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

Abstract

26 The microbial communities that inhabit the distal gut of humans and other mammals exhibit large 27 inter-individual variation. While host genetics is a known factor that influences gut microbiota 28 composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) 29 are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as 30 environmental cues and nutrients to microbes, but they can also have antibacterial effects. We 31 hypothesized that host genetic variation in BA metabolism and homeostasis influence gut 32 microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population 33 of genetically distinct mice derived from eight founder strains. We characterized the fecal 34 microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a 35 high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we 36 identified several genomic regions associated with variations in both bacterial and BA profiles.37 Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped 38 to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and 39 subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression 40 associated with the different strains influences levels of both traits and revealed novel interactions 41 between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to 42 generate testable hypotheses and provide insight into host-microbe interactions. 44Author summary 45 Inter-individual variation in the composition of the intestinal microbiota can in part be attributed 46 to host genetics. However, the specific genes and genetic variants underlying differences in the 47 microbiota remain largely unknown. To address this, we profiled the fecal microbiota composition 3 48 of 400 genetically distinct mice, for which genotypic data is available. We identified many loci of 49 the mouse genome associated with changes in abundance of bacterial taxa. One of these loci is 50 also associated with changes in the abundance of plasma bile acidsmetabolites generated by the 51 host that influence both microbiota composition and host physiology. Follow up validation 52 experiments provide mechanistic insights linking host genetic differences, with changes in ileum 53 gene expression, bile acid-bacteria interactions and bile acid homeostasis. Together, this work 54 demonstrates how genetic approaches can be used to generate testable hypothesis to yield novel 55 insight into how host genetics shape gut microbiota composition. 56 57 Introduction 58The intestinal microbiota has profound effects on host physiology and health (1-3). The 59 composition of the gut microbiota is governed by a combination of environmental factors, 60 including diet, drugs, maternal seeding, cohabitation, and host genetics (4-7). Together, these 61 factors cause substantial inter-i...

High-resolution QTL mapping with Diversity Outbred mice identifies genetic variants that impact gut microbiome composition

“…Genus Lactobacillus was found to have a high and significant heritability (h 2 = 0.36) and it was also found to be highly heritable in one mouse study (h 2 = 0.74 in O'Connor et al 2014) and both highly heritable and significant in a pig study (h 2 = 0.34 in Camarinha-Silva et al 2017) and multiple human studies (h 2 = 0.36 in Davenport et al 2015, 0.26 in Turpin et al 2016, and 0.15 in Lim et al 2017. Genus Turicibacter, also within class Bacilli, was found to have a high and significant heritability as well (h 2 = 0.57) and was found to be highly heritable in one mouse study (h 2 = 0.54 in Org et al 2015) and display a strong QTL association in another (Kemis et al 2019). Turicibacter was also found to be significantly heritable in human studies (h 2 = 0.26 in Turpin et al 2016 and0.36 in Goodrich et al 2016).…”

“…The advantages of this outbreeding include normal levels of heterozygosity -similar to the human genetic condition -and substantially increased genetic resolution (CHURCHILL et al 2012). Both the DO mice and their founder progenitor lines have already proven to be successful in identifying genetic associations with intestinal microbiome composition (O'CONNOR et al 2014, KEMIS et al 2019.…”

Identification of Genetic Variants Regulating the Abundance of Clinically Relevant Plasma Proteins using the Diversity Outbred Mouse Model

“…Additionally, we show that the genetic diversity of the DO mouse model makes it possible to identify trans pQTL that can easily be translated to human, making this mouse model suitable for translational discovery studies. Importantly, we demonstrated that fewer than 150 DO mice are su cient to identify statistically signi cant pQTL compared to the larger number of DO mice used in previous studies [16,17,25,[29][30][31][32]. The methodology detailed in this study can be used to unravel the complex mechanisms between genetic loci and protein abundance.…”

Building community in the gut: a role for mucosal serotonin

“…Although relatively little is known on the role of specific species of Turicibacter, increasing associations with inflammatory conditions, cancer and altered metabolism strengthen their potential contributions to the heritability of host health and disease 8 . Along these lines, an investigation in 2019 by Kemis et al used quantitative trait locus analyses in mice to map overlapping gene loci for Turicibacter, plasma cholic acid and an ileal bile acid transporter 9 . They found that increased bile acid availability in the small intestine affected microbial metabolism of bile acids by Turicibacter, in turn reducing circulating levels of cholic acid.…”