Gut microbiome and kidney disease: a bidirectional relationship

Abstract

Recent technological advances and efforts, including powerful metagenomic and metatranscriptomic analyses, have led to a tremendous growth in our understanding of microbial communities. Changes in microbial abundance or composition of human microbial communities impact human health or disease state. However, explorations into the mechanisms underlying host-microbe interactions in health and disease are still in their infancy. Although changes in the gut microbiota have been described in patients with kidney disease, the relationships between pathogenesis, mechanisms of disease progression, and the gut microbiome are still evolving. Here, we review changes in the host-microbiome symbiotic relationship in an attempt to explore the bidirectional relationship in which alterations in the microbiome affect kidney disease progression and how kidney disease may disrupt a balanced microbiome. We also discuss potential targeted interventions that may help re-establish this symbiosis and propose more effective ways to deploy traditional treatments in patients with kidney disease.

Keywords: Acute kidney injury; Chronic kidney disease; Dysbiosis; End-stage renal disease; Hemodialysis; Hypertension; Microbiota; Peritoneal dialysis; Prebiotics; Probiotics; Transplantation.

Fig. 1

Diversity in the human microbiome. The human microbiome is dominated by four phyla: Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. In the center is a phylogenetic tree of organisms abundant in the human microbiome. Commensal microbes are indicated by circles, and potential pathogens are indicated by stars. The middle ring corresponds to body sites at which various taxa are abundant and is color-coded by site [e.g., Ruminococcus (blue) is found mostly in the gut, whereas Lactobacillus (purple) is found mostly in the vagina]. Bar heights on the outside of the circle are proportional to taxa abundance at the body site of greatest prevalence [e.g., Streptococcus mitis (yellow) dominates the inside of the cheek, whereas the gut is abundant in a variety of Bacteroides]. The intensity of external colors corresponds to species prevalence in each body site (adapted with permission from [12])

Fig. 2

Bioinformatic methods for functional metagenomics. Microbial community samples typically contain many species of bacteria and other microorganisms, here indicated by different colors. After total DNA has been extracted, the composition of the community is determined by amplifying and sequencing the 16S ribosomal RNA (rRNA) gene. Highly similar sequences are grouped into operational taxonomic Units (OTUs), which are labeled by comparison with databases of recognized organisms. OTUs can then be analyzed in terms of presence/absence, abundance, or phylogenetic diversity. In order to determine biomolecular and metabolic functions present in the community, the total metagenomic DNA may be sequenced and compared with function-oriented databases. Alternatively, sequenced community DNA can be compared with reference genomes. This allows identification of microbial sequence variants and polymorphisms and provides an alternative means of detecting the presence and abundance of specific organisms (adapted with permission from [18]). KEGG Kyoto Encyclopedia of Genes and Genomes, BLAST Basic Local Alignment Search Tool, SNPs single-nucleotide polymorphism(s)

Fig. 3

Dysbiosis and chronic kidney disease (CKD). CKD impairs the balance between symbionts and pathobionts in a way that favors pathobiont overgrowth. Consequences are as follows: a Impairment of the intestinal barrier by disrupting the colonic epithelial tight junction (ETJ) and decreasing epithelial survival. An increase in loss of integrity in intestinal permeability allows translocation of bacteria and lipopolysaccharide (LPS). b Dysregulation of immune response and inflammation. LPS could activate innate immune cells through toll-like receptor 4 (TLR4)-dependent and nuclear factor kappa B (NF-κB) pathways. Pathobionts stimulate dendritic cells (DCs) that activate a Th17/Th1 T-cell response and enhance production of inflammatory cytokines. c Modification of carbohydrates, protein, and bile acid (BA) fermentation. Proteins are fermented by intestinal pathobionts, which are then converted preferentially into indoxyl-sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine n-oxide (TMAO). The reduction in symbionts, specifically Bifidobacterium, induces a decrease in short-chain fatty acids (SCFAs). Dysbiosis modifies BA levels and composition. INF-γ interferon γ, IL-1 interleukin-1, TNF-α tumor necrosis factor-α. (Adapted with permission from [57])