Verdugo Meza, A.; Josephson, J. K.; Dadlani, H.; Yuzbashian, E.; Davidson-Hunt, A.; Ishida, R.; Ghosh, S.; Gibson, D. L.

Live biotherapeutic products (LBPs) show promise for treating metabolic and inflammatory diseases, but their efficacy is limited by poor persistence in inflamed gut environments. EcN::ttr is a LBP designed to harness inflammation and is effective in the treatment of acute and chronic colitis. Diet-induced gut dysfunction can drive metabolic and behavioural alterations, we evaluated how EcN::ttr protects mice fed a proinflammatory omega-6-rich diet. EcN::ttr improved insulin sensitivity, associated with increased hepatic insulin receptor expression and reduced GSK3{beta} activation and endoplasmic reticulum stress EcN::ttr-treated mice exhibited notable changes in the gut, including an improved pattern of occludin expression, accompanied by reduced serum LPS-binding protein, indicating protection against endotoxemia. Bile acid analysis revealed more abundant SBA in mice treated with EcN::ttr, along with specific beneficial modulation of bile acids influencing diarrhea and bile acid detoxification. Behavioural assessment highlighted a normalization of long-term memory along with a reduction of stress management behaviours. Altogether, EcN::ttr restores gut liver brain axis function through coordinated modulation of inflammation, barrier integrity, and bile acid metabolism.