Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer.
Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer.
复制标题
微生物群的3-IAA影响胰腺癌的化学疗法功效。
DOI：
10.1038/s41586-023-05728-y
复制
发表时间：
2023-03
期刊：
影响因子：
64.8
通讯作者：
Gagliani, Nicola
中科院分区：
文献类型：
--
作者：
Tintelnot, Joseph;Xu, Yang;Lesker, Till R.;Schoenlein, Martin;Konczalla, Leonie;Giannou, Anastasios D.;Pelczar, Penelope;Kylies, Dominik;Puelles, Victor G. G.;Bielecka, Agata A. A.;Peschka, Manuela;Cortesi, Filippo;Riecken, Kristoffer;Jung, Maximilian;Amend, Lena;Broering, Tobias S. S.;Trajkovic-Arsic, Marija;Siveke, Jens T. T.;Renne, Thomas;Zhang, Danmei;Boeck, Stefan;Strowig, Till;Uzunoglu, Faik G. G.;Gungoer, Cenap;Stein, Alexander;Izbicki, Jakob R. R.;Bokemeyer, Carsten;Sinn, Marianne;Kimmelman, Alec C. C.;Huber, Samuel;Gagliani, Nicola
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，胰腺导管腺癌（PDAC）将成为第二大致命癌症。不到一半的患者对PDAC的主要治疗有反应，化疗和遗传改变本身不能解释这一点。饮食是一种环境因素，可以影响对治疗的反应，但其在PDAC中的作用尚不清楚。在这里，使用鸟枪宏基因组测序和代谢组学筛选，我们表明，微生物来源的色氨酸代谢产物吲哚-3-乙酸（3-IAA）是丰富的患者谁响应治疗。粪便微生物群移植、色氨酸的短期饮食控制和口服3-IAA给药增加了PDAC的人源化gnotobiotic小鼠模型中化疗的功效。使用组合的损失和增益的功能实验，我们表明，3-IAA和化疗的疗效是由嗜中性粒细胞衍生的髓过氧化物酶许可。髓过氧化物酶氧化3-IAA，其与化疗组合诱导活性氧（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。所有这些都会导致癌细胞中ROS的积累和自噬的下调，这会损害它们的代谢适应性，并最终影响它们的增殖。在人类中，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的显著相关性。总之，我们确定了一种微生物群衍生的代谢物，其在PDAC治疗中具有临床意义，并为在癌症患者治疗期间考虑营养干预提供了动力。吲哚-3-乙酸（3-IAA）是一种来自肠道微生物群的色氨酸代谢物，与胰腺导管腺癌（PDAC）对化疗的更好反应有关，饮食干预可能在治疗PDAC中发挥作用。
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. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy, and genetic alterations alone cannot explain this. 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. Indole-3-acetic acid (3-IAA), a tryptophan metabolite derived from the gut microbiota, is associated with a better response to chemotherapy in pancreatic ductal adenocarcinoma (PDAC), and dietary interventions could have a role in the treatment of PDAC.
登录
查看更多内容
影响因子：
32.4
作者：
Hezaveh K;Shinde RS;Klötgen A;Halaby MJ;Lamorte S;Ciudad MT;Quevedo R;Neufeld L;Liu ZQ;Jin R;Grünwald BT;Foerster EG;Chaharlangi D;Guo M;Makhijani P;Zhang X;Pugh TJ;Pinto DM;Co IL;McGuigan AP;Jang GH;Khokha R;Ohashi PS;O'Kane GM;Gallinger S;Navarre WW;Maughan H;Philpott DJ;Brooks DG;McGaha TL
通讯作者：
McGaha TL
DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
7.7
作者：
Beghini F;McIver LJ;Blanco-Míguez A;Dubois L;Asnicar F;Maharjan S;Mailyan A;Manghi P;Scholz M;Thomas AM;Valles-Colomer M;Weingart G;Zhang Y;Zolfo M;Huttenhower C;Franzosa EA;Segata N
通讯作者：
Segata N
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
4.3
作者：
Kaur, Harrisham;Bose, Chandrani;Mande, Sharmila S.
通讯作者：
Mande, Sharmila S.