Akkermansia muciniphila Alleviates Circadian Rhythm Disruption-Induced Intestinal Barrier Injury via Activation of the KEAP1-NRF2 Pathway

<title>Abstract</title> <p>Circadian rhythm disruption (CRD) increases the risk of gastrointestinal disorders, but the role of gut microbiota in this process remains unclear. Here we established a continuous-light-induced CRD mouse model and a clinical cohort of shift workers, and found that CRD induced intestinal barrier injury, oxidative stress and gut dysbiosis, with significant depletion of Akkermansia muciniphila (AKK). Oral AKK supplementation dose-dependently restored barrier integrity, upregulated glycerol-3-phosphate, and activated the KEAP1–NRF2 antioxidant pathway; pharmacological inhibition of NRF2 by ML385 markedly attenuated AKK’s protective effects. Our findings indicate that AKK alleviates CRD-induced intestinal barrier injury via KEAP1–NRF2 activation, supporting a potential probiotic strategy for circadian-related gastrointestinal disorders.</p>