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

Abstract

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.

Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

“…Cani et al, 2009;Li et al, 2019). Our detection results of intestinal barrier integrity related parameters showed that the intestinal barrier integrity was damaged in DCI mice, which was consistent with previous reports (Visser et al, 2010;Li et al, 2022;Xiao et al, 2022). Likewise, our results show that ZSWF exhibits a protective effect on intestinal barrier integrity in DCI mice by increasing colon tight junction protein expression (ZO-1 and occludin) and mucin (Muc2) content, as well as colon content immunoglobulin A (SlgA) levels.…”

Ellagitannins-Derived Intestinal Microbial Metabolite Urolithin A Ameliorates Fructose-Driven Hepatosteatosis by Suppressing Hepatic Lipid Metabolic Reprogramming and Inducing Lipophagy

“…UroA is a gut microbiome-derived metabolite of dietary ellagitannins belonging to the family of urolithins characterized by a chemical structure containing the α-benzo-coumarin scaffold that shows health benefits for metabolic diseases and age-related conditions. Previous studies have demonstrated the protective role of UroA against metabolic dysfunctions in vivo , such as atherosclerosis, metabolic cardiomyopathy, and obesity. − Relevant data concerning the regulation of glucose metabolism have demonstrated that UroA ameliorated hyperglycemia, insulin resistance, and glucose intolerance in diet-induced-obesity mice. , Also, UroA robustly lowered fasting blood glucose in a diet-induced insulin resistance mouse model by inhibiting hepatic gluconeogenesis . Moreover, UroA could reduce fasting blood glucose, after-glucose-loading glucose, and glycated hemoglobin levels by restoring pancreatic β cell function via autophagy activation in a type 2 diabetes model induced by HFD and streptozotocin injection .…”

Ameliorative Effects of Gut Microbial Metabolite Urolithin A on Pancreatic Diseases

“…Moreover, there are many studies on the ameliorative effect of Uro A on DM and its complications, and most of them are mainly achieved by improving insulin resistance [112,113]. However, the effects and mechanisms of Uro A directly acting on β cells to boost glucose metabolism disorders were not discussed in detail.…”

“…Albasher et al further demonstrated that Uro A prevents streptozotocin (STZ)-induced DCM in rats by activating SIRT1 expression and deacetylase activity [112]. Xiao et al suggested that Uro A can attenuate DM-related cognitive impairment by ameliorating systemic inflammation and intestinal barrier dysfunction through the N-glycan biosynthesis pathway [113]. This conclusion was also supported by Lee et al They pointed out that Uro A prevented DM-associated AD by reducing transglutaminase type 2 (TGM2)-dependent mitochondria-associated ER membrane (MAM) formation and maintaining mitochondrial calcium and ROS homeostasis [35].…”