Alternate day fasting alleviates neuroinflammation in diabetic mice by regulating δ-valerobetaine-carnitine-microglia axis via enrichment of Akkermansia muciniphila.

BACKGROUND: Alternate day fasting (ADF) as a healthy dietary pattern has been reported to improve brain functions and behaviors, but the effect of ADF on diabetes-related brain disorders and the potential mechanisms remain unclear. In this study, we investigated the impact of ADF on neuroinflammation and exploratory behavior in type 1 diabetic (T1D) mice and explored the specific molecular mechanisms from the perspective of the gut microbiota and host metabolism. RESULTS: ADF can effectively relieve neuroinflammation and exploratory behavioral disorders in T1D mice. According to fecal microbiota transplant and bacterial supplementation, we demonstrated that ADF-driven enrichment of Akkermansia muciniphila (AKK) was necessary for boosting exploratory behavior in T1D mice. The gut microbiota-derived metabolite δ-valerobetaine (VB) reduced hepatic carnitine synthesis by inhibiting BBOX, and caused exploratory behavioral disorders in mice. In vitro and in vivo studies revealed that AKK bacteria had the ability to consume VB, and thereby increased systemic carnitine level. In addition, carnitine was found to deplete lipid droplet accumulation in microglia by enhancing fatty acid oxidation and lipolysis, reduce neuroinflammation and neuron injury, and then increase exploratory behavior in T1D mice. CONCLUSIONS: Our study sheds light on the gut-liver-brain metabolic axis mechanism on the protective role of ADF in T1D-associated neuroinflammation and exploratory behavioral disorders and AKK bacteria exert as a key mediator. Video Abstract.