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

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Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. / Tintelnot, Joseph; Xu, Yang; Lesker, Till R; Schönlein, 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; Bröring, Tobias S; Trajkovic-Arsic, Marija; Siveke, Jens T; Renné, Thomas; Zhang, Danmei; Boeck, Stefan; Strowig, Till; Uzunoglu, Faik G; Güngör, Cenap; Stein, Alexander; Izbicki, Jakob R; Bokemeyer, Carsten; Sinn, Marianne; Kimmelman, Alec C; Huber, Samuel; Gagliani, Nicola.

in: NATURE, Jahrgang 615, Nr. 7950, 03.2023, S. 168-174.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Tintelnot, J, Xu, Y, Lesker, TR, Schönlein, M, Konczalla, L, Giannou, AD, Pelczar, P, Kylies, D, Puelles, VG, Bielecka, AA, Peschka, M, Cortesi, F, Riecken, K, Jung, M, Amend, L, Bröring, TS, Trajkovic-Arsic, M, Siveke, JT, Renné, T, Zhang, D, Boeck, S, Strowig, T, Uzunoglu, FG, Güngör, C, Stein, A, Izbicki, JR, Bokemeyer, C, Sinn, M, Kimmelman, AC, Huber, S & Gagliani, N 2023, 'Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer', NATURE, Jg. 615, Nr. 7950, S. 168-174. https://doi.org/10.1038/s41586-023-05728-y

APA

Tintelnot, J., Xu, Y., Lesker, T. R., Schönlein, M., Konczalla, L., Giannou, A. D., Pelczar, P., Kylies, D., Puelles, V. G., Bielecka, A. A., Peschka, M., Cortesi, F., Riecken, K., Jung, M., Amend, L., Bröring, T. S., Trajkovic-Arsic, M., Siveke, J. T., Renné, T., ... Gagliani, N. (2023). Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. NATURE, 615(7950), 168-174. https://doi.org/10.1038/s41586-023-05728-y

Vancouver

Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. NATURE. 2023 Mär;615(7950):168-174. https://doi.org/10.1038/s41586-023-05728-y

Bibtex

@article{147d0866c88b493db3765c22a75fa1e5,
title = "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.",
author = "Joseph Tintelnot and Yang Xu and Lesker, {Till R} and Martin Sch{\"o}nlein and Leonie Konczalla and Giannou, {Anastasios D} and Penelope Pelczar and Dominik Kylies and Puelles, {Victor G} and Bielecka, {Agata A} and Manuela Peschka and Filippo Cortesi and Kristoffer Riecken and Maximilian Jung and Lena Amend and Br{\"o}ring, {Tobias S} and Marija Trajkovic-Arsic and Siveke, {Jens T} and Thomas Renn{\'e} and Danmei Zhang and Stefan Boeck and Till Strowig and Uzunoglu, {Faik G} and Cenap G{\"u}ng{\"o}r and Alexander Stein and Izbicki, {Jakob R} and Carsten Bokemeyer and Marianne Sinn and Kimmelman, {Alec C} and Samuel Huber and Nicola Gagliani",
note = "{\textcopyright} 2023. The Author(s).",
year = "2023",
month = mar,
doi = "10.1038/s41586-023-05728-y",
language = "English",
volume = "615",
pages = "168--174",
journal = "NATURE",
issn = "0028-0836",
publisher = "NATURE PUBLISHING GROUP",
number = "7950",

}

RIS

TY - JOUR

T1 - Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

AU - Tintelnot, Joseph

AU - Xu, Yang

AU - Lesker, Till R

AU - Schönlein, Martin

AU - Konczalla, Leonie

AU - Giannou, Anastasios D

AU - Pelczar, Penelope

AU - Kylies, Dominik

AU - Puelles, Victor G

AU - Bielecka, Agata A

AU - Peschka, Manuela

AU - Cortesi, Filippo

AU - Riecken, Kristoffer

AU - Jung, Maximilian

AU - Amend, Lena

AU - Bröring, Tobias S

AU - Trajkovic-Arsic, Marija

AU - Siveke, Jens T

AU - Renné, Thomas

AU - Zhang, Danmei

AU - Boeck, Stefan

AU - Strowig, Till

AU - Uzunoglu, Faik G

AU - Güngör, Cenap

AU - Stein, Alexander

AU - Izbicki, Jakob R

AU - Bokemeyer, Carsten

AU - Sinn, Marianne

AU - Kimmelman, Alec C

AU - Huber, Samuel

AU - Gagliani, Nicola

N1 - © 2023. The Author(s).

PY - 2023/3

Y1 - 2023/3

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-023-05728-y

DO - 10.1038/s41586-023-05728-y

M3 - SCORING: Journal article

C2 - 36813961

VL - 615

SP - 168

EP - 174

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 7950

ER -