A study published in March in Nature shows that microbiota-derived metabolites modulate tumor growth by shaping anti-tumor immunity, as previously described, and also by amplifying chemotherapy responses. Tintelnot et al. investigated how the intestinal microbiota or associated dietary metabolites may determine the efficacy of chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients who respond to chemotherapy were found to have distinct microbiota, which, when transferred into gnotobiotic mice with orthotopic pancreatic tumors, consistently conferred improved chemotherapy responses.
The blood levels of the tryptophan metabolite indole-3-acetic acid (3-IAA), which is produced by intestinal commensals such as Bacteroides fragilis and Bacteroides thetaiotaomicron, correlated with the microbiota profile of responders to chemotherapy. 3-IAA supplementation in specific-pathogen-free mice with pancreatic tumors reversed chemoresistance via a mechanism that did not involve T cells, or the immunomodulatory indole receptor AhR, but required expression of myeloperoxidase (MPO), mainly in neutrophils. MPO oxidizes 3-IAA into toxic byproducts, and high plasma levels of 3-IAA amplified neutropenia in chemotherapy-receiving mice or patients. In addition, the combination of chemotherapy and 3-IAA downregulated the expression of enzymes that degrade reactive oxygen species and impaired autophagy. Based on their findings, the authors highlight the clinical potential of 3-IAA for amplifying chemotherapy responses in patients with mPDAC or other cancers, while also noting the known immunosuppressive effects of long-term indole supplementation.
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