The role of the gut microbiome in graft fibrosis after pediatric liver transplantation
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REVIEW
The role of the gut microbiome in graft fibrosis after pediatric liver transplantation Tian Qin1 · Jingyuan Fu1,2 · Henkjan J. Verkade1 Received: 22 June 2020 / Accepted: 29 August 2020 © The Author(s) 2020
Abstract Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the postLT fibrogenesis, however, to date, neither of the factors seems to fully explain the cause of graft fibrosis. Recently, evidence has accumulated on the important role of the gut microbiome in outcomes after solid organ transplantation. As an altered microbiome is present in pediatric patients with end-stage liver diseases, we hypothesize that the persisting alterations in microbial composition or function contribute to the development of graft fibrosis, for example by bacteria translocation due to increased intestinal permeability, imbalanced bile acids metabolism, and/or decreased production of short-chain fatty acids (SCFAs). Subsequently, an immune response can be activated in the graft, together with the stimulation of fibrogenesis. Here we review current knowledge about the potential mechanisms by which alterations in microbial composition or function may lead to graft fibrosis in pediatric LT and we provide prospective views on the efficacy of gut microbiome manipulation as a therapeutic target to alleviate the graft fibrosis and to improve long-term survival after LT. Abbreviations ALD Alcoholic liver disease BMI Body-mass index DAMP Damage-associated molecular pattern DSA Donor-specific antibody ECM Extracellular matrix FMT Fecal microbiota transplant FXR Farnesoid X receptor HSC Hepatic stellate cell IRI Ischemia–reperfusion injury LT Liver transplantation LPS Lipopolysaccharide NAFLD Non-alcoholic fatty liver disease Jingyuan Fu and Henkjan J. Verkade have shared last authorship. * Henkjan J. Verkade [email protected] 1
Pediatric Gastroenterology/Hepatology, Section of Nutrition and Metabolism, Research Laboratory of Pediatrics, Department of Pediatrics, Beatrix Children’s Hospital/ University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
2
NF-κB Nuclear factor kappa B PAMP Pathogen-associated molecular pattern PRR Pattern recognition receptor PTLD Post-transplantation lymphoproliferative disease SCFA Short-chain fatty acid TGFβ Transforming growth factor β TLR Toll-like receptor
Introduction Pediatric liver transplantation (LT) has become a standard procedure for children with end-stage liver disease, for example due to biliary atresia or progressive familial intrahepatic cholestasis. The number of LTs perfo
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