Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome
Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome
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DOI：
10.1182/blood-2015-04-638858
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发表时间：
2015-10-01
期刊：
影响因子：
20.3
通讯作者：
Holler, Ernst
中科院分区：
文献类型：
--
作者：
Weber, Daniela;Oefner, Peter J.;Holler, Ernst
吲哚是由表达色氨酸酶的共生细菌从 L-色氨酸产生的，不仅是微生物群落中重要的细胞间信号，而且还调节粘膜屏障功能以及肠上皮细胞促炎和抗炎基因的表达。在这里，我们假设硫酸 3-吲哚酚 (3-IS)（人体中发现的主要吲哚结合物）的尿排泄减少可能是肠道微生物群破坏和发生胃肠道 (GI) 移植物抗宿主病风险增加的标志。使用液相色谱/串联质谱法，对 131 名患者进行同种异体干细胞移植 (ASCT) 后的前 28 天内每周收集的尿液样本中的 3-IS 进行测定。 ASCT 后前 10 天内的低 3-IS 水平与 ASCT 后 1 年移植相关死亡率显着升高 (P = .017) 和较差的总生存率 (P = .05) 相关。对源自 16S 核糖体 RNA 基因高变 V3 区下一代测序的 763 个操作分类单元的对数归一化计数进行训练的最小绝对收缩和选择算子回归模型显示，梭菌纲的毛螺菌科和瘤胃球菌科的成员与高尿 3-IS 水平相关，而 杆菌与低 3-IS 水平相关。早期抑制 3-IS 水平的危险因素包括胃肠道净化类型 (P = .01)、抗生素治疗的早期发作 (P = .001) 和受体 NOD2/CARD15 基因型 (P = .04)。总之，我们的研究结果强调了微生物群衍生的吲哚及其代谢物在粘膜完整性和炎症保护中的相关性。
Indole, which is produced from L-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro-and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stemcell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination(P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.