Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Dominique Debray; Haquima El Mourabit; Fatiha Merabtene; Loïc Brot; Damien Ulveling; Yves Chrétien; Dominique Rainteau; Ivan Moszer; Dominique Wendum; Harry Sokol; Chantal Housset

doi:10.1002/hep4.1266

Diet-Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Hepatol Commun. 2018 Oct 10;2(12):1533-1549. doi: 10.1002/hep4.1266. eCollection 2018 Dec.

Authors

Dominique Debray^{1

2}, Haquima El Mourabit¹, Fatiha Merabtene¹, Loïc Brot³, Damien Ulveling⁴, Yves Chrétien¹, Dominique Rainteau³, Ivan Moszer⁴, Dominique Wendum^{1

5}, Harry Sokol^{3

6}, Chantal Housset^{1

6}

Affiliations

¹ Sorbonne Université, INSERM Centre de Recherche Saint-Antoine (CRSA), and Institute of Cardiometabolism and Nutrition (ICAN) Paris France.
² Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants Malades Pediatric Hepatology Unit Paris France.
³ Sorbonne Université, INSERM ERL U1157 Paris France.
⁴ Sorbonne Université, INSERM Institut du Cerveau et de la Moelle Epinière (ICM), Bioinformatics-Biostatistics Core Facility Paris France.
⁵ Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine Pathology Department Paris France.
⁶ Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine Department of Hepato-Gastroenterology Paris France.

Abstract

The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)^-/- mice and Cftr ^+/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr ^-/- mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr ^+/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr ^-/- mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr ^-/- mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immune-related genetic susceptibility, promotes CF-related cholangiopathy.