MON-LB022 Gelesis Novel, Non-Systemic, Superabsorbent Hydrogel Improves Intestinal Barrier Function in Mice with DSS Induced Colitis (2019)

BACKGROUND: Intestinal barrier dysfunction exists when the epithelial tight-junctions are disrupted and permit translocation of bacterial lipopolysaccharides into the blood. The resulting endotoxemia cause systemic low-grade inflammation that contributes to the development of comorbidities associated with obesity like type 2 diabetes and NASH. Superabsorbent hydrogels based on the Gelesis platform technology are orally administered and synthesized from crosslinked modified cellulose. Gelesis100, the first in this class, demonstrated significant weight loss in patients with obesity and improvement in insulin sensitivity. We hypothesized that Gel-B with specific mechanical properties, designed to improve intestinal barrier function, would prevent translocation of small molecule into the blood after intestinal barrier injury. METHODS: Groups of 8 to 15 C57BI/6 male mice were administered 3% dextran sodium sulfate (DSS) in drinking water for a total of 6 days, and randomized to either Vehicle, Gel-B (0.5 to 4%) in their food from days 5 to 19. An active control group received anti-p40 IP q3 days on days 6-18. On day 19, all animals were fasted for 4 hours prior to FITC-Dextran dosing. Three hours post dosing, the mice were sacrificed, colon specimen fixed, and blood collected. The incidence of epithelial barrier breaks was assessed with E-cadherin immunohistochemistry. To verify the involvement of epithelial tight junctions, the expression of ZO-1 was assessed in C57BL/6J mice (5 per group) fed chow, for 4 weeks, with or without Gel-B. RESULTS: The level of FITC-Dextran in the serum of mice receiving DSS and vehicle (mean ± SEM, 7.1 ± 4.1) was 3.4 times higher than the naïve mice (2.1 ± 1.1) demonstrating a significant defect in the gut barrier function. In turn, the mice assigned to Gel-B 1% to 4% had meaningful reduction in FITC-Dextran serum levels compared to vehicle treated mice. The highest dose (4%) of Gel-B prevented spilling of dextran into the circulation with serum levels numerically lower than the naïve group with an intact gut barrier (1.4 ± 0.4 compared to 2.1 ± 1.1, respectively). Accordingly, a reduction in epithelial barrier breaks in distal colon samples was observed in the highest dose of Gel-B (0.58 ± 0.15) compared to vehicle treated animals (0.86 ± 0.1). Healthy mice treated with Gel-B (8%) showed increased expression of ZO-1, essential to tight junction assembly between epithelial cells. CONCLUSION: The present study demonstrated that treatment with Gel-B prevented the translocation of small molecule into the circulation indicating an improved intestinal barrier function. This effect may be explained by a decrease in gaps between the epithelial cells, and increased expression of tight junctions. These findings and future studies could provide new therapeutic approaches for diseases affected by a compromised intestinal barrier function such as obesity, diabetes and NASH. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.