Inflammation in children with chronic kidney disease linked to gut dysbiosis and metabolite imbalance

Abstract

Chronic kidney disease (CKD) is characterized by a sustained pro-inflammatory response. The underlying mechanisms are incompletely understood, but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions. We analyzed the fecal microbiome, metabolites and immune phenotypes in children at three different CKD stages (G3-G4, G5 (hemodialysis), after kidney transplantation) and healthy controls. Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation and gut barrier dysfunction. We observed microbiome alterations in CKD, including a diminished production of short-chain fatty acids. Bacterial tryptophan metabolites were increased in CKD. CKD serum activated the aryl hydrocarbon receptor and stimulated TNF-α production by monocytes, corresponding to a shift towards intermediate/non-classical monocytes. Unsupervised T cell analysis revealed pro-inflammatory shifts in MAIT and Treg cells. Thus, gut barrier dysfunction and microbial metabolites exacerbate inflammation and may therefore contribute to the increased cardiovascular burden in CKD.