Tryptophan Indole Metabolites Reduce Anastomotic Leakage Through Aryl Hydrocarbon Receptor-Driven Interleukin-22...

Colorectal cancer (CRC) often requires surgical resection of the tumor and an anastomosis. Anastomotic leakage (AL) occurs in 2.8% to 30% of patients, which increases postoperative morbidity and complications. The preoperative microbiome composition is implicated in AL. Recent studies have shown that microbial tryptophan (Trp) metabolism into aryl hydrocarbon receptor (AhR) indole-derivatives contributes to intestinal tissue healing. Here, we addressed the role of Trp and its metabolites in AL in a CRC patient cohort and a colon-anastomosis mouse model.

Targeted quantitative metabolomics was performed in preoperative fecal samples from patients with CRC recruited in the REVEAL cohort (n = 388), including 19 AL cases. Anastomotic healing (AH) was tested in a mouse model using wild-type (WT), AhR^-/-, Villin^CreAhr^fl/fl, and interleukin (IL)-22 drug-targeting to evaluate the role of AhR and IL-22 in AL.

Fifty-two of the 388 patients with available preoperative fecal samples were matched for AH/AL occurrence (AL, n = 19; AH, n = 33). Among Trp metabolites, indole-3-acetic acid was significantly reduced in AL compared with matched AH male patients. AhR^-/- mice displayed more severe AL, reduced IL-22 expression, and a marked loss of IL-22-expressing type 3 ILCs compared with WT mice. Neutralizing IL-22 antibody augmented AL in WT mice, whereas IL-22Fc application ameliorated AL in AhR^-/- mice. AhR agonism failed to rescue healing under IL-22 deficiency. Furthermore, low-Trp diet-fed WT mice exhibited reduced fecal concentration of AhR agonists, AhR-agonist producing bacteria, and augmented AL. This phenotype was prevented by dietary supplementation with the AhR agonist indole-3-carbinol.

Stimulation of the AhR/IL-22 by synthetic agonists or dietary-derived Trp-metabolites can prevent AL.