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Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

Anne-Gaëlle Goubet 1, 2, 3 Richard Wheeler 1, 4 Aurélie Fluckiger 1, 3 Bo Qu 5, 1, 3 Fabien Lemaître 6, 1 Kristina Iribarren 1, 6 Laura Mondragón 2, 7, 6, 8 Maryam Tidjani Alou 8, 6 Eugénie Pizzato 6, 8 Sylvère Durand 6 Lisa Derosa 9, 6 Fanny Aprahamian 6 Noélie Bossut 6 Maryse Moya-Nilges 10 Diane Derrien 4 Guo Chen 6, 7, 8 Marion Leduc 6, 7, 8 Adrien Joseph 7, 6, 8 Nicolas Pons 11 Emmanuelle Le Chatelier 11 Nicola Segata 12 Satoru Yonekura 9 Valerio Iebba 9 Oliver Kepp 7, 6 Didier Raoult 13 Fabrice André 2, 6 Guido Kroemer 6, 7, 14, 15, 16 Ivo Gomperts Boneca 4 Laurence Zitvogel 9, 6, 2, * Romain Daillère 6, *
Abstract : A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
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Submitted on : Wednesday, July 7, 2021 - 1:05:05 PM
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Anne-Gaëlle Goubet, Richard Wheeler, Aurélie Fluckiger, Bo Qu, Fabien Lemaître, et al.. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae. Cell Death and Differentiation, Nature Publishing Group, 2021, 28 (7), pp.2276-2295. ⟨10.1038/s41418-021-00753-8⟩. ⟨hal-03280464⟩



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