P-229 Muc5ac Expression Protects the Intestinal Mucosa During Acute Colitis

The mucus gel layer lining the intestinal epithelium is essential for maintaining mucosal homeostasis. Goblet cells within the epithelial barrier are responsible for the secretion of intestinal mucins. Goblet cell depletion and decreased mature mucin production is associated with enhanced mucosal inflammation in patients with ulcerative colitis (UC). Genetic loss of the secreted gel-forming mucin, Muc2 results in the spontaneous development of colitis in mice, suggestive of a key role for the mucus gel layer in colitis pathogenesis. Muc5ac is another member of this family of gel-forming mucins. Elevated Muc5ac expression has been detected in the mucosa of UC patients. However, the role of Muc5ac in UC is unknown. Previous studies demonstrate a beneficial role for gastrointestinal Muc5ac expression during nematode infection. We hypothesize that expression of colonic Muc5ac is a protective response during inflammation associated with ulcerative colitis. Muc5ac expression was studied during the course of acute dextran sulphate sodium (DSS) colitis in C57BL/6 mice. Mice with genetic loss of Muc5ac (Muc5ac-/-) and wildtype control mice (Muc5ac+/+) were subjected to DSS colitis followed by analysis of disease activity parameters. Muc5ac expression in colonic tissue was greatly increased throughout the timecourse of DSS colitis. Upon exposure to DSS, Muc5ac-/- mice demonstrated increased weight loss and colonic shortening in comparison to Muc5ac+/+ mice following 7 days of DSS. Blinded histological analysis revealed that Muc5ac-/- mice experienced dramatically elevated tissue inflammation and injury over that observed in Muc5ac+/+ mice during DSS. Finally, Muc5ac-/- mice exhibited significant mortality compared to wildtype controls as a result of DSS administration. Initial studies indicate that expression of the gel-forming mucin Muc5ac mediates a protective response during acute colitis. This is the first study to present evidence of a direct functional role for Muc5ac in a model of IBD.