Short-term and long-term development of gut microbiota in children after liver transplantation-A prospective observational trial

Abstract

In children, little is known about gut microbiota (GM) in end-stage liver disease and its association with graft function after pediatric liver transplantation (pLT). We analyzed GM composition and function in children before pLT, longitudinally post-pLT and in long-term survivors (LT-pLT) in order to assess the impact of disease severity, treatment, and pLT on GM and delineate associations with graft and patient health. Fecal samples (FS) of 29 children [17f (female), age 2.6 (0.2-15.7) years] awaiting pLT were included with longitudinal follow-ups until 12 months post-transplant in 18, and compared with 38 LT-pLT [21f, age 11 (2.7-17.7) years, 7.8 (1.0-17.0) years post-pLT] and 94 healthy controls (HCs). Samples were analyzed using quantitative 16S rRNA gene analyses combined with shotgun metagenomics (subset of samples). Pre-pLT patients showed reduced alpha-diversities and altered GM composition compared with LT-pLT and HC, associated with disease severity and anti-pruritic treatment with rifampicin. Dysbiosis increased after pLT and started to recover after 3M (months). Although bacterial concentrations, alpha diversity, and gene richness increased post-pLT, levels remained below those of HC. Abundances of key functions, for example, the capacity to synthesize butyrate, also remained reduced. Quantitative analyses revealed the true extent of differences between patients and HC that were underestimated using relative abundance data. GM diversity and functional capacities correlated negatively with transaminase levels mid-term and long-term after pLT. Random Forest analyses based on GM were able to predict hepatocellular damage at high accuracy (AUC: 0.89). We provide comprehensive, quantitative insights into GM composition and function before and after pLT. A link between GM alterations and (long-term) graft health was uncovered, providing possible targets to modulate GM function in order to increase graft and patient health.

Keywords: dysbiosis; graft function; long-term follow-up; pediatric; protocol biopsies.