Gut dysbiosis as a susceptibility factor in childhood idiopathic nephrotic syndrome.

Abstract

Idiopathic nephrotic syndrome (INS) is a relatively common renal disorder of childhood characterized by severe proteinuria and associated hypoproteinemia and edema. Although the pathogenesis of INS remains unknown, the prevailing theory of its pathogenesis is as follows. Antigenic stimulation, such as viral infections or vaccines, in children with susceptibility factors for INS triggers abnormal immune responses, resulting in production of pathogenic substances that injure podocytes (renal glomerular epithelial cells). The injured podocytes then change their function and morphology, resulting in increased permeability of plasma proteins. Consequently, plasma proteins, especially albumin, are leaked into urine and massive proteinuria ensues. Research on susceptibility factors for INS has focused on polymorphisms in several genes including human leukocyte antigen class II genes. However, we propose that dysbiosis of the intestinal microbiota could be a susceptibility factor for relapse. This proposal is based on our research group finding that children with INS and frequent relapses have gut dysbiosis characterized by a decreased proportion of beneficial bacteria such as short-chain fatty acid-producing bacteria. Dysbiosis from the neonatal period to infancy may result from environmental factors, such as cesarean section delivery and antibiotic administration, which prevent the establishment of a normal intestinal microbiota. Dysbiosis leads to aberrant gut immunity and is characterized by a decreased ratio of T helper 1 cells/T helper 2 cells and an increased ratio of T helper 17 cells/regulatory T-cells. Therefore, relapse occurs when immunologically pathogenic factors that injure podocytes are produced in response to trigger events in children with INS and gut dysbiosis. Our recent clinical trial suggested that long-term oral administration of butyric acid-producing bacterium as a probiotic is promising for suppressing relapse. Therefore, studying the causal relationship between dysbiosis and relapses in patients with INS in a larger number of patients is necessary.