Murine Gut Microbiota Is Defined by Host Genetics and Modulates Variation of Metabolic Traits

Abstract

The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes–the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation.

Genetic and environmental control of host-gut microbiota interactions

“…However a recent study with 416 twin pairs demonstrated that MZ twins have greater overall microbial community similarities than DZ twin pairs and identified several microbial taxa with relative abundances that differ depending on host genetics (Goodrich et al 2014). Studies using genetic crosses of mice, where the environment can be controlled, also suggest that host genetics can significantly alter gut microbiota composition (Benson et al 2010;McKnite et al 2012;Srinivas et al 2013).…”

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

“…A large proportion of quantitative trait locus regions reported to regulate microbial abundance contain genes related to immunity and maintenance of barrier function. [225][226][227] The influence of immune-related genes is further evidenced by the dramatic effects on microbial community structure caused by mutations in single genes related to host immunity. 228,229 As an example, mice genetically deficient in the gut mucosal expression of innate immune system modulators (Toll-like receptor 5) developed insulin resistance even in the absence of increased obesity, 217 and high fecal calprotectin levels have been found to be indicative of an inflammatory colonic environment.…”

“…Several groups have reported that enteric microbial composition is a heritable trait, 234,235 although results from twin studies have shown discordant evidence of heritability. 236 However, studies using naturally occurring genetic variation among panels of inbred mouse strains and single gene mutations in genetically modified mice have consistently shown an effect of host genetics on intestinal microbial community structure 225,226,[237][238][239][240] and may have increased power to detect genotype-driven microbial differences. This is especially relevant because murine studies allow tight control over environmental factors, including diet.…”

“…This is especially relevant because murine studies allow tight control over environmental factors, including diet. 226 For example, numerous genetic studies in mice, including those with using genetic reference panels, 225,226,230,241 have demonstrated an effect of genetic background on microbial diversity. Interestingly, Benson and coworkers 226 demonstrated that multiple taxa can colocalize to a single genetic locus, suggesting that a single genetic locus may regulate the abundance of several taxa.…”

Identifying strains that contribute to complex diseases through the study of microbial inheritance

“…This exclusion is not to imply that host genetics play no role. Well-controlled quantitative trait loci mapping studies in mice indicate that microbiota composition is affected by host genetic factors, including those involved in immune responses, as well as by environmental exposures (18,19). Although studies of dizygotic and monozygotic twins suggest that the representation of members of the gut community is impacted by genotype (11,20), genomewide surveys are needed to address the important question of the contributions of host genetics versus environment on microbiota structure and function.…”