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Impact et conséquences de l’atteinte de la barrière intestinale au cours du traitement des leucémies aiguës myéloïdes

Abstract : Induction chemotherapy with consolidation followed by allogeneic stem celltransplantation (allo-SCT) remains the standard of care in patients with acute myeloidleukemia (AML). But, high dose chemotherapy is responsible for intestinal impairmentresponsible for complications such as septicemia and Graft vs. Host disease (GvH) afterallo-SCT. The aim of this work was to investigate the specific impact and consequences ofinduction chemotherapy on intestinal barrier in case of AML.First of all, we investigated on 15 patients with AML, clinical, biological (citrullineand short-chain fatty acid) and microbial (qPCR and sequencing on feces) parametersbefore induction chemotherapy (T0), during aplasia (T1) and after hematological recovery(T2). An induction chemotherapy model was designed in a mouse model (Wt mice) withoutantibiotics and in a transgenic model able to release in intestinal lumen a recombinantprotein strengthening mucosal layer (Tg222). Intestinal damage was investigated withplasmatic citrulline level, terminal ileum mucosa analysis on histological slides withapoptosis (TUNEL) and cellular proliferation (PCNA) staining. Adherent microflora wasassessed with qPCR and sequencing on ileum section. Intestinal translocation wasassessed after oral gavage of Salmonella (S). Typhimurium. The fifteen patients hadneutropenic fever and received broad-spectrum antibiotics after chemotherapy completion.Septicemia with E. coli was diagnosed in 26 % of patients. Plasma citrulline level collapsedat T1 and reached normal value at T2. The alpha and beta diversity decreased significantlyand remained low at T2 with a decrease of all bacteria except for enterobacteria,enterococcus and lactobacillus. In mouse model, chemotherapy induced a transientdecrease of all blood counts, and citrulline level. We observed also a terminal ilealimpairment depicted by the increase of apoptosis and PCNA staining and a decrease ofgoblet cells. Three days after the chemotherapy completion, we observed a higher tissuerepair, citrulline level and a preserved alpha diversity in Tg222 mice compared to Wt mice.Intestinal translocation of S. Typhimurium was also lower than in Wt mice.Secondly, plasmatic citrulline level and in vitro macrophage reactivity wereassessed after microbial stimulation with (PAMP) in patients before allo-SCT procedure.Then, the plasma citrulline level as a predictive surrogate marker of GvH was investigatedin a large cohort of patients. Before allo-SCT procedure, a low citrulline level and anincrease of IL-6 and IL-10 released by macrophages were predictive of GvH. A large studywith 191 patients confirmed that a low citrulline level before allo-SCT procedure was anindependent risk factor of intestinal GvH.Intestinal impairment during induction chemotherapy was responsible for a transientepithelial impairment and prolonged dysbiosis leading to bacterial colonization andtranslocation. Before conditioning regimen, a low citrulline level and increased macrophagereactivity reflect sub-clinical damage and are predictive of GvH after allo-SCT procedure. Inmice, mucosal layer strengthening as a proof of concept may enhance tissue repair,maintain microbial diversity and could limit bacterial translocation after high dosechemotherapy.
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Thomas Hueso. Impact et conséquences de l’atteinte de la barrière intestinale au cours du traitement des leucémies aiguës myéloïdes. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2019. Français. ⟨NNT : 2019LIL2S020⟩. ⟨tel-02466311⟩

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