The JNK2-microbiome axis modulates gut barrier integrity through microbial acetate

Background Weaning involves a nutritional shift from fat-rich milk to carbohydrate-based solid food, reshaping metabolism, microbiota, and gut immune tolerance. While dairy remains a component of the human diet beyond weaning, the impact of continued milk supplementation on gut epithelial homeostasis remains poorly understood.Result Here, using a mouse model, we show that continued milk-based feeding post-weaning promotes intestinal barrier function by enriching the commensal bacterium Dubosiella newyorkensis, which produces acetate to activate epithelial JNK2 signaling. This pathway enhances barrier integrity and suppresses inflammation induced by mild dextran sodium sulfate (DSS) treatment. In contrast, feeding a lard-based high-fat diet or transient pharmacologic inhibition of JNK2 induces epithelial P38 activation, resulting in barrier disruption and inflammation. Importantly, the beneficial effects of milk were observed only if they were initiated during the weaning period, when the microbiome is in a metastable transitional state. Initiation of the same intervention two weeks after weaning led to P38 activation and inflammatory responses.Conclusion Our findings show that immediate post-weaning milk supplementation preserves a beneficial gut microbiome, marked by the persistence of D. newyorkensis and enhanced gut barrier integrity. Even a one-week delay eliminates this protective effect, emphasizing the critical timing of post-weaning nutritional intervention for maintaining intestinal health.