Papel do receptor de hidrocarbonetos aromáticos (AHR) e do metabolismo de triptofano no controle da disbiose e da lesão tecidual associada à mucosite intestinal induzida por 5-fluorouracil

Abstract

Intestinal mucositis is a common adverse effect in patients undergoing chemotherapy, such as with 5-Fluorouracil (5-FU), which may result in discontinuation of treatment. Previous studies have suggested the importance of the microbial metabolites derived from the amino acid tryptophan (TRP) in the attenuation of inflammatory bowel diseases (IBD), through activation of the aryl hydrocarbon receptor (AHR). However, studies correlating AHR with protection against chemotherapy-induced intestinal mucositis are scant. Therefore, our objective was to evaluate the role of TRP metabolites and AHR during 5-FU-induced intestinal mucositis. AHR-deficient mice (AHR-/-) or mice treated with this receptor antagonist (α-naphthoflavone - α-NF) were more susceptible to chemotherapy. Activation of AHR was not dependent on host metabolism from TRP, once IDO1- deficient mice (IDO1-/-), enzyme that convert tryptophan (Trp) to kynurenine (KYN), mice were not more susceptible to chemotherapy. However, treatment with ampicillin aggravated the disease and promoted dysbiosis, similarly to what was seen in AHR-/- animals undergoing chemotherapy. These clinical changes were reversed following administration of Indole-3-aldehyde (Iald), which is an AHR agonist synthesized by some lactic-acid bacteria from TRP. However, Iald did not interfere in the dysbiosis observed in the animals treated with ampicillin. In addition, it was not established whether Iald influences the inflammatory response. Hence, AHR does not appear to interfere with the control of the inflammation present in the gut after administration of 5-FU. Thus, further analyzes are required to demonstrate the mechanism of activation of AHR by microbial metabolites of TRP and its activities during the response to chemotherapeutics. In conclusion the findings of the present study suggest that ampicillin-sensitive lactic-acid bacteria protect against the adverse effects caused by chemotherapy by producing AHR-activating TRP metabolites.