ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR REDUCES VISCERAL HYPERSENSITIVITY IN A MOUSE MODEL OF COLITIS IN REMISSION

Abstract

The aryl hydrocarbon receptor (AhR) is expressed on gut-projecting transient receptor potential vanilloid-1 (TRPV1)+ nociceptors, but whether it has a role in regulating abdominal pain remains to be determined. Approximately 50% of inflammatory bowel disease (IBD) patients experience chronic abdominal pain, even when their inflammatory disease is in remission. Previous work has shown that tryptophan metabolism to indole derivatives is reduced in IBD patients. Since microbial tryptophan metabolites (indole derivatives) serve as ligands for AhR, we hypothesized that reduced AhR activation contributes to enhanced pain sensitivity. We used a post-colitis mouse model of visceral hypersensitivity to examine the role of AhR as a mediator of nociception. AhR activation using both natural and synthetic agonists reduced visceral hypersensitivity in both male and female post-colitis mice. Conversely, pharmacological inhibition of AhR blocked the antinociceptive effects of indoles. Mechanistically, AhR activation by indole-3-pyruvic acid (IPyA) increased the transcription of the inward rectifying potassium channel Kir2.2, in TRPV1+ neurons and markedly reduced neuronal activation within the dorsal horn of the spinal cord. Metagenomic analysis revealed sex differences in indole-producing bacteria, with control males exhibiting enriched abundance of Akkermansia muciniphila and Alistipes compared to post-colitis males and female controls. These findings demonstrate that oral IPyA supplementation in post-colitis mice attenuates visceral hypersensitivity in part through activation of nociceptor AhR, providing insights that support the therapeutic targeting of AhR to treat abdominal pain in IBD patients in remission.