biostudies-literatureUnknownSoRelle JNIDDK NIH HHSNIAID NIH HHSIntestinal homeostasis relies on a protective mucus layer that separates bacteria from the host, with Muc2 as its primary component. This secreted, gel-forming mucin is heavily O-glycosylated, allowing it to retain water and support beneficial bacteria. For the first time, we demonstrate that Muc2 N-glycosylation plays a critical in mucin maturation, O-glycosylation, barrier integrity, and the prevention of dysbiosis. Using mouse models with global and intestine-specific N-glycan deficiency- caused by the loss of the mannose producing enzyme, Mpi- we uncover an unexpected link between N-glycosylation and intestinal homeostasis. Our findings reveal that Mpi hypomorphic mice are highly sensitive to DSS-induced colitis, while Mpiflox; VillinCre mice spontaneously develop disease, exhibiting iResearch squarers.3.rs-6222474https://www.ebi.ac.uk/biostudies/studies/S-EPMC11975007biostudies-literatureN-glycosylation enzyme Mpi is essential for mucin O-glycosylation, host-microbe homeostasis, Paneth cell defense, and metabolism.PMC11975007R01 AI125581U19 AI100627R01 DK135511K08 AI155832Argula TBeutler BChen ZCho HJRoy AMeregini SZaki ASoRelle JfalseN-glycosylation enzyme Mpi is essential for mucin O-glycosylation, host-microbe homeostasis, Paneth cell defense, and metabolism.Intestinal homeostasis relies on a protective mucus layer that separates bacteria from the host, with Muc2 as its primary component. This secreted, gel-forming mucin is heavily O-glycosylated, allowing it to retain water and support beneficial bacteria. For the first time, we demonstrate that Muc2 N-glycosylation plays a critical in mucin maturation, O-glycosylation, barrier integrity, and the prevention of dysbiosis. Using mouse models with global and intestine-specific N-glycan deficiency- caused by the loss of the mannose producing enzyme, Mpi- we uncover an unexpected link between N-glycosylation and intestinal homeostasis. Our findings reveal that Mpi hypomorphic mice are highly sensitive to DSS-induced colitis, while Mpiflox; VillinCre mice spontaneously develop disease, exhibiting i2025-01-01T00:00:00Z2025 Mar2025-07-03T03:04:43.811Z2025-07-03T03:04:43.811ZS-EPMC119750074019597810.21203/rs.3.rs-6222474/v1