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.
Highlights
The gastrointestinal tract contains a vast community of organisms that collectively comprise the microbiota, which is critical for the development of the intestinal epithelium and mucosal immunity as well as contributing digestive metabolic functionalities [1,2]
While gut microbiota of C57BL/6J-based genetic resources were previously profiled in various environments, here we introduce the gut microbial profile of DBA/2J, a strain known for its high proportion of body fat mass and predisposition to obesity [15,16]
Using a parallelized version of the CLASSIFIER from Ribosomal Database Project (RDP), 97.12% of the sequences were assigned to five phyla groups
Summary
The gastrointestinal tract contains a vast community of organisms that collectively comprise the microbiota, which is critical for the development of the intestinal epithelium and mucosal immunity as well as contributing digestive metabolic functionalities [1,2]. The composition of this complex community is established early in life and influenced soon after birth by maternal environment and stochastic exposure to different microbes. Several studies in monogenic models have demonstrated the role of innate immune response in altering the composition of mouse gut microbiota and disease susceptibility [6,12,13]. Benson et al (2010) using Quantitative Trait Locus (QTL) mapping methods detected genome-wide linkages with the relative abundance of several taxa in the gut of a large murine advanced intercross population [7]
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