Akkermansia muciniphila alleviates antibiotic- and LPS-induced oxidative stress via the p38α MAPK–Nrf2 signaling axis

Background: Antibiotic abuse and subsequent infection induce dysregulation of the intestinal epithelial kinome, characterized by p38α hyperphosphorylation (encoded by MAPK14), a common molecular trigger for barrier failure. Readily druggable nodes to repair this dysregulation remain elusive. Methods: (AKK) exerts protective effects via modulation of specific host signaling pathways. Results: We found that AKK reactivates the "p38α MAPK-Nrf2" signaling pathway. Mechanistically, AKK specifically alleviates p38α subtype-mediated suppression of Nrf2, thereby synergistically enhancing the expression of antioxidant enzymes such as HO-1 and NQO1, reducing excessive reactive oxygen species (ROS) production, and restoring the integrity of epithelial tight junctions and mucus layers. Conclusion: Our work is the first to establish the "AKK-p38α MAPK-Nrf2" axis as a druggable kinase module for antibiotic-associated intestinal disease, providing an immediately translatable molecular foundation for developing oral, mechanism-defined, and precise microecological therapies.