Aryl hydrocarbon receptor ligand production by the gut microbiota is decreased in celiac disease leading to intestinal inflammation

Abstract:

Metabolism of tryptophan by the gut microbiota into derivatives that activate the aryl hydrocarbon receptor (AhR) contributes to intestinal homeostasis.

Many chronic inflammatory conditions, including celiac disease involving a loss of tolerance to dietary gluten, are influenced by cues from the gut microbiota. We investigated whether AhR ligand production by the gut microbiota could influence gluten immunopathology in nonobese diabetic (NOD) mice expressing DQ8, a celiac disease susceptibility gene.

NOD/DQ8 mice, exposed or not exposed to gluten, were subjected to three interventions directed at enhancing AhR pathway activation. These included a high-tryptophan diet, gavage with Lactobacillus reuteri that produces AhR ligands or treatment with an AhR agonist. We investigated intestinal permeability, gut microbiota composition determined by 16S rRNA gene sequencing, AhR pathway activation in intestinal contents, and small intestinal pathology and inflammatory markers.

In NOD/DQ8 mice, a high-tryptophan diet modulated gut microbiota composition and enhanced AhR ligand production. AhR pathway activation by an enriched tryptophan diet, treatment with the AhR ligand producer L. reuteri, or pharmacological stimulation using 6-formylindolo (3,2-b) carbazole (Ficz) decreased immunopathology in NOD/DQ8 mice exposed to gluten.

We then determined AhR ligand production by the fecal microbiota and AhR activation in patients with active celiac disease compared to nonceliac control individuals.

Patients with active celiac disease demonstrated reduced AhR ligand production and lower intestinal AhR pathway activation.

These results highlight gut microbiota-dependent modulation of the AhR pathway in celiac disease and suggest a new therapeutic strategy for treating this disorder.

The advantage of a high-tryptophan diet

Although 40% of the worldwide population express celiac disease susceptibility genes, only 1% will develop the disorder, suggesting a role for environmental factors, including the gut microbiota.

Lamas et al. show that celiac disease is associated with an impaired capacity of the gut microbiota to metabolize tryptophan into aryl hydrocarbon receptor (AhR) ligands in patients with celiac disease.

Gluten-induced immunopathology in mice expressing a celiac disease susceptibility gene was ameliorated after AhR pathway activation by a high-tryptophan diet, or by treatment with a pharmacological AhR agonist or bacteria producing AhR ligands.

AhR pathway modulation by the gut microbiota may have potential as a therapeutic strategy for treating celiac disease.