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Inflammation in Children with CKD Linked to Gut Dysbiosis and Metabolite Imbalance
Johannes Holle1,2,3,4, Hendrik Bartolomaeus2,3,4,5, Ulrike Löber2,3,4,6
1Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Insights
Children with chronic kidney disease (CKD) show gut dysbiosis and immune system inflammation. This gut-immune axis disruption contributes to CKD progression and cardiovascular disease risk.
Area of Science:
- Pediatric Nephrology
- Microbiome Research
- Immunology
Background:
- Chronic kidney disease (CKD) involves sustained inflammation, hypertension, and cardiovascular disease.
- Underlying mechanisms are unclear, but gut dysbiosis is a potential factor.
- Previous studies in adults are limited by comorbidities, necessitating CKD-specific pediatric research.
Purpose of the Study:
- To investigate the relationship between gut microbiome alterations, immune phenotypes, and CKD progression in children.
- To identify specific microbial and immune markers associated with CKD stages and treatment modalities.
Main Methods:
- Analysis of fecal microbiome, metabolites, and immune cell profiles in 48 children across different CKD stages (including hemodialysis and kidney transplant recipients).
- Measurement of serum inflammatory markers (TNF-α, sCD14) and gut barrier function indicators.
- Assessment of T cell populations and monocyte activation.
Main Results:
- Elevated serum TNF-α and sCD14 indicated inflammation and gut barrier dysfunction.
- Microbiome alterations included reduced short-chain fatty acid production and increased bacterial tryptophan metabolites.
- Hemodialysis patients exhibited proinflammatory immune shifts, loss of MAIT cells, and regulatory T cell subtypes.
Conclusions:
- Gut barrier dysfunction and microbial metabolite imbalance drive the proinflammatory immune phenotype in pediatric CKD.
- The microbiota-immune axis is crucial in CKD pathogenesis, influencing cardiovascular disease susceptibility.
- Findings emphasize the importance of targeting the gut-immune axis in managing pediatric CKD.
Background:
CKD is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. 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.
Methods:
We analyzed the fecal microbiome, metabolites, and immune phenotypes in 48 children (with normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis [HD], or kidney transplantation) with a mean±SD age of 10.6±3.8 years.
Results:
Serum TNF-α and sCD14 were stage-dependently elevated, indicating inflammation, gut barrier dysfunction, and endotoxemia. We observed compositional and functional alterations of the microbiome, including diminished production of short-chain fatty acids. Plasma metabolite analysis revealed a stage-dependent increase of tryptophan metabolites of bacterial origin. Serum from patients on HD activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a proinflammatory shift from classic to nonclassic and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in patients on HD.
Conclusions:
Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the proinflammatory immune phenotype, thereby driving the susceptibility to cardiovascular disease. The data highlight the importance of the microbiota-immune axis in CKD, irrespective of confounding comorbidities.
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