A polymer that reinforces luminal barrier function and attenuates inflammation in murine colitis.

Wet epithelial surfaces are protected by mucus, a hydrated gel formed primarily by heavily glycosylated mucins that supports lubrication and limits microbial access to the epithelium. In the colon, barrier function depends on mucus properties that restrict bacterial penetration. Disruption of the mucus barrier integrity allows bacteria and bacterial toxins to contact the epithelium, promoting inflammation and colitis. When sustained, barrier dysfunction and inflammation are associated with an increased risk of colorectal cancer. Although current therapies primarily target downstream immune responses, there remains interest in approaches that directly reinforce mucosal barrier function. Here, we tested the hypothesis that reinforcing luminal separation between bacteria and the epithelium reduces microbial product sensing and innate inflammatory activation in colitis. We developed a polymer that reinforces luminal barrier function and characterized its therapeutic potential in two murine models of compromised epithelial-microbial segregation: a genetic model with impaired mucus production (Agr2-knockout) and a chemically induced injury model (dextran sulfate sodium colitis). Oral administration of the polymer was associated with improved disease indices, reduced histopathological injury, and broad suppression of innate inflammatory programs. Multi-omics profiling further indicates attenuation of LPS-associated signaling and enhancement of epithelial homeostatic signatures following treatment. Our results suggest that reinforcing luminal barrier function may represent a therapeutic approach for attenuating intestinal inflammation by limiting host exposure to luminal microbial products.