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Polymorphic immune mechanisms regulate commensal repertoire

ABSTRACT: Environmental influences such as infections and dietary changes strongly affect a host’s microbiota. In the steady state, however, host genetics may influence the microbiota composition, as suggested by the greater similarity between the microbiomes of identical twin pairs compared to non-identical twins. Understanding the role of polymorphic mechanisms in regulating the commensal communities is complicated by the variability of human genomes and microbiomes, and by microbial sensitivity to the environment. Animal studies allow genetic modifications, but are also sensitive to influences known as ‘cage’ or ‘legacy’ effects. Here, we analyzed ex-germ-free mice of various genetic backgrounds, including immunodeficient and Major Histocompatibility Complex (MHC)-congenic strains repopulated with identical input microbiota. We found that the host’s genetic polymorphic mechanisms did indeed affect the gut microbiome and that both innate (e.g. anti-microbial peptides, complement, pentraxins and enzymes affecting microbial survival), as well as adaptive (both MHC-dependent and MHC-independent) pathways influenced the microbiota. These polymorphic mechanisms regulated only a limited number of microbial lineages (independently of their abundance). In addition, our comparative analyses suggested that some microbes might benefit from the specific immune responses that they elicit.

ORGANISM(S): Mus musculus

PROVIDER: GSE136572 | GEO | 2019/08/29

REPOSITORIES: GEO

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Project description:The mammalian gut harbors a diverse microbial community (gut microbiota) that mainly consists of bacteria. Their combined genomes (the microbiome) provide biochemical and metabolic functions that complement host physiology. Maintaining symbiosis seems to be a key requirement for health as dysbiosis is associated with the development of common diseases. Previous studies indicated that the microbiota and the host’s epithelium signal bidirectional inducing transcriptional responses to fine-tune and maintain symbiosis. However, little is known about the host’s responses to the microbiota along the length of the gut as earlier studies of gut microbial ecology mostly used either colonic or fecal samples. This is of importance as not only function and architecture of the gut varies along its length but also microbial distribution and diversity. Few recent studies have begun to investigate microbiota-induced host responses along the length of the gut. However, these reports used whole tissue samples and therefore do not allow drawing conclusions about specificity of the observed responses. Which cells in the intestinal tissue are responsible for the microbially induced response: epithelial, mesenchymal or immune cells? Where are the responding cells located? Furthermore, the gut microbiota has been implicated in epigenetic regulation of the host’s transcriptional profile. We used using extensive microarray analysis of laser capture microdissection (LCM) harvested ileal and colonic tip and crypt fractions from germ-free mice before and during the time course of colonization with a normal microbiota (on days 1, 3, 5 and 7) to investigate the microbiota-induced transcriptional responses and their kinetics in specific and well-defined cell populations of the host’s epithelium. Ileum and colon segments were dissected from germ-free 10-12 weeks old female C57Bl/6 mice and on day 1, 3, 5 and 7 after colonization, washed and frozen as OCT blocks. Cryosections were prepared from these OCT blocks and tip/crypt fractions isolated using laser capture microdissection.

Project description:Resident microorganisms (microbiota) have far-reaching effects on the biology of their animal hosts, with major consequences for the host’s health and fitness. Some of these effects can be explained by microbial impacts on the expression of individual genes but a full understanding of microbiota-dependent gene regulation requires analysis of the overall architecture of the host transcriptome. In this study, we investigated the impact of the microbiota on the global structure of the transcriptome of Drosophila. Our transcriptomic analysis of 17 Drosophila lines representative of the global genetic diversity of this species yielded a total of 11 transcriptional modules of co-expressed genes. For 7 of these modules, the strength of the transcriptional network (defined as gene-gene coexpression) differed significantly between flies bearing a defined gut microbiota (gnotobiotic flies) and flies reared under microbiologically-sterile conditions (axenic flies). Furthermore, the network structure was uniformly stronger in these microbiota-dependent modules than in both the microbiota-independent modules in gnotobiotic flies and all modules in axenic flies, indicating that the presence of the microbiota tightens gene regulation in a subset of the transcriptome. The genes constituting the microbiota-dependent transcriptional modules include regulators of growth, metabolism and neurophysiology, previously implicated in mediating phenotypic effects of microbiota on Drosophila phenotype. Together these results provide the key first evidence that the microbiota strengthens the co-expression of genesin specific networks of functionally-related transcripts relative to the animal’s intrinsic baseline level of co-expression. Our system-wide analysis demonstrates that the presence of microbiota enhances the structure of the transcriptional network in the animal host. This finding has potentially major implications for understanding of the mechanisms by which microbiota affect host health and fitness, and the ways in which hosts and their resident microbiota coevolve.

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Polymorphic immune mechanisms regulate commensal repertoire

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