Characteristics and Dysbiosis of the Gut Microbiome in Renal Transplant Recipients

Abstract

Renal transplantation is life-changing in many aspects. This includes changes to the gut microbiome likely due to exposure to immunosuppressive drugs and antibiotics. As a consequence, renal transplant recipients (RTRs) might suffer from intestinal dysbiosis. We aimed to investigate the gut microbiome of RTRs and compare it with healthy controls and to identify determinants of the gut microbiome of RTRs. Therefore, RTRs and healthy controls participating in the TransplantLines Biobank and Cohort Study (NCT03272841) were included. We analyzed the gut microbiome using 16S rRNA sequencing and compared the composition of the gut microbiome of RTRs to healthy controls using multivariate association with linear models (MaAsLin). Fecal samples of 139 RTRs (50% male, mean age: 58.3 ± 12.8 years) and 105 healthy controls (57% male, mean age: 59.2 ± 10.6 years) were collected. Median time after transplantation of RTRs was 6.0 (1.5-12.5)years. The microbiome composition of RTRs was significantly different from that of healthy controls, and RTRs had a lower diversity of the gut microbiome (p < 0.01). Proton-pump inhibitors, mycophenolate mofetil, and estimated glomerular filtration rate (eGFR) are significant determinants of the gut microbiome of RTRs (p < 0.05). Use of mycophenolate mofetil correlated to a lower diversity (p < 0.01). Moreover, significant alterations were found in multiple bacterial taxa between RTRs and healthy controls. The gut microbiome of RTRs contained more Proteobacteria and less Actinobacteria, and there was a loss of butyrate-producing bacteria in the gut microbiome of RTRs. By comparing the gut microbiome of RTRs to healthy controls we have shown that RTRs suffer from dysbiosis, a disruption in the balance of the gut microbiome.

Keywords: 16S rRNA sequencing; Proteobacteria; butyrate-producing bacteria; diarrhea; gut microbiome; gut microbiota; immunosuppressive medication; kidney transplantation; renal transplant recipient.

Figure 1

This is a figure showing the diversity of the gut microbiome of renal transplant recipients (RTRs) compared to healthy controls: (A) a boxplot depicting the Shannon diversity index, which is a measure for the diversity of the gut microbiome, was significantly lower in RTRs compared to healthy controls (p < 0.001); (B) a boxplot showing the number of observed operation taxonomic units (OTUs) between RTRs and healthy controls (p < 0.001).

Figure 2

Principal coordinate analysis of 139 RTRs and 105 healthy controls. The principal coordinates plot shows principal coordinates for the Bray–Curtis distance, a measure for the composition of the gut microbiome, for RTRs and healthy controls. Separation in the composition of the gut microbiome between RTRs and healthy controls can be observed. PCo1 is principal coordinate 1 and PCo2 is principal coordinate 2. The gut microbiome of RTRs is significantly different from that of healthy controls in the first coordinate (PCo1 vs. PCo2: p < 0.01). RTR or healthy control status significantly explained 5.8% of variation in the gut microbiome (p < 0.001).

Figure 3

Depiction of variables that are associated with variation in the gut microbiome within RTRs. In the bar plots, the x-axis represents the percentage of explained variance in the gut microbiome of RTRs expressed as the Bray–Curtis distance. The heatmap depicts significant negative correlations (red) and positive correlations (blue) with the Shannon diversity index (p < 0.01). These variables were tested only in the gut microbiome of RTRs. Bars in orange represent variables which significantly explain variance in gut microbiota composition (p < 0.05).

Figure 4

This figure depicts the abundance of phyla and species for RTRs and healthy controls. Bar plots represent the mean proportion and differences in mean proportions with 95% confidence intervals are depicted on the right. Taxa that are depicted were filtered for a difference in mean proportion >0.2%. p_FDR < 0.10 was considered as statistically significant and indicated in the plot with a star (*).