium-intensity endurance exercise has yielded most beneficial effects on the GM, but the results vary depending on the study population and exercise protocol. In addition, the literature shows that certain microbes own the potency to increase physical activity and performance. Generally, a physically active lifestyle and exercise associate with a "healthy" GM. However, in previously sedentary subjects, the exercise-induced improvements in the GM seem to disappear unless the active lifestyle is continued. Unfortunately, several studies are not controlled for the diet. Thus, in the future, more longitudinal studies on the GM and physical performance are needed, with detailed dietary information.
| S-EPMC8619554 | biostudies-literature
Project description:Alzheimer's disease (AD) is a neurodegenerative disease that impacts 45 million people worldwide and is ranked as the 6th top cause of death among all adults by the Centers for Disease Control and Prevention. While genetics is an important risk factor for the development of AD, environment and lifestyle are also contributing risk factors. One such environmental factor is diet, which has emerged as a key influencer of AD development/progression as well as cognition. Diets containing large quantities of saturated/trans-fats, refined carbohydrates, limited intake of fiber, and alcohol are associated with cognitive dysfunction while conversely diets low in saturated/trans-fats (i.e., bad fats), high mono/polyunsaturated fats (i.e., good fats), high in fiber and polyphenols are associated with better cognitive function and memory in both humans and animal models. Mechanistically, this could be the direct consequence of dietary components (lipids, vitamins, polyphenols) on the brain, but other mechanisms are also likely to be important. Diet is considered to be the single greatest factor influencing the intestinal microbiome. Diet robustly influences the types and function of micro-organisms (called microbiota) that reside in the gastrointestinal tract. Availability of different types of nutrients (from the diet) will favor or disfavor the abundance and function of certain groups of microbiota. Microbiota are highly metabolically active and produce many metabolites and other factors that can affect the brain including cognition and the development and clinical progression of AD. This review summarizes data to support a model in which microbiota metabolites influence brain function and AD.
| S-EPMC8639879 | biostudies-literature