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

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 treatment[ 1, 2 ]. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy[ 3, 4 ], and genetic alterations alone cannot explain this[ 5 ]. 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.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）预计到2040年将成为第二大致死性癌症，究其原因在于转移性疾病高发且患者对治疗的响应率有限[1, 2]。仅有不足半数的PDAC患者可对一线化疗方案产生应答[3, 4]，而仅依靠遗传变异无法解释这一现象[5]。饮食作为一种可影响治疗响应的环境因素，其在PDAC中的作用仍不明确。本研究借助鸟枪宏基因组测序（shotgun metagenomic sequencing）与代谢组学筛选（metabolomic screening）技术，发现治疗应答患者体内菌群衍生的色氨酸代谢物吲哚-3-乙酸（indole-3-acetic acid, 3-IAA）水平显著富集。粪便菌群移植（faecal microbiota transplantation）、短期色氨酸饮食干预以及口服3-IAA，均可在人源化无菌小鼠PDAC模型中增强化疗疗效。通过结合功能丧失与功能获得性实验，我们证实3-IAA联合化疗的疗效由中性粒细胞（neutrophil）衍生的髓过氧化物酶（myeloperoxidase）介导。髓过氧化物酶可氧化3-IAA，该代谢物与化疗联合后可诱导活性氧（reactive oxygen species, ROS）降解酶谷胱甘肽过氧化物酶3与谷胱甘肽过氧化物酶7的表达下调。上述所有过程最终导致癌细胞内ROS积累以及自噬（autophagy）下调，削弱癌细胞的代谢适应性，最终抑制其增殖。在人类受试者中，我们在两个独立的PDAC队列中观察到3-IAA水平与治疗疗效之间存在显著相关性。综上，本研究鉴定出一种具有临床转化价值的菌群衍生代谢物，并为癌症治疗期间考虑营养干预策略提供了理论依据。