Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.

Microbiota-Derived Tryptophan Metabolite Indole-3-Acetic Acid Improves Chemoresistance in Pancreatic Ductal Adenocarcinoma

“…Mechanistically, 3-IAA can be oxidized to various toxic products such as 3-methylene-2-oxindole by neutrophil-derived myeloperoxidase (MPO), thereby inducing neutrophil necrosis and enhancing the inhibitory effects of FIRINOX on tumor growth. 6 This observation was in line with a recent report that neutropenia (low neutrophil count) caused by chemotherapy was associated with longer survival in metastatic PDAC. 7 On the other hand, 3-IAA and MPO co-treatment significantly increase reactive oxygen species (ROS) accumulation by inhibiting antioxidant enzymes glutathione peroxidases3/7 (GPX3/GPX7) expression, and high ROS levels can act as crucial inducer for chemotherapy-induced program cell death.…”

“…Notably, autophagy has been reported to be extraordinary eminent in PDAC and considered as a promising target for therapy. In line with it, Tintelnot and his colleagues 6 found that high concentration of ROS can subsequently decrease autophagy in cancer cells, which ultimately mediated the synergistic antitumor effect of 3-IAA and FIRINOX (shown in Fig. 1).…”

“…5 As highlighted previously, microbiota diversity can influence chemotherapy efficacy in PDAC. More recently, Tintelnot et al 6 found that intestinal microbiota was different between PDAC R patients (responsive to chemotherapy) and NR patients (nonresponsive to chemotherapy). With shotgun metagenomic sequencing and metabolomic screening, they further identified that the microbiota-derived tryptophan (Trp) metabolite indole-3-acetic acid (3-IAA) was significantly enriched in the serum of R patients compared with NR patients, mainly produced by Bacteroides fragilis and Bacteroides thetaiotaomicron.…”

Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology

“…And most of the pancreatic cancer tissues have been detected with bacteria, the majority of which are Gammaproteobacteria , 141 indicating the underlying mechanisms of poor response to chemotherapy in pancreatic cancer. On the other hand, microbiota‐derived tryptophan metabolite indole‐3‐acetic acid enhanced the chemotherapeutic effects of pancreatic cancer via elevating the accumulation of Reactive Oxygen Species (ROS) and downregulating autophagy in cancer cells 142 . And intratumor Clostridium butyricum and its metabolite butyrate could promote susceptibility to ferroptosis in pancreatic cancer, 143 which is a promising way to enhance therapeutic effects 144 .…”

The double‐edged role of neutrophil heterogeneity in inflammatory diseases and cancers

“…Targeting tumor‐associated CXCR2 + neutrophils and CCR2 + macrophages was reported to improve chemotherapeutic responses in pancreatic ductal adenocarcinoma 342 . In a nutshell, a series of studies have shown that it is necessary to investigate neutrophil heterogeneity in the context of pancreatic cancer treatment 266–343 . For subsequent investigation, the inductive factors of the emergence of diverse neutrophil subsets may be probed, enabling a brand‐new viewpoint for the treatment of pancreatic cancer.…”