1. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening
- Author
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Hueso, Thomas, Ekpe, Kenneth, Mayeur, Camille, Gatse, Anna, Joncquel-Chevallier Curt, Marie, Gricourt, Guillaume, Rodriguez, Christophe, Burdet, Charles, Ulmann, Guillaume, Neut, Christel, Amini, Salah-Eddine, Lepage, Patricia, Raynard, Bruno, Willekens, Christophe, Micol, Jean-Baptiste, de Botton, Stéphane, Yakoub-Agha, Ibrahim, Gottrand, Frédéric, Desseyn, Jean-Luc, Thomas, Muriel, Woerther, Paul-Louis, Seguy, David, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Lille (CHU Lille), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Emergence de la résistance bactérienne in vivo (EA3964), Université Paris Diderot - Paris 7 (UPD7), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Centre hospitalier universitaire Henri-Mondor [Créteil], Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospital of Lille, MSD, École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Lille, and Tâche, Roselyne
- Subjects
Adult ,Male ,[SDV]Life Sciences [q-bio] ,Mice, Transgenic ,chemotherapy ,Feces ,Mice ,mucus ,Antineoplastic Combined Chemotherapy Protocols ,microbiota ,Animals ,Humans ,acute leukemia ,Intestinal Mucosa ,lcsh:RC799-869 ,Aged ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Induction Chemotherapy ,Middle Aged ,Fatty Acids, Volatile ,Gastrointestinal Microbiome ,[SDV] Life Sciences [q-bio] ,Leukemia, Myeloid, Acute ,intestinal barrier ,Dysbiosis ,Female ,lcsh:Diseases of the digestive system. Gastroenterology ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Research Article ,Research Paper - Abstract
International audience; Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except forEscherichia coliandEnterococcusspp., which became dominant. Both the alpha and beta-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase ofE. coliandEnterococcusspp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved alpha-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.
- Published
- 2020