Overexpression of mitochondrial STAT3 protein improves colonic inflammation and fibrosis in inflammatory bowel disease by enhancing mitochondrial function.

Abstract

INTRODUCTION: The STAT3 protein is involved in mitochondrial functions such as the respiratory electron transport chain, regulation of cellular metabolism, and scavenging of reactive oxygen species. Inflammatory bowel disease (IBD) is associated with damaged intestinal cells and mitochondrial dysfunction due to the inflammatory environment of the intestine. Here, we studied the potential use of thegene to induce STAT3 expression in mitochondria to help treat IBD. METHODS: We transferred thegene and examined its effects on the expression of proinflammatory cytokines and fibrosis markers, and mitochondrial function, in intestinal tissues via immunohistochemistry. The microbiomes of mice were also analyzed. RESULTS: The gene increased the expression of mitochondrial STAT3 (mtSTAT3), which reduced the levels of iNOS and fibrosis factors (aSMA, COL1A1) as well as proinflammatory cytokines (IL-17, IL-6) in the colon. It also enhanced mitochondrial function in the colon, and in immune cells, and led to higher levels of the beneficial bacteriaandin the intestine. Taken together, these changes helped alleviate colitis and protected against intestinal damage. DISCUSSION: Stat3 gene transfer targeting mtSTAT3 expression ameliorates colitis, enhances mitochondrial function in the colon, and reduces inflammation via inhibition of the inflammatory response and necroptosis, offering a potential treatment for IBD.