Loss of immune tolerance to commensal microbial antigens is a central driver of inflammatory bowel disease. While regulatory T cells are well recognized in maintaining intestinal homeostasis, the contribution of B cells-particularly IgA-secreting cells-remains incompletely defined. In the T cell transfer colitis model, cotransfer of splenic B cells attenuates disease, an effect largely attributed to IL-10-producing regulatory B cells (Bregs). However, alternative B cell-dependent mechanisms have not been fully explored. Here, we investigated whether splenic B cells regulate T cell transfer colitis through IgA-dependent mechanisms independent of Breg-associated cytokines. We show that splenic B cells from wild-type C57BL/6 (B6) mice reconstitute bone marrow and peripheral B cell compartments in RAG1(-)/(-) recipients, undergo class switching, migrate to the colonic lamina propria as sIgA(+) B lineage cells, and partially restore luminal secretory IgA. B cell cotransfer significantly attenuated clinical and histological colitis without increased expression of canonical Breg-associated cytokines, including interleukin-10, transforming growth factor beta, and interleukin-35 subunits. In contrast, splenic B cells from IgA-deficient mice failed to attenuate colitis despite comparable peripheral B cell reconstitution. Restoration of secretory IgA was associated with increased bacterial IgA coating, reduced fecal bacterial burden, and remodeling of the colonic microbiota, including enrichment of beneficial commensal taxa. Importantly, because IgA-deficient B cells failed to attenuate colitis despite comparable peripheral B cell reconstitution, these findings support an important role for IgA in mediating the protective effect of B cell transfer. Collectively, these findings identify IgA-mediated modulation of the microbiota as an alternate mechanism by which B cells attenuate T cell transfer colitis, highlighting a Breg-independent regulatory pathway with potential relevance to inflammatory bowel disease pathogenesis. Brief summarySplenic B cells reconstitute the B cell/antibody-secreting cell compartment in RAG1-deficient mice, migrate to lamina propria, reconstitute lamina propria IgA-antibody-secreting cell and luminal SIgA, and attenuate T cell transfer colitis by modulating the colonic microbiota.
Background Inflammatory bowel diseases (IBDs) are heterogeneous disorders in which gut microbial dysbiosis may influence disease activity and clinical outcomes. However, it remains unclear whether microbiome-based stratification identifies clinically relevant IBD subtypes.Methods We profiled the gut microbiome of a cohort comprising patients with IBD (n = 260), at-risk individuals (n = 166), and healthy control individuals (n = 57) using 16S rRNA gene amplicon sequencing. Unsupervised clustering was used to define gut microbial enterotypes. Associations with clinical characteristics and outcomes, including fecal calprotectin levels and medication step-up, were evaluated. Statistical and machine learning approaches were applied to identify enterotype-specific microbial signatures.Results Four enterotypes were identified and labeled according to their most discriminative genera: Faecalibacterium and Blautia, Prevotella, Phocaeicola, and Bifidobacterium with reduced Faecalibacterium (Bif + Faec-low). Faecalibacterium and Blautia and Prevotella were enriched in healthy control individuals, Phocaeicola was enriched in at-risk individuals, and Bif + Faec-low was enriched in patients with IBD. The Bif + Faec-low enterotype was associated with lower body mass index, higher fecal calprotectin levels, and an increased risk of medication step-up (hazard ratio, 1.71; 95% confidence interval, 1.10-2.66). Microbial composition and network analyses identified distinct enterotype-specific taxa and hub genera, suggesting functional divergence among enterotypes.Conclusions Gut microbial enterotypes are associated with distinct clinical phenotypes and treatment escalation in IBD, and exhibit enterotype-specific microbial community structures and alterations across disease states. Enterotype-based stratification may provide a clinically relevant framework for assessing risk assessment and guiding personalized disease management. Four enterotypes across inflammatory bowel disease, at-risk individuals, and control individuals were identified, each showing distinct microbial composition and functional and association patterns, supporting personalized, enterotype-based treatment strategies. The Bifidobacterium with reduced Faecalibacterium enterotype was specifically linked to adverse outcomes.
