JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate
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The weaning process accompanies changes in the nutritional profile, metabolism, and gut immune tolerance of offspring. However, the molecular changes associated with this transition and their implications for gut health are not well understood. Here, we show that post-weaning milk-based diets modulate the gut microbiome of pups by enriching Dubosiella newyorkensis. This, in turn, enhances gut barrier function by activating the JNK2 pathway in the epithelium through acetate. However, an inflammation-inducing lard-based high-fat diet, a brief pharmacological inhibition of JNK2, or a two-week delay in the initiation of milk-based diets post-weaning leads to the activation of P38 in the epithelial cells, which leads to inflammation. These observations reveal a microbiome-dependent, short-chain fatty acid-driven dichotomy between JNK2 and P38 pathways in the gut epithelium that modulate gut inflammation. These results provide a framework connecting diets, microbiome, and molecular changes in the epithelium, which may aid the design of microbiome-directed dietary interventions.
