we addressed whether the established dialogue between IFNg and glucose metabolism involves a third player – the gut microbiota. By using systems biology approaches and analyzing trans-kingdom interactions we found that, indeed, the effect of IFNg on glucose tolerance is mediated by one of the members of mouse gut microbiota, Akkermansia muciniphila. Further, we have identified Irgm1 as a IFNg-regulated host gene responsible for control of A. muciniphila levels in the gut. In addition, the investigation of human subjects revealed that A. muciniphila may play similar roles in mouse and human physiology.. Akkermansia muciniphila mediates negative effects of IFNg on glucose metabolism

There is growing appreciation for how extensive cooperation across seemingly distant biological systems is critical for human health. Microbiota is emerging as a frequent mediator of this cooperation with studies demonstrating the importance of cross-talk between the gut microbiota and the host immune regulates host for maintaining a healthy metabolism, and its dysregulation can cause metabolic disease. Here In the current work, we addressed whether the gut microbiota mediates the established dialogue between interferon-gamma (IFNg and glucose metabolism. By using systems biology approaches and analyzing transkingdom interactions we found show that the gut microbe Akkermansia muciniphila mediates the negative effects of IFNg on glucose tolerance. In IFN-deficient mice, A. muciniphila is significantly increased and restoration of IFN levels reduces A. muciniphila abundance. Importantly, we further show that IFN-knockout mice whose microbiota does not contain A. muciniphila do not show is required for the improvements of in glucose tolerance that is observed in these mice. Furthermore, We go on to identify have identified Irgm1 as an IFNg-dependent regulated gene in the mouse ileum that involved in controls of gut A. muciniphila levels in the gut. Lastly, A. muciniphila is also linked to IFNg dependent gene expression in the intestine and glucose parameters in humans, suggesting that this trialogue between IFNg, A. muciniphila and glucose tolerance might be an evolutionally conserved mechanism regulating metabolic health in mice and humans.