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

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Item Type:	Article
Title:	Inflammation in children with chronic kidney disease linked to gut dysbiosis and metabolite imbalance
Creators Name:	Holle, J., Bartolomaeus, H., Löber, U., Behrens, F., Bartolomaeus, T.U.P., Anandakumar, H., Wimmer, M., Vu, D.L., Kuhring, M., Brüning, U., Maifeld, A., Geisberger, S., Kempa, S., Schumacher, F., Kleuser, B., Bufler, P., Querfeld, U., Kitschke, S., Engler, D., Kuhrt, L.D., Drechsel, O., Eckardt, K.U., Forslund, S., Thürmer, A., McParland, V., Kirwan, J., Wilck, N. and Mueller, D.
Abstract:	BACKGROUND: Chronic kidney disease (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 (normal kidney function, CKD stage G3-G4, G5 treated by hemodialysis (HD) or kidney transplantation) with a mean 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 HD patients activated the aryl hydrocarbon receptor and stimulated TNF-α production in monocytes, corresponding to a proinflammatory shift from classical to non classical and intermediate monocytes. Unsupervised analysis of T cells revealed a loss of mucosa-associated invariant T (MAIT) cells and regulatory T cell subtypes in HD patients. CONCLUSIONS: Gut barrier dysfunction and microbial metabolite imbalance apparently mediate the pro-inflammatory 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.
Keywords:	Cardiovascular Diseases, Dysbiosis, Gastrointestinal Microbiome, Inflammation, Chronic Renal Insufficiency, Tumor Necrosis Factor-alpha
Source:	Journal of the American Society of Nephrology
ISSN:	1046-6673
Publisher:	American Society of Nephrology
Volume:	33
Number:	12
Page Range:	2259-2275
Date:	December 2022
Additional Information:	Copyright © 2022 by the American Society of Nephrology
Official Publication:	https://doi.org/10.1681/ASN.2022030378
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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