Accepted_test

Intestinal barrier dysfunction, also known as “leaky gut”, is characteristic of gastrointestinal diseases, especially inflammatory bowel diseases (IBD), celiac disease, enteric infections, irritable bowel syndrome (IBS), and others. Despite the extensive research in this field, there are only a few drugs available for the treatment of IBD in clinical practice. Although numerous works have investigated the mechanisms underlying the regulation of gut barrier function using models of acute inflammation, there is still a lack of understanding about how the barrier function of the intestine is compromised during the development of low-grade inflammation. Here we show that phospholipid metabolism is impaired in transgenic Muc2 mouse model of chronic colitis, which is supported by the transcriptomic and metabolomic analysis of the descending large intestine. This data was supported in two alternative models of chronic colitis in mice in vivo: chemically-induced and associated with T-cells adoptive transfer colitis. We proposed that the upregulated ceramide metabolism might be responsible for the impairment of filamentous actin dynamics impairment, which in turn controls barrier function. The addition of ceramide and ceramide-synthase inhibitors affect actin polymerization, tight- and adherence junction proteins localization to the membrane, and intestinal barrier function in two independent mouse colitis models in vivo. This data agrees with current studies suggesting upregulation of ceramide in IBD patients. Thus, our data provides a novel mechanism that underlies intestinal barrier disfunction upon chronic colitis.