Innate mechanism of mucosal barrier erosion in the pathogenesis of acquired colitis

The colonic mucosal barrier protects against infection, inflammation, and tissue ulceration. Composed primarily of Mucin-2, proteolytic erosion of this barrier is an invariant feature of colitis; however, the molecular mechanisms are not well understood. We have applied a recurrent food poisoning model of acquired inflammatory bowel disease using Salmonella enterica Typhimurium to investigate mucosal barrier erosion. Our findings reveal an innate Toll-like receptor 4-dependent mechanism activated by previous infection that induces Neu3 neuraminidase among colonic epithelial cells concurrent with increased Cathepsin-G protease secretion by Paneth cells. These anatomically separated host responses merge with the desialylation of nascent colonic Mucin-2 by Neu3 rendering the mucosal barrier susceptible to increased proteolytic breakdown by Cathepsin-G. Depletion of Cathepsin-G or Neu3 function using pharmacological inhibitors or genetic-null alleles protected against Mucin-2 proteolysis and barrier erosion and reduced the frequency and severity of colitis, revealing approaches to preserve and potentially restore the mucosal barrier. [Display omitted] •Recurrent Salmonella infection models acquired colitis and inflammatory bowel disease•Colonic mucosal barrier erosion with Mucin-2 proteolysis is a hallmark of colitis•Inductions of host Neu3 and Cathepsin-G are linked to increased Mucin-2 proteolysis•Loss of Neu3 or Cathepsin-G function protects against Mucin-2 proteolysis and colitis Biochemistry; Molecular biology; Immunology; Microbiology