Cancer induces a stress ileopathy depending on B-adrenergic receptors and promoting dysbiosis that contribute to carcinogenesis

Satoru Yonekura, Safae Terrisse, Carolina Alves Costa Silva, Antoine Lafarge, Valerio Iebba, Gladys Ferrere, Anne-Gaelle Goubet, Jean-Eudes Fahrner, Imran Lahmar, Kosuke Ueda, Gibrail Mansouri, Eugenie Pizzato, Pierre Ly, Marine Mazzenga, Cassandra Thelemaque, Marine Fidelle, Fanny Jaulin, Jerome Cartry, Marc Deloger, Marine AglaveNathalie Droin, Paule Opolon, Angelique Puget, Fanny Mann, Michel Neunlist, Anne Bessard, Laetitia Aymeric, Tamara Matysiak-Budnik, Jacques Bosq, Paul Hofman, Connie P M Duong, Sophie Ugolini, Valentin Quiniou, Sylvie Berrard, Bernhard Ryffel, Oliver Kepp, Guido Kroemer, Bertrand Routy, Leonardo Lordello, Mohamed-Amine Bani, Nicola Segata, Fjodor Yousef Yengej, Hans Clevers, Jean-Yves Scoazec, Edoardo Pasolli, Lisa Derosa, Laurence Zitvogel

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Gut dysbiosis has been associated with intestinal and extra-intestinal malignancies but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. Rapid onset of tumorigenesis induced a burst of Reg3y release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long lasting dysbiosis dominated by Gram positive Clostridium species. Pharmacological blockade of B-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin or co-housing of tumor bearers with tumor free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Cancer patients harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extra-intestinal malignancies requiring specific therapies.

Original languageEnglish
JournalCancer Discovery
DOIs
Publication statusE-pub ahead of print - 20 Dec 2021

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