Genetic determinants of gut microbiota composition and bile acid profiles in mice

Emerging evidence links dietary fiber with altered gut microbiota composition and bile acid signaling in maintaining metabolic health. Yeast β-glucan (Y-BG) is a dietary supplement known for its immunomodulatory effect, yet its impact on the gut microbiota and bile acid composition remains unclear. This study investigated whether dietary forms of Y-BG modulate these gut-derived signals. We performed 4-week dietary supplementation in healthy mice to evaluate effects of different fiber composition (soluble vs particulate Y-BG) and dose (0.1 vs. 2%). We found that 2% particulate Y-BG induced robust gut microbiota community shifts with elevated liver Cyp7a1 mRNA abundance and bile acid synthesis. These diet-induced responses were notably different when compared to the prebiotic inulin, and included a marked reduction in fecal Bilophila abundance which we demonstrated as translatable to obesity in population-scale American Gut and TwinsUK clinical cohorts. This prompted us to test whether 2% Y-BG maintained metabolic health in mice fed 60% HFD over 13 weeks. Y-BG consistently altered the gut microbiota composition and reduced Bilophila abundance, with trends observed in improvement of metabolic phenotype. Notably, Y-BG improved insulin sensitization and this was associated with enhanced ileal Glpr1r mRNA accumulation and reduced Bilophila abundance. Collectively, our results demonstrate that Y-BG modulates gut microbiota community composition and bile acid signaling, but the dietary regime needs to be optimized to facilitate clinical improvement in metabolic phenotype in an aggressive high-fat diet animal model.

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Genetic determinants of gut microbiota composition and bile acid profiles in mice

10.1101/571075 ◽

2019 ◽

Cited By ~ 1

Author(s):

Julia H. Kemis ◽

Vanessa Linke ◽

Kelsey L. Barrett ◽

Frederick J. Boehm ◽

Lindsay L. Traeger ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Fecal Microbiota ◽

Microbiota Composition ◽

Host Genetics ◽

Host Genetic ◽

Insight Into ◽

Gut Microbiota Composition ◽

Validation Experiments

AbstractThe microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ∼22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL forTuricibacter sp.and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter,Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences inSlc10a2gene expression associated with the different strains influences levels of both traits and revealed novel interactions betweenTuricibacterand BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.Author summaryInter-individual variation in the composition of the intestinal microbiota can in part be attributed to host genetics. However, the specific genes and genetic variants underlying differences in the microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is also associated with changes in the abundance of plasma bile acids—metabolites generated by the host that influence both microbiota composition and host physiology. Follow up validation experiments provide mechanistic insights linking host genetic differences, with changes in ileum gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel insight into how host genetics shape gut microbiota composition.

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Gut Microbiota Dysbiosis Is Associated with Altered Bile Acid Metabolism in Infantile Cholestasis

mSystems ◽

10.1128/msystems.00463-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 5

Author(s):

Yizhong Wang ◽

Xuefeng Gao ◽

Xinyue Zhang ◽

Yongmei Xiao ◽

Jiandong Huang ◽

...

Keyword(s):

Bile Acid ◽

Liver Function ◽

Gut Microbiota ◽

Liver Diseases ◽

Human Liver ◽

Microbiota Composition ◽

Impaired Liver Function ◽

Impaired Liver ◽

Gut Microbiota Dysbiosis ◽

Gut Microbiota Composition

ABSTRACT The co-occurrence of gut microbiota dysbiosis and bile acid (BA) metabolism alteration has been reported in several human liver diseases. However, the gut microbiota dysbiosis in infantile cholestatic jaundice (CJ) and the linkage between gut bacterial changes and alterations of BA metabolism have not been determined. To address this question, we performed 16S rRNA gene sequencing to determine the alterations in the gut microbiota of infants with CJ, and assessed their association with the fecal levels of primary and secondary BAs. Our data reveal that CJ infants show marked declines in the fecal levels of primary BAs and most secondary BAs. A decreased ratio of cholic acid (CA)/chenodeoxycholic acid (CDCA) in infants with CJ indicated a shift in BA synthesis from the primary pathway to the alternative BA synthesis pathway. The bacterial taxa enriched in infants with CJ corresponded to the genera Clostridium, Gemella, Streptococcus, and Veillonella and the family Enterobacteriaceae and were negatively correlated with the fecal BA level and the CDCA/CA ratio but positively correlated with the serological indexes of impaired liver function. An increased ratio of deoxycholic acid (DCA)/CA was observed in a proportion of infants with CJ. The bacteria depleted in infants with CJ, including Bifidobacterium and Faecalibacterium prausnitzii, were positively and negatively correlated with the fecal levels of BAs and the serological markers of impaired liver function, respectively. In conclusion, the reduced concentration of BAs in the gut of infants with CJ is correlated with gut microbiota dysbiosis. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. IMPORTANCE Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ.

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Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults

Clinical Nutrition ◽

10.1016/j.clnu.2021.04.008 ◽

2021 ◽

Vol 40 (5) ◽

pp. 2609-2619

Author(s):

A. Figge ◽

S. Sydor ◽

C. Wenning ◽

P. Manka ◽

S. Assmuth ◽

...

Keyword(s):

Bile Acid ◽

Inflammatory Response ◽

Gut Microbiota ◽

Fast Food ◽

Healthy Adults ◽

Microbiota Composition ◽

Hepatic Bile ◽

Gut Microbiota Composition

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Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00172.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. E418-E432 ◽

Cited By ~ 9

Author(s):

Jay V. Patankar ◽

Chi K. Wong ◽

Vijay Morampudi ◽

William T. Gibson ◽

Bruce Vallance ◽

...

Keyword(s):

Bile Acid ◽

Gut Microbiota ◽

Respiratory Function ◽

De Novo ◽

De Novo Lipogenesis ◽

Microbiota Composition ◽

Genetic Ablation ◽

Gene And Protein Expression ◽

Severe Impairment ◽

Gut Microbiota Composition

Both type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH) are associated with reduced hepatic mitochondrial respiratory capacity. Cholic acid (CA) is the predominant 12α-hydroxylated bile acid that regulates hepatic lipid metabolism, and its circulating levels are negatively correlated with insulin resistance. Abolishing CA synthesis via the genetic disruption of the enzyme sterol 12α-hydroxylase ( Cyp8b1−/−) leads in resistance to diabetes and hepatic steatosis. Here, we show that long-term stimulation of hepatic lipogenesis leads to a severe impairment in overall metabolic and respiratory function in control mice ( Cyp8b1+/+) but strikingly not in Cyp8b1−/− mice. Cyp8b1−/− mice are protected from such metabolic impairments associated with T2D and NASH by inhibiting hepatic de novo lipogenic gene and protein expression and altering gut microbiota composition. The protective phenotype is compromised when NASH induction is independent of impairment in de novo lipogenesis (DNL). Consequently, Cyp8b1−/− mice also show a reduction in hepatic inflammation and fibrosis along with a shift in antimicrobial dynamics in the small intestine. Our data show that the altered bile acid composition of Cyp8b1−/− mice preserves metabolic and respiratory function by repressing hepatic DNL and driving favorable changes in gut antimicrobial responses.

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