Strain-level differences in gut microbiome composition determine fecal IgA levels and are modifiable by gut microbiota manipulation

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. By accessing the IgA-inducing capacity of a diverse set of human gut microbial strains, we identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied biomodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through both T-cell-dependent and T-cell-independent B cell-activation pathways. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Thus, microbial strain specificity is essential for the optimal induction of high-IgA responses in the gut. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.