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

As these GEITP pages continue to emphasize, any multifactorial trait reflects the contributions of genetics, epigenetic factors, environmental effects, endogenous influences, and each individual’s microbiome. It is now well appreciated that the intestinal microbiome has profound effects on the physiology and health of each of us. Composition of the gut microbiota is governed by a combination of environmental factors — including diet, drugs, maternal “seeding”, co-habitation (people living together), and host genetics; together, these factors cause substantial inter-individual variation in microbiome composition and modulate disease risk.

Alterations in the composition of the microbiome are associated with a spectrum of undesirable cognitive, inflammatory and metabolic disorders; in addition, certain bacterial taxa have been causally associated with modulation of disease. Several mouse and human studies have examined the role of host genetics in shaping the composition of the gut microbiome. These studies are often difficult to interpret, however, due to differences in environmental variables among populations. Some associations are consistently detected among geographically discrete populations [e.g. association between Bifidobacterium abundance and the lactase (LCT) gene] — indicating that abundance of specific taxa is influenced by host genetic variation.

Bile Acids (BAs) are host-derived and microbial-modified metabolites that regulate both the gut microbiome and host metabolism. BAs are synthesized in liver from cholesterol, stored in the gallbladder, and then secreted in the proximal small intestine, where they facilitate absorption of fat-soluble vitamins and lipids. Once in the intestine, BAs can be metabolized by gut bacteria through different reactions (including deconjugation, dehydroxylation, epimerization, and dehydrogenation) — to produce secondary BAs with varying effects on the host. In addition to their direct effects on the host, BAs shape the gut microbiome composition through antimicrobial activities. Detergent properties of BAs cause plasma membrane damage (bactericidal activity of a BA molecule corresponds to its hydrophobicity). Therefore, authors [see attached article] hypothesized that host genetic variation associated with changes in BA homeostasis mediates alterations in composition of the gut microbiome.

To investigate this hypothesis, authors [see attached article] used the Diversity Outbred (DO) mouse population — which is a heterogenous population derived from eight founder strains: C57BL6/J, A/J, 1291, NOD, NZO, CAST, PWK, and WSB. These eight strains are believed to capture a large breadth of the genetic diversity found among inbred mouse strains. Furthermore, the founder strains are well known to harbor distinct gut microbial communities and exhibit disparate metabolic responses to diet-induced metabolic disease. The genetic diversity and many generations of outbreeding therefore make it an ideal resource for high-resolution genetic mapping of microbial and metabolic traits; this is intended to reflect the heterogeneity of all human populations. 😊

Authors characterized 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, authors identified several genomic regions associated with variations in both bacterial and BA profiles. For example, authors found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the Slc10a2 gene (which encodes an ileal bile acid transporter). Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression — associated with the different strains — influences levels of both traits (Turicibacter sp. Levels and plasma cholic acid levels) and revealed novel interactions between Turicibacter and BAs. This study illustrates how the field of “systems genetics” can be used to generate testable hypotheses, and to provide insight into host-microbe interactions. 😊


PLoS Genet Aug 2019; 15: e1008073

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