Abstract
A chronic kidney disease (CKD) causes uremic toxin accumulation and gut dysbiosis, which further induces gut leakage and worsening CKD. Lipopolysaccharide (LPS) of Gram-negative bacteria and (1➔3)-β-D-glucan (BG) of fungi are the two most abundant gut microbial molecules. Due to limited data on the impact of intestinal fungi in CKD mouse models, the influences of gut fungi and Lacticaseibacillus rhamnosus L34 (L34) on CKD were investigated using oral C. albicans-administered 5/6 nephrectomy (5/6Nx) mice. At 16 weeks post-5/6Nx, Candida-5/6Nx mice demonstrated an increase in proteinuria, serum BG, serum cytokines (tumor necrotic factor-α; TNF-α and interleukin-6), alanine transaminase (ALT), and level of fecal dysbiosis (Proteobacteria on fecal microbiome) when compared to non-Candida-5/6Nx. However, serum creatinine, renal fibrosis, or gut barrier defect (FITC-dextran assay and endotoxemia) remained comparable between Candida- versus non-Candida-5/6Nx. The probiotics L34 attenuated several parameters in Candida-5/6Nx mice, including fecal dysbiosis (Proteobacteria and Bacteroides), gut leakage (fluorescein isothiocyanate (FITC)-dextran), gut-derived uremic toxin (trimethylamine-N-oxide; TMAO) and indoxyl sulfate; IS), cytokines, and ALT. In vitro, IS combined with LPS with or without BG enhanced the injury on Caco-2 enterocytes (transepithelial electrical resistance and FITC-dextran permeability) and bone marrow-derived macrophages (supernatant cytokines (TNF-α and interleukin-1 β; IL-1β) and inflammatory genes (TNF-α, IL-1β, aryl hydrocarbon receptor, and nuclear factor-κB)), compared with non-IS activation. These injuries were attenuated by the probiotics condition media. In conclusion, Candida administration worsens kidney damage in 5/6Nx mice through systemic inflammation, partly from gut dysbiosis-induced uremic toxins, which were attenuated by the probiotics. The additive effects on cell injury from uremic toxin (IS) and microbial molecules (LPS and BG) on enterocytes and macrophages might be an important underlying mechanism.
Highlights
Chronic kidney disease (CKD) has been recognized as an extensive worldwide burden for decades [1], causing an accumulation of various metabolic chemicals known as “uremic toxins”
Candida Administration Enhanced Proteinuria, Glucanemia, and Liver Damage in 5/6 Nephrectomy Mice That Were Attenuated by Lacticaseibacillus rhamnosus L34 (L34)
Sci. 2022, 23, 2511 acteristics in 5/6Nx mice, compared with sham, was demonstrated by retardation of weight gain, increase in urine volume and proteinuria, increase in serum creatinine, presence of anemia, and gut barrier defect determined by endotoxemia, increased serum bacteria and (1→3)-β-D-glucan (BG), and FITC-dextran assay, as early as 8 weeks after surgery (Figure 1A–H)
Summary
Chronic kidney disease (CKD) has been recognized as an extensive worldwide burden for decades [1], causing an accumulation of various metabolic chemicals known as “uremic toxins”. Such toxins mainly derived from food components or metabolic activities in the body can contribute to various complications, such as cardiovascular diseases, pulmonary problems, and CKD progression [2]. Because of the defect of toxin elimination through kidneys in advanced CKD, the accumulated toxins are compensatorily excreted into the intestinal tract and selectively promote the overgrowth of pathogenic intestinal bacteria, so-called gut dysbiosis [5]. Gut translocation of microbial molecules and uremic toxins facilitates the inflammatory reaction and accelerate CKD progression [11]
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