MC-LR induces and exacerbates Colitis in mice through the JAK1/STAT3 pathway.

Abstract

Inflammatory bowel disease (IBD) is a complex gastrointestinal disorder attributed to genetic and environmental factors. Microcystin-leucine-arginine (MC-LR) is an environmental toxin that accumulates in the gut and produces intestinal damage. The aim of this study was to investigate the effects of exposure to MC-LR on development and progression of IBD as well examine the underlying mechanisms of microcystin-initiated tissue damage. Male C57BL/6 mice were treated with either MC-LR alone or concurrently with dextran-sulfate sodium (DSS). Mice were divided into 4 groups (1): PBS gavage (control, CT) (2); 200 μg/kg MC-LR gavage (MC-LR) (3); 3% DSS Drinking Water (DSS); and (4) 3% DSS Drinking Water + 200 μg/kg MC-LR gavage (DSS + MC-LR). The mice in each experimental group exhibited reduced body weight, shortened colon length, increased disease activity index (DAI) score, a disrupted intestinal barrier, and elevated levels of proinflammatory cytokines compared to control. Compared to the group treated with MC-LR alone, colitis symptoms were exacerbated following combined exposure to both DSS and MC-LR. Subsequent experiments confirmed that MC-LR or DSS increased protein phosphorylation levels of Janus Kinase1 (JAK1) and Signal Transducer and Activator of Transcription3 (STAT3). Compared to group treated with MC-LR alone, the combined treatment of DSS and MC-LR also significantly upregulated the expression of related proteins. In conclusion, our study indicates that MC-LR-induced colitis involves activation of JAK1/STAT3 signaling pathway and that MC-LR exacerbates DSS-induced colitis through the same pathway.