Interspecies commensal interactions have nonlinear impacts on host immunity

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. Female 6-week-old germ-free C57BL/6 mice were colonized with mock community bacteria (MC), MC+Allobaculum sp. 128, MC+A. muciniphila, or MC+Allobaculum sp. 128+A. muciniphila (n=3 mice/group) for 4 weeks, microbiotas were confirmed by 16S rRNA sequencing, then euthanized for harvest of mesenteric lymph nodes (MLN) and Peyer's patches (PP). Cells were gently isolated by digestion, stirring, and filtration, then normalized and pooled for 10X Genomics Chromium 5P V2 library preparation. Cellular transcriptomic responses were analyzed by single cell RNA sequencing.