Dietary Tryptophan Enhances Aryl Hydrocarbon Receptor Activation and Reduces Colitis Through Microbial Metabolism

Disrupted microbial tryptophan metabolism and impaired aryl hydrocarbon receptor activation are implicated in inflammatory bowel disease pathogenesis. However, strategies to restore this pathway through diet or microbial modulation remain poorly defined. This study investigates how dietary tryptophan and human and mouse microbiota modulate metabolism, aryl hydrocarbon receptor activation, and intestinal inflammation in preclinical models.

Gnotobiotic mice colonized with microbiota of varying complexity or human fecal microbiota from patients with ulcerative colitis and healthy controls were used to assess the impact of microbiota and dietary tryptophan supplementation on aryl hydrocarbon receptor activation and colitis severity. Chemically induced and spontaneous colitis models were investigated.

Inflammatory bowel disease fecal samples showed reduced aryl hydrocarbon receptor activation compared with healthy controls, and fecal microbiota transplantation into germ-free mice demonstrated that impaired aryl hydrocarbon receptor is microbiota-dependent. Mice colonized with minimal microbiota had impaired microbial tryptophan metabolism, lower aryl hydrocarbon receptor activation, and worsened colitis severity compared with those colonized with complex microbiota. Dietary tryptophan supplementation in conventional and ulcerative colitis-humanized mice enhanced microbial production of aryl hydrocarbon receptor agonists, restored aryl hydrocarbon receptor activation, and reduced colitis severity in an aryl hydrocarbon receptor-dependent manner. Cocolonization with a tryptophan-metabolizing bacterium, Clostridium sporogenes, further improved tryptophan metabolism and colitis severity in mice with impaired microbial tryptophan metabolism.

Microbial tryptophan metabolism is critical for determining intestinal inflammation. Dietary tryptophan supplementation restores microbial metabolic pathways, mitigates colitis severity in preclinical models, and may address key metabolic deficiencies in patients with inflammatory bowel disease with impaired tryptophan metabolism. This study demonstrates the therapeutic potential of targeting microbial metabolism with diet in inflammatory bowel disease management.