Abstract
Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease. Here, we show that the gut microbe Akkermansia muciniphila can mediate negative effects of IFNγ on glucose tolerance. In IFNγ-deficient mice, A. muciniphila is significantly increased and restoration of IFNγ levels reduces A. muciniphila abundance. We further show that IFNγ-knockout mice whose microbiota does not contain A. muciniphila do not show improvement in glucose tolerance and adding back A. muciniphila promoted enhanced glucose tolerance. We go on to identify Irgm1 as an IFNγ-regulated gene in the mouse ileum that controls gut A. muciniphila levels. A. muciniphila is also linked to IFNγ-regulated gene expression in the intestine and glucose parameters in humans, suggesting that this trialogue between IFNγ, A. muciniphila and glucose tolerance might be an evolutionally conserved mechanism regulating metabolic health in mice and humans.
Highlights
Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease
Numerous studies have revealed the involvement of the immune system in regulation of metabolism, and how the alteration of the immune system can contribute to metabolic abnormalities such as type 2 diabetes and metabolic syndrome[1,2,3,4,5]
Similar to previous reports[6,7,8], we observed that glucose tolerance is significantly improved in IFNgKO mice (Fig. 1a)
Summary
Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease. Numerous studies have revealed the involvement of the immune system in regulation of metabolism, and how the alteration of the immune system can contribute to metabolic abnormalities such as type 2 diabetes and metabolic syndrome[1,2,3,4,5] These studies have primarily focused on immune cell effects on fat, liver and muscle, as besides the pancreas, these tissues are considered major metabolic organs responsible for glucose and lipid metabolism. One such example is the influence of IFNg, which is a central cytokine of the immune system, on systemic glucose metabolism. This phenomenon has been attributed to reduced hepatic glucose production[6] and increased insulin sensitivity, possibly related to reduced adipose inflammation in case of obese animals[8]
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