Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor

Abstract

<jats:p>Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.</jats:p>

Kynurenic acid may underlie sex-specific immune responses to COVID-19

“…S6A). Because KA is a ligand for AhR, which regulates immune responses and inflammation ( 5 ), we analyzed AhR activation using a previously defined score ( 9 ) and found that AhR activation correlated most positively with KYAT3 expression in the brain and muscle in older males while closely correlating in colon (fig. S6B).…”

B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease

“…However, a recent study found that an alternate mechanism may also be involved in the development of NTDs independently of one-carbon metabolism. Kim et al found that folate and B12 are competitive antagonists of the aryl hydrocarbon receptor (AhR), a nuclear receptor that binds hydrocarbon compounds, like the poison dioxin, and induces expression not only of detoxifying enzymes, but also of homeostatic and developmental genes [86]. Loss of AhR antagonism by folate or B12 due to deficiency or activation of AhR by known agonists increases AhR activity and mimics symptoms of B9 and B12 deficiency [86].…”

“…This blastic change can even lead to the misdiagnosis of leukemia in B12-deficient patients [90,91] and is most often attributed to a maturation arrest of cells due to impaired DNA synthesis from altered one-carbon metabolism [89]. However, activation of the aryl hydrocarbon receptor, potentially from loss of antagonism due to B12 or folate deficiency, can also cause megaloblastic anemia [86], so this alternate mechanism must not be ruled out and can be explored further in clinical studies.…”

Kynurenic acid underlies sex-specific immune responses to COVID-19

“…4a ). Because KA is a ligand for AhR which regulates immune responses and inflammation 6 , we analyzed AhR activation using a previously defined score 10 and found that AhR activation correlates most positively with KYAT3 expression in older males in brain and muscle, while closely correlating in colon ( Extended Data Fig. 4b ).…”