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Etude de microbiote biliaire associé aux cholangiocarcinomes (CCA) et caractérisation des mécanismes impliqués

Abstract : Cancer is the leading cause of death in France. Cholangiocarcinomas (CCAs) orcancers of the bile ducts represent 3% of all digestive cancers. Intrahepatic CCAs, with 10 to 20% of the total, are the second most common primary malignant tumor of the liver after hepatocarcinoma. Bile is a biologically sterile fluid, synthesized in the liver, housed in the gallbladder and released into the duodenum after food intake.Microbial populations in different parts of the mammalian gastrointestinal tract (stomach, small intestine, colon, stool) have been studied. Changes in the human microbiota have been associated with the development of colorectal, pancreatic and lung cancer. In most of the series studied, the mechanism linking the microbiota tocarcinogenesis seems to be of epigenetic type. Biliary carcinogenesis is poorly understood, with genetic characteristics of individuals and environmental factors playing a major role. The characterization of the biliary microbiota has only been approached in a fragmentary way until now.We characterized the biliary microbiota in patients with extrahepatic ACC and in control subjects without tumors. Bile samples were collected by ERCP endoscopic retrograde pancreatic cholangiography from 28 sporadic patients CCA and 47 control subjects (gallstone carriers).Bile was subjected to bacterial DNA extractions as well as human genome methylation characterization using bacteria 16S ribosomal RNA sequencing and methylation arrays (Illumina). In addition, gene methylation profiles were characterized in tissue samples of pancreatic adenocarcinoma and CCAs.We were able to show a biliary dysbiosis associated with CCAs, identified a signaturenepigenetic linked to CCAs and distinguished its specificity versus that of peripheral blood mononuclear cells (PBMC). Two candidate genes were selected by methylation microarray analysis and their expression was then studied by immunohistochemistry (IHC) in tumor tissues of intra- and extrahepatic CCAs and pancreatic adenocarcinoma. We concluded on a possible relationship between biliary dysbiosis and the expression level of the two genes through the phenomenon of dysmethylation. These results could have a diagnostic impact and become therapeutic targets.
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Submitted on : Friday, May 13, 2022 - 6:41:49 PM
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Massa Saab. Etude de microbiote biliaire associé aux cholangiocarcinomes (CCA) et caractérisation des mécanismes impliqués. Médecine humaine et pathologie. Université Paris-Est, 2021. Français. ⟨NNT : 2021PESC0053⟩. ⟨tel-03667959⟩

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