小柯机器人

德国汉堡大学医学中心Nicola Gagliani等研究人员合作发现，微生物群衍生的3-IAA影响胰腺癌的化疗疗效。2023年2月22日，国际知名学术期刊《自然》在线发表了这一成果。

利用猎枪元基因组测序和代谢组筛选，研究人员表明，微生物群衍生的色氨酸代谢物吲哚-3-乙酸（3-IAA）在对治疗有反应的患者中富集。粪便微生物群移植、短期饮食操纵色氨酸和口服3-IAA可以增加胰腺导管腺癌（PDAC）人源定菌小鼠模型的化疗疗效。利用功能缺失和功能增益的组合实验，研究人员表明3-IAA和化疗的疗效是由中性粒细胞衍生的骨髓过氧化物酶实现的。髓过氧化物酶氧化3-IAA，与化疗相结合，诱导活性氧（ROS）降解酶谷胱甘肽过氧化物酶3和谷胱甘肽过氧化物酶7的下调。所有这些都导致了ROS的积累和癌细胞自噬的下调，这损害了它们的代谢能力，并最终影响了它们的增殖。在人类中，研究人员观察到在两个独立的PDAC队列中，3-IAA的水平和疗效之间存在着明显的相关性。总之，研究人员确定了一种微生物群衍生的代谢物，对PDAC的治疗有临床意义，并为在治疗癌症患者期间考虑营养干预提供了动力。

据了解，由于转移性疾病的高发病率和对治疗的有限反应，预计到2040年，PDAC将成为第二大致命的癌症。不到一半的患者对PDAC的主要治疗方法——化疗有反应，仅靠基因改变不能解释这种情况。饮食是一个环境因素，可以影响对治疗的反应，但它在PDAC中的作用还不清楚。

附：英文原文

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

Author: Tintelnot, Joseph, Xu, Yang, Lesker, Till R., Schnlein, Martin, Konczalla, Leonie, Giannou, Anastasios D., Pelczar, Penelope, Kylies, Dominik, Puelles, Victor G., Bielecka, Agata A., Peschka, Manuela, Cortesi, Filippo, Riecken, Kristoffer, Jung, Maximilian, Amend, Lena, Brring, Tobias S., Trajkovic-Arsic, Marija, Siveke, Jens T., Renn, Thomas, Zhang, Danmei, Boeck, Stefan, Strowig, Till, Uzunoglu, Faik G., Gngr, Cenap, Stein, Alexander, Izbicki, Jakob R., Bokemeyer, Carsten, Sinn, Marianne, Kimmelman, Alec C., Huber, Samuel, Gagliani, Nicola

Issue&Volume: 2023-02-22

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 peroxidase3 and glutathione peroxidase7. 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.

DOI: 10.1038/s41586-023-05728-y

Source: https://www.nature.com/articles/s41586-023-05728-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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