The role of the gut microbiome in graft fibrosis after pediatric liver transplantation

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 post-LT 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.

Fig. 1

Possible mechanisms of persistent dysbiosis in liver fibrosis. DAMP damage-associated molecular pattern, ECM extracellular matrix, FXR farnesoid X receptor, PAMP pathogen-associated molecular pattern, SCFA short-chain fatty acid, TGFβ transforming growth factor β, TLR toll-like receptor

Fig. 2

Translocation of PAMPs due to higher intestinal permeability. Alteration of the intestinal microbiome, caused by liver diseases, administration of antibiotics or potential post-LT complications, is hypothesized to contribute to the graft fibrogenesis. Thus, the altered microbial composition/function leads to increased intestinal permeability and translocation of bacteria along with PAMPs to liver via the portal vein. Translocated PAMPs activate TLRs on hepatic Kupffer cells to induce the proinflammatory pathways, further resulting in the activation of HSCs. HSCs produce the ECM and initiate the liver fibrogenesis. ECM, extracellular matrix, HSC hepatic stellate cell, PAMP pathogen-associated molecular pattern, TLR toll-like receptor

Fig. 3

Experimental framework to understand the role of microbial composition/function on the development of graft fibrosis post LT. a Hypothesis that altered gut microbial composition/function contributes to the development of graft fibrosis in pediatric LT; b Experimental framework containing three objectives to systematically evaluate various aspects of the hypothesized role of the gut microbiome on graft fibrosis after pediatric LT. FMT fecal microbiota transplant, LT liver transplantation, PAMP pathogen-associated molecular pattern; SCFA short-chain fatty acid