Urolithin A Attenuates Diabetes-Associated Cognitive Impairment by Ameliorating Intestinal Barrier Dysfunction via N-glycan Biosynthesis Pathway

Scope This study aims to investigate the effect of Urolithin A (UA) on diabetes-associated cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ). Methods and Results The UA-treated T2DM mice display an attenuated cognitive impairment as well as reduced levels of metabolic endotoxemia and proinflammatory cytokines in serum. A systemic restraint of gut/brain inflammation in UA-treated T2DM mice is also observed as the downregulation of TLR4 and Myd88 in colon along with the inhibition of GFAP, Iba-1, NLRP3, and inflammation-related genes in brain. Moreover, UA ameliorates gut barrier dysfunction by upregulating tight-junction proteins levels. Furthermore, UA restores the hyperglycemia-mediated downregulation of genes involved in N-glycan biosynthesis both in vivo and in vitro, which plays a crucial role in barrier integrity. Although UA shares similar beneficial effects on diabetes with metformin, unlike metformin, the effect of UA is independent of gut microbiome and short chain fatty acids. Taken together, these data suggest that feeding UA can attenuate diabetes-associated cognitive impairment by ameliorating systemic inflammation and intestinal barrier dysfunction via N-glycan biosynthesis pathway. The study implies UA as a potential novel pharmaceutic target for diabetes therapy via manipulating gut-brain axis and N-glycan metabolism.

Automated summary

This study investigates the effect of Urolithin A (UA) on diabetes-associated cognitive impairment in a mouse model of type 2 diabetes mellitus (T2DM) induced by a high-fat diet (HFD) and streptozotocin (STZ). The results show that UA treatment can attenuate cognitive impairment and reduce levels of metabolic endotoxemia and proinflammatory cytokines in serum. UA also suppresses gut/brain inflammation, improves gut barrier function, and restores the dysregulation of genes involved in N-glycan biosynthesis. Unlike metformin, the beneficial effects of UA are independent of the gut microbiome and short-chain fatty acids. These findings suggest that UA has the potential to be a novel pharmacological target for diabetes therapy by manipulating the gut-brain axis and N-glycan metabolism.