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Interspecies commensal interactions have nonlinear impacts on host immunity

ABSTRACT: The impacts of individual commensal microbes on immunity and disease can differ dramatically depending on the surrounding microbial context, yet the specific bacterial combinations that dictate divergent immunological outcomes in humans remain largely undefined. We isolated a novel Allobaculum strain from an inflammatory bowel disease (IBD) patient that elicited antigen-specific mucosal and systemic antibody responses at homeostasis and exacerbated colitis in gnotobiotic mice. Using human microbiota-associated mouse models, we uncovered an inverse correlation between Allobaculum and the taxonomically-divergent immunostimulatory species Akkermansia muciniphila, which was also reflected in human cohorts. Co-colonization with Allobaculum and A. muciniphila reprogrammed the immune responses evoked by each microbe on its own, ameliorated Allobaculum-induced colitis, and blunted A. muciniphila-induced T and B cell responses. These studies thus identify a reciprocal ‘epistatic’ interaction between unique immunostimulatory human gut bacteria and establish a generalizable framework to dissect the role of microbial context in strain-specific microbial effects on human disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE179165 | GEO | 2021/12/01

REPOSITORIES: GEO

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Project description:Epithelial cells of the mammalian intestine are covered with a mucus layer that prevents direct contact with intestinal microbes but also constitutes a substrate for mucus-degrading bacteria. To study the effect of mucus degradation on the host response, germ-free mice were colonized with Akkermansia muciniphila. This anaerobic bacterium belonging to the Verrucomicrobia is specialized in the degradation of mucin, the glycoprotein present in mucus, and found in high numbers in the intestinal tract of human and other mammalian species. Efficient colonization of A. muciniphila was observed with highest numbers in the cecum, where most mucin is produced. In contrast, following colonization by Lactobacillus plantarum, a facultative anaerobe belonging to the Firmicutes that ferments carbohydrates, similar cell-numbers were found at all intestinal sites. Whereas A. muciniphila was located closely associated with the intestinal cells, L. plantarum was exclusively found in the lumen. The global transcriptional host response was determined in intestinal biopsies and revealed a consistent, site-specific, and unique modulation of about 750 genes in mice colonized by A. muciniphila and over 1500 genes after colonization by L. plantarum. Pathway reconstructions showed that colonization by A. muciniphila altered mucosal gene expression profiles toward increased expression of genes involved in immune responses and cell fate determination, while colonization by L. plantarum led to up-regulation of lipid metabolism. These indicate that the colonizers induce host responses that are specific per intestinal location. In conclusion, we propose that A. muciniphila modulates pathways involved in establishing homeostasis for basal metabolism and immune tolerance toward commensal microbiota. Keywords: Analysis of target gene regulation by using microarrays Adult germ-free female NMRI-KI mice (45 – 65 days) were used for bacterial mono-association. Two bacterial strains were used in this study, A. muciniphila MucT (ATTC BAA-835) and L. plantarum WCFS1 (NCIMB 8826). A. muciniphila was grown anaerobically in a basal mucin based medium and L. plantarum was grown anaerobically at 37°C in Man-Rogosa-Sharpe broth (MRS; Le Pont de Claix, France). After 7 days of colonization, mice were killed by cervical dislocation and terminal ileum, cecum and ascending colon specimens were sampled.

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Interspecies commensal interactions have nonlinear impacts on host immunity

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