OTOP2 proton channel couples luminal pH sensing to intestinal immune homeostasis.

Extracellular acidification is a hallmark of the inflamed intestinal tract in individuals with inflammatory bowel disease (IBD). The proton channel Otopetrin-2 (OTOP2), which is enriched in intestinal tissues, becomes dysregulated during inflammation. However, the specific role of OTOP2 in IBD pathogenesis remains unclear. In this study, we demonstrate a significant reduction of OTOP2 mRNA and protein in the inflamed mucosa of pediatric patients with IBD, which inversely correlates with disease progression. Otop2 knockout (Otop2-/-) mice exhibit growth retardation and heightened susceptibility to intestinal inflammation, which is linked to intestinal pH dysregulation, altered gut microbiota composition, and compromised tight junction integrity. Accordingly, Otop2-/- mice exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis. Mechanistically, Otop2 deficiency reduces Paneth cell numbers and diminishes antimicrobial factor expression, likely due to impaired autophagy-lysosomal processes within these cells. Similarly, Otop2 deficiency impairs phagocytic function in bone marrow-derived macrophages (BMDMs). Together, these findings establish OTOP2 as a critical, pH-sensitive regulator of intestinal homeostasis and highlight its potential as a therapeutic target in IBD.