New studies in mice show how an inability to metabolize tryptophan may be related to celiac disease, according to Bruno Lamas and colleagues. The findings offer one environmental factor that could help explain why 40% of the global population expresses a celiac disease susceptibility gene, but only 1% of those people develop the gluten intolerance disease. It may also point to new molecular targets or possible dietary strategies to treat the disease. Gut bacteria metabolize tryptophan, a dietary amino acid, into aryl hydrocarbon receptor (AhR) ligand molecules. These molecules then bind with AhR receptor proteins to trigger molecular signaling that orchestrates immune responses in sites such as the gut mucosa. In mice that express a celiac disease susceptibility gene, impaired tryptophan metabolism promoted celiac disease inflammation. Lamas et al. show that a high-tryptophan diet can shift the gut bacteria composition in these mice to produce more AhR ligand molecules and consequently reduce gluten-related inflammation. Treatment with bacteria such as Lactobacillus reuteri that produce AhR ligand molecules relieved celiac inflammation in the mice; in a separate experiment, treatment with a drug called Ficz that boosts AhR activity also yielded similar results. The researchers also analyzed fecal samples from people with active celiac disease, finding fewer AhR ligands than in people with healthy guts and those with the disease in remission from a gluten-free diet.