Abstract
Dysregulation of the gut-brain metabolic axis has been implicated in the progression of diabetes-associated cognitive decline (DACD), yet its underlying mechanism remains largely unknown. Herein, we identified a low abundance of Akkermansia muciniphila (AKK) and high leucine levels as key driving factors of DACD in both diabetic mice and patients. Our results revealed that AKK bacteria hold the capacity to catabolize leucine, and the elevated leucine levels observed in diabetic mice and patients are partly attributed to a low abundance of AKK bacteria. Moreover, leucine supplementation and deprivation further confirmed that excessive leucine accelerated and aggravated the progression of DACD in mice. Mechanistically, leucine directly modulated the phosphorylation of TBK1 and, in turn, phosphorylated the autophagy adaptor OPTN, thereby enhancing its binding capacity to LC3 and Ub chains and triggering neuronal excessive mitophagy. Therefore, this study uncovers a new mechanism of the gut-brain metabolic axis involved in DACD progression and provides a novel perspective for gut-targeted therapy of cognitive disorders.