Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Abstract

Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics. However, the exact status and causal role of CLDN3 in IBD and regulation of gut dysbiosis remain unknown. Analysis of mouse and human IBD cohorts helped examine CLDN3 expression in IBD. The causal role was determined by modeling CLDN3 loss of expression during experimental colitis. 16S sequencing and in silico analysis helped examine gut microbiota diversity between Cldn3 KO and WT mice and potential host metabolic responses. Fecal microbiota transplant (FMT) studies were performed to assess the role of gut dysbiosis in the increased susceptibility of Cldn3 KO mice to colitis. A significant decrease in CLDN3 expression characterized IBD and CLDN3 loss of expression promoted colitis. 16S sequencing analysis suggested gut microbiota changes in Cldn3 KO mice that were capable of modulating fatty acid metabolism and oxidative stress response. FMT from naïve Cldn3 KO mice promoted colitis susceptibility in recipient germ-free mice (GFM) compared with GFM-receiving microbiota from WT mice. Our data demonstrate a critical role of CLDN3 in maintaining normal gut microbiota and inflammatory responses, which can be harnessed to develop novel therapeutic opportunities for patients with IBD.

Stable Dietary Ora-Curcumin Formulation Protects from Experimental Colitis and Colorectal Cancer

“…They were kept in individually ventilated cages in compliance with the approved protocol from the University of Nebraska Medical Center, Omaha (protocol # 17-126-11FC). Colitis was induced in mice using Dextran Sodium Sulfate (DSS) as described previously [ 28 ]. Briefly, male ( n = 18) and female ( n = 6) mice (10–12 weeks old) were provided regular drinking water or 2.5%DSS ( w / v ; MW = 36–40 kD, TdB Labs, Sweden) for nine days.…”