Gut Microbiota Dysbiosis in Children with Relapsing Idiopathic Nephrotic Syndrome

Abstract

Background: While the etiology of idiopathic nephrotic syndrome (idiopathic nephrotic syndrome [INS]; characterized by repeated relapses and comorbid allergic conditions) remains unknown, recent evidence suggests that dysfunction in regulatory T cells (Tregs) plays an important role in the development of INS as well as allergic diseases. We hypothesized that dysbiosis involving decreased butyric acid-producing gut microbiota leads to defective induction and differentiation of peripherally induced Tregs, resulting in INS relapse. Methods: Study subjects were 12 children with INS, 8 classified as relapsing (R group; median age: 3.0 years) and 4 as non-relapsing (NR group; median age: 4.3 years), and 11 healthy children (HC group; median age: 5.1 years) serving as normal controls. Measurement of microbiota was performed using 16S ribosomal RNA metagenomic analysis, and fecal butyric acid was measured using high performance liquid chromatography. Flow-cytometric analysis of Tregs and CD4-positive (CD4+) cells in peripheral blood was also performed. Results: Metagenomic analysis of gut microbiota using feces showed that the proportion of butyric acid-producing bacteria was significantly lower in R (median 6.36%) than HC (median 18.84%; p = 0.0013), but no different between NR (median 16.71%) and HC (p = 0.29). Fecal organic acid analysis revealed significantly lower butyric acid quantities in R than HC (medians: 0.48 vs. 0.99 mg/g, p = 0.042). Circulating Tregs as a proportion of CD4+ cells were decreased in 75% of R and NR. Conclusion: Pediatric relapsing INS patients show gut microbiota dysbiosis, characterized by a decreased proportion of butyric acid-producing bacteria and lower fecal butyric acid quantities, concomitant with reduced circulatory Tregs.