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Lactobacillus rhamnosus L34 attenuates chronic kidney disease progression in 5/6 nephrectomy mouse model through the excretion of anti-inflammatory molecules.

  • 2022-02-09
  • Nephrology Dialysis Transplantation 37(8)
    • S. Tungsanga
    • P. Katavetin
    • Wimonrat Panpetch
    • Kanyarat Udompornpitak
    • Wilasinee Saisorn
    • K. Praditpornsilpa
    • S. Eiam‐Ong
    • K. Tungsanga
    • S. Tumwasorn
    • A. Leelahavanichkul

Abstract

Background: Although pathogenic gut microbiota causes gut leakage, increases translocation of uremic toxins into circulation and accelerates CKD progression, the local strain of Lactobacillus rhamnosus L34 might attenuate gut leakage. We explored the effects of L34 on kidney fibrosis and levels of gut-derived uremic toxins (GDUTs) in 5/6 nephrectomy (5/6Nx) mice.

Methods: At 6 weeks post-5/6Nx in mice, either L34 (1 × 106 CFU) or phosphate buffer solution (as 5/6Nx control) was fed daily for 14 weeks. In vitro, the effects of L34-conditioned media with or without indoxyl sulfate (a representative GDUT) on inflammation and cell integrity (transepithelial electrical resistance; TEER) were assessed in Caco-2 (enterocytes). In parallel, the effects on proinflammatory cytokines and collagen expression were assessed in HK2 proximal tubular cells.

Results: At 20 weeks post-5/6Nx, L34-treated mice showed significantly fewer renal injuries, as evaluated by (i) kidney fibrosis area (P < 0.01) with lower serum creatinine and proteinuria, (ii) GDUT including trimethylamine-N-oxide (TMAO) (P = 0.02) and indoxyl sulfate (P < 0.01) and (iii) endotoxin (P = 0.03) and serum TNF-α (P = 0.01) than 5/6Nx controls. Fecal microbiome analysis revealed an increased proportion of Bacteroidetes in 5/6Nx controls. After incubation with indoxyl sulfate, Caco-2 enterocytes had higher interleukin-8 and nuclear factor κB expression and lower TEER values, and HK2 cells demonstrated higher gene expression of TNF-α, IL-6 and collagen (types III and IV). These indoxyl sulfate-activated parameters were attenuated with L34-conditioned media, indicating the protective role of L34 in enterocyte integrity and renal fibrogenesis.

Conclusion: L34 attenuated uremia-induced systemic inflammation by reducing GDUTs and gut leakage that provided renoprotective effects in CKD.

Keywords: Lactobacillus rhamnosus; 5/6 nephrectomy mouse model; chronic kidney disease; gut leakage; gut-derived uremic toxins; probiotics.

Research Insights

SupplementHealth OutcomeEffect TypeEffect Size
Lactobacillus rhamnosus R0343NDImproved Gut IntegrityBeneficial
Moderate
Lactobacillus rhamnosus R0343NDReduced Inflammation LevelsBeneficial
Large
Lactobacillus rhamnosus R0343NDReduced Kidney FibrosisBeneficial
Large
Lactobacillus rhamnosus R0343NDReduced Levels of Gut-Derived Uremic ToxinsBeneficial
Large
Lactobacillus rhamnosus R0343NDReduced Proteinuria LevelsBeneficial
Moderate
Lactobacillus rhamnosus R0343NDReduced Serum Creatinine LevelsBeneficial
Moderate
Lactobacillus rhamnosus R0343NDReduced TNF-α LevelsBeneficial
Moderate
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