Vitamin B12 and gut-brain homeostasis in the pathophysiology of ischemic stroke

Abstract

Stroke is a leading cause of morbidity and mortality worldwide. It inflicts immeasurable suffering on patients and their loved ones and carries an immense social cost. Efforts to mitigate the impact of stroke have focused on identifying therapeutic targets for the prevention and treatment. The gut microbiome represents one such potential target given its multifaceted effects on conditions known to cause and worsen the severity of stroke. Vitamin B12 (VB12) serves as a cofactor for two enzymes, methylmalonyl-CoA synthase and methionine synthase, vital for methionine and nucleotide biosynthesis. VB12 deficiency results in a buildup of metabolic substrates, such as homocysteine, that alter immune homeostasis and contribute to atherosclerotic disorders, including ischemic stroke. In addition to its support of cellular function, VB12 serves as a metabolic cofactor for gut microbes. By shaping microbial communities, VB12 further impacts local and peripheral immunity. Growing evidence suggests that gut dysbiosis-related immune dysfunction induced by VB12 deficiency may potentially contributes to stroke pathogenesis, its severity, and patient outcomes. In this review, we discuss the complex interactions of VB12, gut microbes and the associated metabolites, and immune homeostasis throughout the natural history of ischemic stroke.

Keywords: Atherosclerosis; Cerberovascular Disease; Cobalamin; Homocysteine; Inflammation; Ischemic stroke; Microglia; Neuroinflammation; Stroke; Vitamin B12; gut microbiome; gut-brain axis; innate immunity; metabolism; metabolites; microbiome.

Fig. 1

Vitamin B12 Biosynthetic Pathways. De Novo biosynthesis occurs with divergent enzymatic pathways based on the availability of oxygen. Gut microbes with necessary biochemical machinery convert glutamate and glycine to 5-aminolevulinate, which is then converted to uroporphyrinogen III (UroIII). The cobA gene product converts UroIII to precorrin-2, the last common intermediate between the anaerobic and aerobic pathways which converge with the production of Cob(II)yrinic acid, a,c-diamide, which, through an additional series of reactions, is then converted to adenosylcobalamin (VB12).

Fig. 2

VB12 absorption and impact on neuroinflammation after ischemic stroke. Gut microbes compete with IF for dietary VB12. VB12 promotes growth of SCFA-producing bacteria. SCFAs bind GPR41/43 in the intestinal epithelium and promote differentiation of naïve Th cells to functional FoxP3⁺ Tregs in the intestinal submucosa. Peripheral circulating immune cells are recruited to the brain parenchyma by crossing the disrupted BBB. Centrally-recruited Helios⁺ Tregs suppress highly activated astrocytes and microglia, which produce tissue injury and exacerbation of the inflammatory cascade by secreting inflammatory cytokines and injurious ROS. By contrast, dysfunctional Tregs lack the regulation of overactivated microglia with proinflammatory M1 phenotype and astrocytes, all of which further exacerbate toxic inflammation, potentially resulting in scar formation and tissue injury.