Acetobacter and lactobacillus alleviate the symptom of insulin resistance by blocking the JNK-JAK/STAT pathway in Drosophila melanogaster

The dysregulation of intestinal microbiota is well-known to be one of the main causes of insulin resistance in both vertebrates and invertebrates. Specially, the acetobacter and lactobacillus have been identified as potentially capable of alleviating insulin resistance. However, the molecular mechanism underlying this effect requires further elucidation. In this study, we employed Drosophila melanogaster (fruit fly) as a model organism to delineate how intestinal microbiota disrupts the host intestinal signaling pathway, contributing to insulin resistance. Our findings demonstrate that a long-term high-sugar diet lead to a reduction in the general diversity of intestinal microbiota in flies, as well as a marked decrease in the abundances of acetobacter and lactobacillus. Furthermore, we observed that symptoms of insulin resistance were alleviated by feeding flies with acetobacter or lactobacillus, indicating that these microorganisms play an essential role in maintaining blood sugar homeostasis in flies. Conversely, when all intestinal microbiota was removed, flies show severe symptoms of insulin resistance, confirming that the critical role of intestinal microbiota in maintaining host blood sugar homeostasis. Our studies suggested that the intestinal but not fat body JNK pathway mediates the communication of intestinal microbiota and host insulin pathway. In flies, downregulation of JNK activity alleviates symptoms of insulin resistance by decreasing the activity of the JAK/STAT pathway. However, this offsets the therapeutic effects of supplying flies with acetobacter or lactobacillus, suggesting that the therapeutic function of these microorganisms is based on their interaction with JNK-JAK/STAT axis. Taken together, our study reveals that acetobacter and lactobacillus alleviate insulin resistance symptoms in a JNK-JAK/STAT pathway-dependent manner, indicating the therapeutic potential of probiotic supplementation and regulation of the activities of JNK-JAK/STAT pathway for diabetes control.