Cellular and molecular gastroenterology and hepatology · 2026
Tryptophan Indole Metabolites Reduce Anastomotic Leakage Through Aryl Hydrocarbon Receptor-Driven Interleukin-22 Production.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Bantavi Vasiliki, Gloeck Laura, Leven Patrick, Zafeiropoulou Konstantina, Welting Olaf, Sengül Hilal, Efferz Patrik, Schneiker Bianca, McCulloch Timothy Ryan, Wilhelm Christoph, Blaess Sandra, Fuss Anneke, REVEAL study group, Derikx Joep P M, Sovran Bruno, de Jonge Wouter J, Wehner Sven
Аннотация
BACKGROUND & AIMS: 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.
METHODS: 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-/-, VillinCreAhrfl/fl, and interleukin (IL)-22 drug-targeting to evaluate the role of AhR and IL-22 in AL.
RESULTS: 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.
CONCLUSIONS: Stimulation of the AhR/IL-22 by synthetic agonists or dietary-derived Trp-metabolites can prevent AL.
METHODS: 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-/-, VillinCreAhrfl/fl, and interleukin (IL)-22 drug-targeting to evaluate the role of AhR and IL-22 in AL.
RESULTS: 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.
CONCLUSIONS: Stimulation of the AhR/IL-22 by synthetic agonists or dietary-derived Trp-metabolites can prevent AL.