Aberrant gut microbiota alters host metabolome and impacts renal failure in humans and rodents

Abstract

ObjectivePatients with renal failure suffer from symptoms caused by uraemic toxins, possibly of gut microbial origin, as deduced from studies in animals. The aim of the study is to characterise relationships between the intestinal microbiome composition, uraemic toxins and renal failure symptoms in human end-stage renal disease (ESRD).DesignCharacterisation of gut microbiome, serum and faecal metabolome and human phenotypes in a cohort of 223 patients with ESRD and 69 healthy controls. Multidimensional data integration to reveal links between these datasets and the use of chronic kidney disease (CKD) rodent models to test the effects of intestinal microbiome on toxin accumulation and disease severity.ResultsA group of microbial species enriched in ESRD correlates tightly to patient clinical variables and encode functions involved in toxin and secondary bile acids synthesis; the relative abundance of the microbial functions correlates with the serum or faecal concentrations of these metabolites. Microbiota from patients transplanted to renal injured germ-free mice or antibiotic-treated rats induce higher production of serum uraemic toxins and aggravated renal fibrosis and oxidative stress more than microbiota from controls. Two of the species, Eggerthella lenta and Fusobacterium nucleatum, increase uraemic toxins production and promote renal disease development in a CKD rat model. A probiotic Bifidobacterium animalis decreases abundance of these species, reduces levels of toxins and the severity of the disease in rats.ConclusionAberrant gut microbiota in patients with ESRD sculpts a detrimental metabolome aggravating clinical outcomes, suggesting that the gut microbiota will be a promising target for diminishing uraemic toxicity in those patients.Trial registration numberThis study was registered at ClinicalTrials.gov (NCT03010696).

Characterization of the Gut DNA and RNA Viromes in A Cohort of Chinese Residents and Visiting Pakistanis

“…Permutational multivariate analysis of variance (PERMANOVA) was performed with the adonis function of the vegan package, and the adonis P-value was generated based on 1,000 permutations. The method of effect size analysis was referred as Wang et al [10]. The no-metric multidimensional scaling (NMDS) analysis was used as the ordination methods (metaMDS function in vegan package) for compositional data.…”

“…amplicon or whole-metagenomic sequencing), the gut bacterial community have been well studied over the past years [6][7][8]. Gut bacteria was shown to exert profound effects on regulating host metabolism [9,10], and thereby had been linked to host health and diseases [11,12]. However, as another part of the gut microbial ecosystem, the holistic viral community of enteric microbiome (or "gut virome") was less well characterized [13].…”

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

“…and Lactobacillus spp., and an elevation of Enterobacteriaceae and Escherichia coli with progressive stages of CKD [20]. Recently, Wang et al demonstrated that alterations in the gut microbiome mediate metabolome changes in patients with ESKD [21]. The alterations in the gut microbial composition, as a potential cause of a change in the gut biochemical milieu in CKD, is further enhanced by several uremia-related factors, while the gut microbiota per se also contribute to CKD by generating the uremic toxin precursor metabolites.…”

Total Flavones of Abelmoschus manihot Remodels Gut Microbiota and Inhibits Microinflammation in Chronic Renal Failure Progression by Targeting Autophagy-Mediated Macrophage Polarization

“…Therefore, the discovery of a new treatment to delay CRF progression would be an important step toward achieving improved general kidney health. There are many factors that contribute to CRF progression, including increased production of oxidative stress and acidosis, proinflammatory cytokines, chronic and recurrent infections, altered metabolism of adipose tissue, and last but not least gut microbiota dysbiosis, which is a source of systematic microinflammation in vivo (Machowska et al, 2016;Mahmoodpoor et al, 2017;Wang et al, 2020). Currently, investigators concern that gut microbiota dysbiosis and microinflammatory lesions play fundamental roles during CRF progression.…”