Although the gut microbiome plays important roles in host physiology, health and disease1, we lack understanding of the complex interplay between host genetics and early life environment on the microbial and metabolic composition of the gut. We used the genetically diverse Collaborative Cross mouse system2 to discover that early life history impacts the microbiome composition, whereas dietary changes have only a moderate effect. By contrast, the gut metabolome was shaped mostly by diet, with specific non-dietary metabolites explained by microbial metabolism. Quantitative trait analysis identified mouse genetic trait loci (QTL) that impact the abundances of specific microbes. Human orthologues of genes in the mouse QTL are implicated in gastrointestinal cancer. Additionally, genes located in mouse QTL for Lactobacillales abundance are implicated in arthritis, rheumatic disease and diabetes. Furthermore, Lactobacillales abundance was predictive of higher host T-helper cell counts, suggesting an important link between Lactobacillales and host adaptive immunity.
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The authors thank S.E. Cates, N.N. Robinson and G.D. Shaw in the Systems Genetics Core at UNC for technical assistance and M.H. Stoiber for helpful discussions, especially regarding statistical analysis. This work was primarily supported by funding from the Office of Naval Research under ONR contract N0001415IP00021 (J.J., J.H.M. and A.M.S.). Additional support was provided by the Low Dose Scientific Focus Area, Office of Biological and Environmental Research, US Department of Energy (G.K., J.H.M. and A.M.S.) and the Lawrence Berkeley National Laboratory Directed Research and Development (LDRD) program funding under the Microbes to Biomes (M2B) initiative (S.C., B.B., G.K., J.H.M. and A.M.S.). C.N. was supported by an NSF IGERT DGE-1258485 fellowship and in part by New Innovator Award DP2 AT007802-01 to E.B. Partial support was also provided under the Microbiomes in Transition (MinT) Initiative as part of the Laboratory Directed Research and Development Program at PNNL. Metabolomic measurements were performed in the Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by the US DOE OBER and located at PNNL in Richland, Washington. PNNL and LBNL are multi-program national laboratories operated by Battelle for the DOE under contract DE-AC05-76RLO 1830 and the University of California for the DOE under contract DE AC02-05CH11231, respectively.
The authors declare no competing financial interests
Supplementary Figures 1-10, Supplementary Tables 1-12 (PDF 36706 kb)
Normalized amplicon abundance. (XLSX 4809 kb)
Differentially abundant fecal operational taxonomic units (OTUs) between animal facility built environments (BE1 vs BE2). (XLSX 320 kb)
P-values for each genetic locus obtained using Mann-Whitney U test for all OTUs. (XLSX 237480 kb)
Joint QTL intervals and candidate genes. (XLSX 88 kb)
Linkage analysis of microbial families. (XLSX 8304 kb)
Candidate genes in genetic loci associated with specific microbial families. (XLSX 167 kb)
Metabolomics data including original intensity of the detected metabolites from murine feces and their zscored transformed values in separate tabs. (XLSX 677 kb)
Metabolite profiles in fecal samples of four CC strains maintained on different diets. (XLSX 84 kb)
A list of all metabolites assayed and analyzed in terms of community metabolic potential for each subset of the data, detailing correlations between metabolomics data and community metabolic potential scores and potential taxonomic contributors. (XLSX 256 kb)
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Snijders, A., Langley, S., Kim, YM. et al. Influence of early life exposure, host genetics and diet on the mouse gut microbiome and metabolome. Nat Microbiol 2, 16221 (2017). https://doi.org/10.1038/nmicrobiol.2016.221
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