Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis

Abstract

Background The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis. Methods We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis. Results Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac-/- mice to that of antibiotic-treated control mice. Conclusions MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL.

Extracellular Vesicles Secreted by Mesenchymal Stromal Cells Exert Opposite Effects to Their Cells of Origin in Murine Sodium Dextran Sulfate-Induced Colitis

“…Increased mucus secretion could help restoring the intestinal barrier, thus contributing to the observed reduction in mucosal inflammation. Regulation of MUC5ac secretion is poorly understood (67). Therefore, the mechanisms underlying these novel findings are presently unknown and require further investigation.…”

“…The mucus layer lining the epithelial surface of the intestine has several functions, including the control of the passage of nutrients and the regulation of host interactions with the intestinal microbiota (65,66). Secreted mucins are the major proteins found in the mucus layer, with MUC2 being largely predominant in the healthy intestinal mucosa, while MUC5AC (human)/Muc5ac (murine) is alternatively secreted in IBD and in experimental colitis (67). Previous studies both in mice and in patients with IBD suggest that Muc5ac/MUC5AC expression in the gastrointestinal tract is a tissue-protective response during active inflammation (67,68).…”

“…Secreted mucins are the major proteins found in the mucus layer, with MUC2 being largely predominant in the healthy intestinal mucosa, while MUC5AC (human)/Muc5ac (murine) is alternatively secreted in IBD and in experimental colitis (67). Previous studies both in mice and in patients with IBD suggest that Muc5ac/MUC5AC expression in the gastrointestinal tract is a tissue-protective response during active inflammation (67,68). Here, we show that MUC5ac was reduced following the induction of chemical colitis, probably because of mucosal cell destruction and of the detergent effect of DSS on the mucus layer.…”

Pic Protein From Enteroaggregative E. coli Induces Different Mechanisms for Its Dual Activity as a Mucus Secretagogue and a Mucinase

“…MUC2 is expressed in both mucus layers of colon, the outer unattached or the inner adherent. MUC5AC, is mainly present at the inner mucus layer of gastric mucosa, but is also expressed at some extent in the small intestine and colon ( 2 , 3 ). Human MUC2, a major component of intestinal mucin, has a protein core of ~ 5,179 amino acids.…”

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“…MUC2 is expressed in both mucus layers of colon, the outer unattached or the inner adherent. MUC5AC, is mainly present at the inner mucus layer of gastric mucosa, but is also expressed at some extent in the small intestine and colon (2,3). Human MUC2, a major component of intestinal mucin, has a protein core of~5,179 amino acids.…”