Etude prospective du microbiote et du profil des acides biliaires dans la cholangite sclérosante primitive et/ou auto-immune (overlap syndrome) de l’enfant et de l’efficacité des traitements modificateurs de la flore.

Details

Supervisors

Sokal, Etienne

Faculty

Faculté de médecine et médecine dentaire

Degree label

Master [180] en médecine

Abstract

enIntroduction: Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) can both be present, resulting in overlap syndrome (OS) diagnosis, also called autoimmune sclerosing cholangitis (ASC), and can be associated with ulcerative colitis (UC). The physiopathology of sclerosing cholangitis could be based on the cross-talk between gut microbiota and bile acids (BA). Antibiotic therapy is an innovative therapy for PSC. The objective of this interventional academic study is to demonstrate the efficacy of Metronidazole (MTZ) in OS or PSC and to evaluate its effects on the gut microbiota and the BA profile. Methods: Patients with OS or PSC from the paediatric hepato-gastroenterology department of Cliniques universitaires Saint-Luc (CUSL), with or without UC, are enrolled in the so called “treated group”. The “control group” is composed with untreated MTZ paediatric patients with none hepatologic or intestinal disease. The study drug is MTZ (Flagyl®) administrated for 14 days. Faeces and blood samples are collected before treatment with MTZ (T0) and after treatment with MTZ (T14) to analyze the BA profile and the gut microbiota. The outcome is a sustained biochemical remission defined as AST, ALT and GGT levels below 1,5x upper limit of normal (ULN) and CRP below laboratory standards, until 12 months after MTZ treatment. Results: 18 patients were enrolled in the treated group: 7 in the retrospective study part (from April 2016), and 12 in the prospective study part (from December 2017 to February 2020), with a mean age at inclusion of 13,2 years (+/- 4,5). One patient was included in both study parts. Thirteen patients had OS, 5 had only PSC and 13 had concomitant UC. Six patients were recruited in the control group with a mean age of 7,7 years (+/- 5,7). CRP, AST, ALT and GGT levels decreased after MTZ therapy (except for GGT in “relapse patients”). For “remission patients”, AST decreased by -44,4 U/L as mean difference (p-value 0,0497), ALT by -64,7 U/L (p-value 0,0182) ; for “relapse patients”, AST decreased by -35,8 U/L (p-value 0,0338), ALT by -55,6 U/L (p-value 0,0088). The mean sum of plasma BA was smaller in the control group (1637,5 pmol/mL) than in treated group (34833,5 pmol/mL) (p-value 0,0006). In remission patients, hydrophilic plasma BA mean relative abundance increased by + 6,3% (p-value 0,0391) after MTZ therapy. Their faecal BA profile MANON KAREMERA - MASTER EN MÉDECINE – 2020-2021 - UCLouvain Page 6 sur 102 changed too. Concerning the gut microbiota, no statistically significant difference was observed about alpha- and beta-diversity metrics at T0, and between T0 and T14 (in “remission” nor in “relapse patients”). Conclusion: These discriminating biochemical data tend to demonstrate a long-term benefit of MTZ therapy for patients at an early stage of PSC or OS. This is combined with a significant increase of hydrophilic BA abundance for remission patients. It could unfortunately not be associated with changes in the gut microbiota at the same time. Our results support the design of larger studies about this population of paediatric OS / PSC patients.