Pathobiont-directed mucosal immunotherapy targets Ruminococcus gnavus and remodels host-microbiota interactions in colitis

Disease-associated pathobionts are recurrently enriched in inflammatory bowel disease (IBD), yet their causal contribution and selective therapeutic control remain incompletely defined. Here, through clinical microbiome profiling and causal animal studies, we identified Ruminococcus gnavus (Rg) as a key ulcerative colitis (UC)-associated pathobiont whose abundance positively correlates with intestinal oxidative stress and inflammatory levels. To selectively constrain Rg, we engineered CP-EV@Ca, an oral microbiota-directed mucosal immunotherapy that combines pathogen-specific immune targeting with redox modulation. CP-EV@Ca enhanced mucosal antigen presentation, promoted T follicular helper cell-germinal-center B-cell responses and induced robust Rg-specific secretory IgA (sIgA). CP-EV@Ca-induced mucosal immune responses, including enhanced Rg-specific sIgA production, were associated with increased immune coating and reduced Rg expansion. In both acute and chronic colitis models, CP-EV@Ca outperformed 5-aminosalicylic acid (5-ASA), suppressing inflammation and restoring microbial, epithelial and immune homeostasis. These findings demonstrate that pathobiont-specific mucosal immunity can be harnessed to selectively constrain disease-associated bacteria and restore intestinal homeostasis.