Individuality in gut microbiota composition is a complex polygenic trait shaped by multiple environmental and host genetic factors

Abstract

In vertebrates, including humans, individuals harbor gut microbial communities whose species composition and relative proportions of dominant microbial groups are tremendously varied. Although external and stochastic factors clearly contribute to the individuality of the microbiota, the fundamental principles dictating how environmental factors and host genetic factors combine to shape this complex ecosystem are largely unknown and require systematic study. Here we examined factors that affect microbiota composition in a large (n = 645) mouse advanced intercross line originating from a cross between C57BL/6J and an ICR-derived outbred line (HR). Quantitative pyrosequencing of the microbiota defined a core measurable microbiota (CMM) of 64 conserved taxonomic groups that varied quantitatively across most animals in the population. Although some of this variation can be explained by litter and cohort effects, individual host genotype had a measurable contribution. Testing of the CMM abundances for cosegregation with 530 fully informative SNP markers identified 18 host quantitative trait loci (QTL) that show significant or suggestive genomewide linkage with relative abundances of specific microbial taxa. These QTL affect microbiota composition in three ways; some loci control individual microbial species, some control groups of related taxa, and some have putative pleiotropic effects on groups of distantly related organisms. These data provide clear evidence for the importance of host genetic control in shaping individual microbiome diversity in mammals, a key step toward understanding the factors that govern the assemblages of gut microbiota associated with complex diseases.16S rDNA | pyrosequencing | quantitative trait loci mapping | microbiome phenotyping | population

Host genetic and environmental effects on mouse intestinal microbiota

“…Two such studies (Benson et al, 2010;Buhnik-Rosenblau et al, 2011) found ties between host genetics and Lactobacillus in mice. Another study (Alexander et al, 2006) in which mice from 23 inbred strains were inoculated with and tested for the altered Schaedler's flora using specific quantitative PCR assays noted significant differences for these species.…”

“…With thousands of segregating genes and millions of segregating polymorphisms in mouse populations, comprehensive mapping of potential deterministic associations between host genotype and the hundreds of bacterial taxonomic or functional units, as well as distinguishing environmental and stochastic effects, requires an extensive population genetics and statistical framework. A recent study using quantitative trait locus analysis of advanced intercross lines identified a subset of microbial lineages that cosegregate with host genetic loci (Benson et al, 2010).…”

“…Such studies have used both conventionally reared and germ-free animals inoculated selectively with different bacterial isolates or natural microbiota samples. Strong evidence exists that the global host genotype influences specific microbiota composition (beta diversity) (Benson et al, 2010;Kovacs et al, 2011), and mutations and inactivation of specific genes have been associated with discrete community changes, in some cases linked to metabolic diseases (for example, obesity, diabetes and metabolic syndrome) (reviewed in Spor et al (2011)). At the same time, however, studies using embryo transplantation, litter cross-fostering and other variation in mouse rearing and housing have shown that experimental manipulations, environmental and stochastic factors (for example, founder effects) can exert dominating contributions in microbiota taxonomic composition (Friswell et al, 2010).…”

Divergence across diet, time and populations rules out parallel evolution in the gut microbiomes of Trinidadian guppies

“…The ongoing discovery of particular loci that shape the gut microbiome in model organisms (Benson et al, 2010) presents an intriguing target for future studies across animal systems in both the lab and field. Such host encoded genes may affect aspects of host physiology or immunity, as illustrated by the recent finding that the types and diversity of major histocompatibility Figure 4 Relationships between guppy gut microbes and those from other habitats.…”

“…Research that takes these and the aforementioned factors into account will be important in pinpointing the sources of natural variation, enabling a better understanding of how the complex trait of the gut microbiome is mediated by host genetics, the environment and their intersection (Benson et al, 2010).…”