Depletion of gut microbiota alleviates proteinuria in puromycin aminonucleoside-induced nephrosis in rats.

Abstract

The gut-kidney axis has been implicated in chronic kidney disease, however its role in minimal change nephrotic syndrome (MCNS) is poorly understood. We investigated the impact of gut microbiota on proteinuria in MCNS. A puromycin aminonucleoside (PAN)-induced rat model of MCNS was used. Rats received a cocktail of antibiotics, PBS (control), or antibiotics plus indoxyl sulfate (IS). To assess causality, fecal microbiota transplantation (FMT) was performed in additional PAN rats. Urinary protein, kidney histology, urinary IS, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and gut microbiota composition were evaluated. On day 8 after PAN injection, antibiotic-treated rats exhibited markedly reduced proteinuria (1.4 g/gCre) compared with controls (16.8 g/gCre, p = 0.014), whereas IS-treated rats developed severe proteinuria (117.3 g/gCre). Electron microscopy revealed podocyte foot process effacement in control and IS-treated rats but not in antibiotic-treated rats. Antibiotic-treatment decreased indole-producing bacteria, lowered urinary IS, and reduced 8-OHdG levels, indicating attenuation of oxidative stress. Importantly, FMT abolished the protective effect of antibiotics, re-emerging proteinuria. Depletion of the gut microbiota by antibiotic treatment in a rat MCNS model alleviated proteinuria, which was reversed by FMT. This causally implicates gut microbiota, particularly indole-producing bacteria that generate toxins including IS, as a key therapeutic target for MCNS. This study demonstrated that depleting the gut microbiota with antibiotics reduced proteinuria in a rat model of minimal change nephrotic syndrome, suggesting that harmful gut bacteria play a critical role in this disease. This research also identified indoxyl sulfate as a key uremic toxin produced by gut bacteria that worsens proteinuria and kidney damage, highlighting its role in disease progression. These findings could lead to novel treatments that target gut microbiota, including antibiotics or activated charcoal adsorbents that reduce proteinuria in minimal change nephrotic syndrome, and potentially minimize steroid use.