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.

Figure 1. Genome-wide QTL mapping of the gut microbiota in BXD strains.

The heat map is represented in “Grey+Blue+Red” in which more intense colors mark chromosomal regions with statistical values associated with high linkage while the spectrum indicates the allelic effect. The blue-green regions are those in which B allele is associated with higher trait values, whereas red-yellow regions are those in which the D allele is associated with higher trait values. Grey and black regions correspond to insignificant linkage between traits and DNA markers.

Figure 2. Genome-wide QTL mapping of Bacteroides composition in the gut of BXD strains.

The Left y axis represents the strength of the linkage between Bacteroides composition to different DNA marker intervals on A) each chromosome (blue line) and B) detailed region of the QTL located on Chr 4 (LRS = 20.2, 82.12–95.05 Mb) that explains 27.5% of the composition in Bacteroides. The Right y axis represents the additive effect and indicates if the D (green line) or B (red line) allele contributes to an increase in the abundance of Bacteroides. Pink and gray horizontal lines indicates the significant (<0.05) and suggestive (<0.67) QTL threshold. b) B haplotype (red) is associated with a reduced level of Bacteroides while the D haplotype (green) is associated with an increased level of Bacteroides. Grey regions represent recombination spots. Yellow seismograph represents the SNP density between the sequence of the parental genomes. The QTL region is rich in genes from interferon family such as Ifna1, Ifna12 and Ifnab, all expressed in the cecum of BXD. Additional positional candidates include Ptplad2, BC057079 and Mtap.