An Engineered Live Biotherapeutic Restores Gut–Liver–Brain Axis Function by Reducing Inflammatory Pathways from Diet-Induced Stress

Systemic inflammatory diseases can be influenced by dietary intake, with gastrointestinal dysfunction driving both metabolic and behavioural changes mirroring the altered inflammatory profile. Additionally, the use of live biotherapeutic products (LBPs) shows promise for treating metabolic and inflammatory diseases, but their efficacy is limited by poor persistence in inflamed gut environments. Designed to utilize inflammatory byproducts, the LBP EcN:: ttr has proven efficacy in the treatment of acute and chronic colitis, however its effects on the metabolic and behavioural patterns remain uncharacterized.

We evaluated the effects of EcN:: ttr on mice fed a proinflammatory omega-6 PUFA-rich diet. EcN:: ttr -treated mice exhibited notable changes in the gut, including an improved expression of tight junction protein occludin, accompanied by reduced serum lipopolysaccharide (LPS) - binding protein, indicating protection against endotoxemia. EcN:: ttr improved insulin sensitivity compared to the parental strain, associated with increased hepatic insulin receptor expression and reduced GSK3β activation and endoplasmic reticulum stress. Secondary bile acids in mice treated with EcN:: ttr were more abundant, with increases in those associated with resolving 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.