Vitamin B12-mediated microglial immunometabolic reprogramming: A novel mechanistic insight into diabetes-associated cognitive impairment.
TL;DR
Current evidence linking VB12 deficiency to microglial immunometabolic remodeling in diabetes-associated cognitive impairment is summarized and the therapeutic potential of targeting VB12 metabolism and gut microbial ecology for preventing diabetes-related cognitive decline is discussed.
Abstract
Diabetes-associated cognitive impairment (DCI) is an increasingly recognized neurological complication of type 2 diabetes mellitus characterized by chronic neuroinflammation and microglial immunometabolic dysregulation. Vitamin B12 (VB12) deficiency, which is highly prevalent in patients with diabetes, has been strongly associated with cognitive decline, hippocampal atrophy, and white matter injury. Emerging evidence suggests that VB12 plays a critical role in maintaining one‑carbon metabolism, mitochondrial function, and redox homeostasis. Mechanistically, VB12 deficiency promotes homocysteine accumulation, disrupts the S-adenosylmethionine/S-adenosylhomocysteine balance, impairs mitochondrial oxidative phosphorylation, and enhances oxidative stress, thereby driving pro-inflammatory microglial activation and sustained neuroinflammation. In addition, gut microbiota dysbiosis, particularly reduced abundance of Akkermansia muciniphila and other VB12-producing bacteria, may further impair VB12 bioavailability and aggravate neuroinflammation through the gut-brain axis. This review summarizes current evidence linking VB12 deficiency to microglial immunometabolic remodeling in DCI and discusses the therapeutic potential of targeting VB12 metabolism and gut microbial ecology for preventing diabetes-related cognitive decline.