Vitamin B12 coordinates ileal epithelial cell and microbiota functions to resist Salmonella infection in mice

Vitamin B12 (VB12), is an essential water-soluble micronutrient that is synthesized exclusively by bacteria and is obtained in the diet through consumption of animal-source foods. VB12 is an important cofactor of methionine-synthase, converting homocysteine into methionine. Subclinical VB12 deficiency reduces the conversion of homocysteine to methionine, leading to an elevated intracellular homocysteine level. Homocysteine has been discussed as mediating reactive oxygen species accumulation through multiple mechanisms, including autooxidation of homocysteine, leading to H₂O₂, and by inhibition of cellular antioxidant enzymes, namely, glutathione peroxidase and superoxide dismutase. When homocysteine levels become out of control, this increases the risk of cardiovascular diseases.

Clinical VB12 deficiency leading to myeloneuropathy or megaloblastic anemia is rare in developed countries, but subclinical VB12 deficiency is common and can be found in 10 -15% of individuals older than 60 years and in 25 – 35% of individuals aged over 80 years. In addition to inadequate dietary intake, VB12 deficiency can result from low bioavailability or impaired absorption, due to pernicious anemia (an autoimmune disease affecting parietal cells and release of intrinsic factor, required for vitamin B-12 absorption); atrophic gastritis, malabsorption, and risk of pernicious anemia, which increase with age; medications (e.g., proton pump inhibitors); and gastrointestinal diseases (e.g., inflammatory bowel disease) or gastrointestinal infections.

Micronutrients calibrate intestinal homeostasis and human health by regulating cellular molecular dynamics, microbial structure, and the accompanying metabolism. Although the clinical effects of VB12 deficiency have been thoroughly investigated, further research is still needed to understand the VB12-dependent molecular pathways controlling the genomic and metabolic homeostasis of ileal epithelial cells (iECs).

In a recent study published in the Journal of Experimental Medicine, scientists from the University of Texas Health: Yong Ge, Mojgan Zadeh, and led by distinguished Professor Mansour Mohamadzadeh elucidated VB12-dependent regulation of the genomic fitness of iECs and gut microbiome, as well as associated metabolic responses, during steady-state and Salmonella Typhimurium (STm) infection. They suggested that oral VB12 supplementation modifies the transcriptional and metabolic machinery of iECs and supports microbiota composition and activity, which may work in concert to control iECs’ mitochondrial metabolisms and limit intestinal oxygen-dependent STm infection.

Professor Mansour Mohamadzadeh laboratory is internationally recognized for mucosal inflammation and gastrointestinal infectious diseases research. In the new study, his research team looked at the functions of VB12 in preserving iECs’ functional homeostasis both in steady state and during STm infection. VB12 administration boosted the transcription of genes with mitochondrial encoding as well as the metabolic activity of the carnitine shuttle and TCA cycle in iECs. Importantly, no mitochondrial activation was identified in cecal or colonic ECs, whereas this VB12-dependent regulation was only observed in iECs. The authors found that VB12 preserved the diversity and composition of gut bacteria and more crucially, the metabolites that the bacteria produced. For example, VB12 intake enhanced the amount of Turicibacter, which was linked to changes in the routes for fatty acid synthesis and activation, particularly in the ileal lumen during STm infection. This increased bioavailability of luminal free fatty acids like γ-linolenic acid and 13(S)-HODE, which may act as ligands to activate PPARs in iECs, led to the STm infection.

The research team demonstrated in animal studies the evidence that VB12 therapy increases the number of Bacteroidetes and the related propionate during STm infection in the colon. They showed that mice orally infected with STm were protected by VB12-supported Bacteroidetes, which encouraged the formation of short-chain fatty acids, particularly propionate. Researchers reported using elegant experimental studies the mechanism of how resisting Salmonella infection via VB12 administration. The authors found that fecal water extracts from VB12-gavaged mice inhibited the expression of SPI-1 genes, which may have limited the mice’s susceptibility to systemic STm infection. Moreover, VB12 supplementation inhibited oxygen-mediated STm development, possibly due to an increase in short-chain fatty acids produced by the cecal and colonic microbiota, however, it had no effect on those metabolites in the intestine.

In conclusion, Professor Mansour Mohamadzadeh and his research group findings are in line with a unique perspective paradigm in which VB12 mediates the coordination of microbial and epithelial responses to intestine STm infection. The emerging mechanisms showing this intricate interaction at the intestinal mucosal surface may offer interesting targets to enhance the contribution of essential cofactors, including VB12, to strengthen host and microbial balance, thereby enhancing host health.