Homocysteine, Nutrition, and Gut Microbiota: A Comprehensive Review of Current Evidence and Insights

Abstract

Homocysteine, a sulfur-containing amino acid, is an intermediate product during the metabolism of methionine, a vital amino acid. An elevated concentration of homocysteine in the plasma, named hyperhomocysteinemia, has been significantly related to the onset of several diseases, including diabetes, multiple sclerosis, osteoporosis, cancer, and neurodegenerative disorders such as dementia, Alzheimer's and Parkinson's diseases. An interaction between metabolic pathways of homocysteine and gut microbiota has been reported, and specific microbial signatures have been found in individuals experiencing hyperhomocysteinemia. Furthermore, some evidence suggests that gut microbial modulation may exert an influence on homocysteine levels and related disease progression. Conventional approaches for managing hyperhomocysteinemia typically involve dietary interventions alongside the administration of supplements such as B vitamins and betaine. The present review aims to synthesize recent advancements in understanding interventions targeted at mitigating hyperhomocysteinemia, with a particular emphasis on the role of gut microbiota in these strategies. The emerging therapeutic potential of gut microbiota has been reported for several diseases. Indeed, a better understanding of the complex interaction between microbial species and homocysteine metabolism may help in finding novel therapeutic strategies to counteract hyperhomocysteinemia.

Keywords: diet; folic acid; gut microbiota; homocysteine; supplements; vitamin B12.

Figure 1

Schematic diagram of Hcy biosynthesis, including the metabolic processes of reverse transsulfuration pathway and de novo pathway and re-methylation associated with the folate cycle. L-Methionine is activated by ATP in a reaction catalyzed by methionine S-adenosyl-transferase with the concomitant hydrolysis of ATP and formation of S-Adenosyl-L-Methionine (SAM). The latter is demethylated into S-adenosyl-L-homocysteine (SAH) coupled with methylation of an acceptor -R into -RCH₃. SAH is hydrolyzed into L-homocysteine (Hcy) and adenosine by S-adenosyl-L-homocysteine hydrolase. In the reverse transsulfuration pathway, the condensation of L-serine (L-Ser) with Hcy forms L-cystathionine through the PLP-dependent cystathionine β-synthase (CBS) activity, followed by the conversion of L-cystathionine into cysteine (Cys) and α-ketobutyrate catalyzed by PLP– dependent cystathionine-γ-lyase (CGL). Demethylation of N5-methyl-tetrahydrofolate (5-methyl-THF) into THF and concomitant Hcy remethylation into L-Methionine by methionine synthase dependent on vitamin B12. The reduction of 5,10-methylene-THF into 5-methyl-THF is catalyzed by N5,10-methylenetetrahydrofolate reductase (MTHFR). In bacteria and plants, the de novo pathway forms L-cysteine from L-serine through the intermediate O-acetylserine by two tandem reactions mediated by serine O-acetyl transferase (SAT) and O-acetylserine sulfhydrylase (OASS).

Figure 2

Schematic diagram of the mechanisms of gut microorganisms likely influencing homocysteine metabolism. The microbial species mentioned represent only a fraction of gut microorganisms involved in processes such as inflammation, sulfur reduction, and the production of B vitamins, which could impact homocysteine metabolism.