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 Using an antibiotic-LPS co-exposure enteropathy model, we investigated whether Akkermansia muciniphila (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
Ye et al. (Tue,) studied this question.