Health-related quality of life is linked to the gut microbiome in kidney transplant recipients

Abstract

Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species are associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome distance to the general population is highest among KTR with an impaired physical HRQoL (R = -0.20, P = 2.3 × 10^-65) and mental HRQoL (R = -0.14, P = 1.3 × 10^-3). Physical and mental HRQoL explain a significant part of variance in the gut microbiome (R² = 0.58%, FDR = 5.43 × 10^-4 and R² = 0.37%, FDR = 1.38 × 10^-3, respectively). Additionally, multiple metabolic and neuroactive pathways (gut brain modules) are associated with lower HRQoL. While the observational design of our study does not allow us to analyze causality, we provide a comprehensive overview of the associations between the gut microbiome and HRQoL while controlling for confounders.

Fig. 1. Disease-associated bacterial species in the gut microbiome of KTR are associated with HRQoL.

a, b Principal component analysis on the clr-transformed species reflecting the Aitchison distances between KTR. The physical component score (a) and the mental component score (b) are divided into quartiles (KTR were divided into quartiles (Q1, Q2, Q3, Q4) based on their PCS and MCS with Q1 containing the lowest HRQoL scores and Q4 the highest HRQoL scores). The large dots represent centroids per group and the dashed circles represent 95% confidence ellipses. c, d Correlation plot with spearman correlation and 95% confidence interval for the physical component score (c) the mental component score (d) and the distance to general population controls. This dysbiosis score was calculated previously by calculating the Aitchison distance from KTR with 1183 age-, sex- and BMI-matched general population controls¹³. e Heatmap depicting significant correlations between species that have previously been associated with disease vs. no disease in the Dutch microbiome project (DMP)²¹. Species that are associated with no disease in the DMP (green squares) were consistently, positively and significantly associated with principal component 1 (i.e. higher HRQoL) in our study while the opposite effect was observed for species that were associated with disease in the DMP.

Fig. 2. Overview of associations of HRQoL and physical and mental assessments with gut microbial species.

Heatmap depicting significant spearman correlations (indicated with blue color for negative correlations and red for positive correlations) of general, HRQoL, physical health and mental health variables with Shannon diversity index (Shannon div.). In the Permutational Multivariate Analysis of Variance (PERMANOVA) column the percentage of explained variance from the ADONIS analysis are shown. Bars in green represent the number of included microbiome features in the elastic-model with a β < -0.1 or (a) β > 0.1. In the columns, species, metabolic pathways and gut brain modules, the number of selected features for the elastic net model are depicted. Shannon div.: Shannon diversity, eGFR: estimated glomerular filtration rate, Pre-Tx: pre-transplantation, FDR: false discovery rate.

Fig. 3. Multiple bacterial species in the post-transplant gut microbiome are associated with HRQoL and assessments reflecting physical and mental health.

This heatmap depicts the results from the elastic net analysis for associations with a β > 0.3 or β < 0.3 that was performed for HRQoL scores and assessments of physical and mental health. For numerical variables, the RMSE of each elastic net model is shown in the first two columns (test and train set, respectively) and for categorical variables, the accuracy is depicted in the next two columns (test and train set, respectively). Selected features in the elastic net model are colored by effect size. Gray tiles encompass phenotypes or species that were not included in the model. Plus-sign depict associations that were also observed in the control cohort. RMSE: Root-mean-square error, Accur.: accuracy.

Fig. 4. Multiple assessments of physical- and mental health are associated with alpha- and beta diversity indices.

a, b, c Overview of PC1, Shannon diversity index and distance to general population controls for categorical physical- and mental phenotypes, n = 507. Boxplots depict minimal, quartiles, median and maximal values. A Wilcoxon rank sum test was used to test for significance. (d) Overview of PC1, Shannon diversity index and distance to general population controls for continuous physical phenotypes. We did not find any significant associations for the mental phenotypes using the spearman correlation test (P > 0.05).