The Influence of Prebiotic Arabinoxylan Oligosaccharides on Microbiota Derived Uremic Retention Solutes in Patients with Chronic Kidney Disease: A Randomized Controlled Trial

The colonic microbial metabolism is a key contributor to uremic retention solutes accumulating in patients with CKD, relating to adverse outcomes and insulin resistance. Whether prebiotics can reduce intestinal generation of these microbial metabolites and improve insulin resistance in CKD patients not yet on dialysis remains unknown. We performed a randomized, placebo-controlled, double-blind, cross-over study in 40 patients with eGFR between 15 and 45 ml/min/1.73 m2. Patients were randomized to sequential treatment with prebiotic arabinoxylan oligosaccharides (AXOS) (10 g twice daily) and maltodextrin for 4 weeks, or vice versa, with a 4-week wash-out period between both intervention periods. Serum levels and 24h urinary excretion of p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate, trimethylamine N-oxide and phenylacetylglutamine were determined at each time point using liquid chromatography—tandem mass spectrometry. In addition, insulin resistance was estimated by the homeostatic model assessment (HOMA-IR). A total of 39 patients completed the study. We observed no significant effect of AXOS on serum p-cresyl sulfate (P 0.42), p-cresyl glucuronide (P 0.59), indoxyl sulfate (P 0.70) and phenylacetylglutamine (P 0.41) and a small, albeit significant decreasing effect on serum trimethylamine N-oxide (P 0.04). There were neither effect of AXOS on 24h urinary excretion of p-cresyl sulfate (P 0.31), p-cresyl glucuronide (P 0.23), indoxyl sulfate (P 0.87) and phenylacetylglutamine (P 0.43), nor on 24h urinary excretion of trimethylamine N-oxide (P 0.97). In addition, we observed no significant change in HOMA-IR (P 0.93). In conclusion, we could not demonstrate an influence of prebiotic AXOS on microbiota derived uremic retention solutes and insulin resistance in patients with CKD not yet on dialysis. Further study is necessary to elucidate whether prebiotic therapy with other characteristics, higher cumulative exposure or in different patient populations may be of benefit.Trial Registration: Clinicaltrials.gov NCT02141815

结肠微生物代谢是慢性肾脏病（Chronic Kidney Disease, CKD）患者体内尿毒症潴留溶质（uremic retention solutes）蓄积的关键诱因，且与不良结局及胰岛素抵抗（insulin resistance）密切相关。目前尚不明确，在尚未接受透析的CKD患者中，益生元（prebiotics）是否可减少此类微生物代谢产物的肠道生成并改善胰岛素抵抗。本研究纳入40例估算肾小球滤过率（estimated glomerular filtration rate, eGFR）介于15~45 ml/min/1.73 m²的患者，开展一项随机、安慰剂对照、双盲交叉试验。将患者随机分为两组，依次接受益生元阿拉伯木聚糖寡糖（arabinoxylan oligosaccharides, AXOS，每日2次，每次10g）与麦芽糊精（maltodextrin）治疗，各持续4周，两组干预顺序交叉，两次干预间设置4周洗脱期（wash-out period）。在每个时间点采用液相色谱-串联质谱法（liquid chromatography-tandem mass spectrometry）检测受试者血清中对甲酚硫酸盐（p-cresyl sulfate）、对甲酚葡糖苷酸（p-cresyl glucuronide）、吲哚硫酸盐（indoxyl sulfate）、氧化三甲胺（trimethylamine N-oxide）及苯乙酰谷氨酰胺（phenylacetylglutamine）的水平，以及24小时尿排泄量。此外，采用稳态模型评估-胰岛素抵抗指数（homeostatic model assessment for insulin resistance, HOMA-IR）估算受试者的胰岛素抵抗程度。最终共有39例患者完成本研究。结果显示，AXOS对血清对甲酚硫酸盐（P=0.42）、对甲酚葡糖苷酸（P=0.59）、吲哚硫酸盐（P=0.70）及苯乙酰谷氨酰胺（P=0.41）均无显著影响，但可小幅降低血清氧化三甲胺水平，该差异具有统计学意义（P=0.04）。AXOS对受试者24小时尿中对甲酚硫酸盐（P=0.31）、对甲酚葡糖苷酸（P=0.23）、吲哚硫酸盐（P=0.87）、苯乙酰谷氨酰胺（P=0.43）及氧化三甲胺（P=0.97）的排泄量均无显著影响。此外，HOMA-IR未出现显著变化（P=0.93）。综上，本研究未证实益生元AXOS可对尚未接受透析的CKD患者的微生物源性尿毒症潴留溶质及胰岛素抵抗产生影响。未来仍需开展进一步研究，以明确具有其他特性、更高累积暴露剂量或应用于不同患者人群的益生元治疗是否可使患者获益。试验注册：Clinicaltrials.gov NCT02141815