Aryl hydrocarbon receptor (AHR): Towards understanding intestinal microbial ligands including vitamin B12 and folic acid as natural antagonists

AHR has been identified as ligand-modulated transcription factor and environmental sensor. However, explanation of its multiple agonistic and antagonistic ligands is far from complete. Studies of AHR's role in hostmicrobiome interaction are currently a fruitful area of research. Microbial products and virulence factors have been identified as AHR agonists. In steady state they are involved in safeguarding intestinal barrier integrity. When virulence factors from pathogenic bacteria are identified by AHR of intestinal immune cells, anti-microbial defense mechanisms are activated by generating reactive oxygen species (ROS) in intestinal epithelial cells and recruited immune cells. ROS production has to be strictly controlled, and anti-inflammatory responses have to be initiated timely in the resolution phase of inflammation to avoid tissue damage and chronic inflammatory responses. Surprisingly, bacteria-generated vitamin B12/cobalamin and vitamin B9/folic acid have been identified as natural AHR antagonists, stimulating the interest of biochemists. Hints for AHR-cobalamin antagonism are pointing to cobalamin-dependent enzymes leading to alterations of TCA cycle intermediates, and TCDD-mediated loss of serum cobalamin. Although we are still at the beginning to understand mechanisms, it is likely that scientific efforts are on a rewarding path to understand novel AHR functions.

Automated summary

AHR is a ligand-modulated transcription factor and environmental sensor, but the explanation of its multiple agonistic and antagonistic ligands remains incomplete. The role of AHR in host-microbiome interaction is currently a fruitful area of research. Microbial products and virulence factors have been identified as AHR agonists, playing a role in maintaining intestinal barrier integrity. The activation of anti-microbial defense mechanisms by AHR contributes to ROS production and recruitment of immune cells.