An Altered Glycome Shapes IgA B-Cell Responses and Gut Immunity During Intestinal Inflammation

Abstract

A healthy gut immune system balances pathogen defense and tolerance to beneficial microbes. This equilibrium is sustained by coordinated mechanisms where B cells (BCs) play a central role, and secretory immunoglobulin A (SIgA) regulates microbiome composition. In ulcerative colitis (UC), impaired tolerogenic pathways result in exaggerated immune activation, epithelial dysfunction, and tissue damage; however, the contribution of BCs to disease pathogenesis remains unclear. Notably, sialylation is crucial to B-cell function, but its relevance in the intestinal IgA B-cell response has been scarcely explored. Here, we show that SIgA from active UC patients displays an inflammation-dependent reduction in (2,6)-sialylation. This desiaylation is recapitulated in dextran sodium sulfate-induced colitis, where IgA plasma cells (IgA+ PCs) and BCs exhibit a similar glycophenotype. Functional analyses reveal that BCs lacking (2,6)-sialylation on N-glycans exhibit defective differentiation into IgA PCs and diminished capacity to suppress intestinal inflammation in vivo, with increased neutrophil infiltration. Moreover, transcriptomic analyses of UC patient samples suggest a synergistic contribution of neuraminidase activity and reduced bioavailability of sialic acid precursors, leading to SIgA desialylation. Collectively, these findings uncover a glycosylation-dependent pathological circuit in which altered sialylation of SIgA and BCs disrupts their function, compromising mucosal homeostasis in intestinal inflammation.