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

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-a 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-a 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.

慢性肾脏病（Chronic Kidney Disease, CKD）以持续性促炎反应为核心特征。其潜在发病机制尚未完全阐明，但可能与肠道菌群失调（gut dysbiosis）存在关联。目前已有研究报道成人CKD患者存在菌群失调现象，但合并症的存在限制了针对CKD特异性结论的推导。本研究对处于三种不同CKD分期（G3-G4期、G5期（血液透析）、肾移植术后）的儿童患者及健康对照者的粪便微生物组、代谢物及免疫表型进行了系统分析。血清肿瘤坏死因子-α（TNF-α）与可溶性CD14（sCD14）水平随疾病分期呈依赖性升高，提示机体存在炎症反应与肠道屏障功能障碍。研究观察到CKD患者存在微生物组谱改变，包括短链脂肪酸（short-chain fatty acids）生成量显著减少；CKD患者体内细菌色氨酸代谢物水平升高。CKD患者血清可激活芳香烃受体（aryl hydrocarbon receptor），并刺激单核细胞分泌TNF-α，这一现象与单核细胞向中间型/非经典型单核细胞的表型转化相对应。无监督T细胞分析显示，黏膜相关恒定T细胞（mucosal-associated invariant T cells, MAIT）与调节性T细胞（Treg）均呈现促炎表型偏移。综上，肠道屏障功能障碍与微生物代谢物可加重机体炎症反应，因此可能是导致CKD患者心血管负担升高的潜在诱因之一。