Disease Severity and Immune Activity Relate to Distinct Interkingdom Gut Microbiome States in Ethnically Distinct Ulcerative Colitis Patients.
Disease Severity and Immune Activity Relate to Distinct Interkingdom Gut Microbiome States in Ethnically Distinct Ulcerative Colitis Patients.
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DOI：
10.1128/mbio.01072-16
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发表时间：
2016-08-16
期刊：
影响因子：
6.4
通讯作者：
Lynch SV
中科院分区：
文献类型：
--
作者：
Mar JS;LaMere BJ;Lin DL;Levan S;Nazareth M;Mahadevan U;Lynch SV
溃疡性结肠炎（UC）患者中存在显著的肠道微生物群异质性，尽管这种差异的临床意义尚不清楚。我们假设，不同种族的UC患者表现出离散的肠道微生物菌群，具有独特的代谢程序，差异影响免疫活性和临床状态。使用粪便样本的平行16 S rRNA和内部转录间隔区2测序（UC，30;健康，13），我们证实了先前观察到的UC相关细菌多样性耗竭，并证明了UC肠道生态失调的特征是显著的放线菌目扩张。此外，我们在队列中确定了四种不同的微生物群落状态（MCS），证实了它们在独立的UC队列中的存在，并证明了它们与患者种族和疾病严重程度的相关性。每种MCS都独特地富集了特定的氨基酸、碳水化合物和脂质代谢途径，并表现出这些途径代谢产物的显著管腔富集。使用一种新的离体人树突状细胞和T细胞共培养试验，我们表明，暴露于粪便水从UC患者引起显着的Th 2的CD 4 + T细胞群相比，健康参与者的倾斜。此外，来自其MCS与疾病严重程度最高水平相关的患者的粪便水诱导了最显著的Th 2偏斜。结合未来的研究，这些观察结果可能会导致基于定义的微生物梯度或离散的微生物特征识别高度分辨率的UC子集，可用于开发新的，更有效的疗法。尽管多年的研究，UC的病因仍然是谜。诊断是困难的，患者群体的异质性，这是一个显着的障碍，更有效的，定制的治疗的发展。在这项研究中，我们通过识别UC患者群体中存在的四种不同的王国间致病微生物群来证明肠道微生物组在UC患者分层中的临床实用性，这些微生物群在组成和代谢上不同，与疾病严重程度的临床标志物协变，并驱动离散的CD 4 + T细胞离体扩增。这些发现为肠道微生物组作为细分UC患者的工具的潜在价值提供了新的见解，为开发更个性化的治疗计划和靶向治疗开辟了途径。
Significant gut microbiota heterogeneity exists among ulcerative colitis (UC) patients, though the clinical implications of this variance are unknown. We hypothesized that ethnically distinct UC patients exhibit discrete gut microbiotas with unique metabolic programming that differentially influence immune activity and clinical status. Using parallel 16S rRNA and internal transcribed spacer 2 sequencing of fecal samples (UC, 30; healthy, 13), we corroborated previous observations of UC-associated bacterial diversity depletion and demonstrated significant Saccharomycetales expansion as characteristic of UC gut dysbiosis. Furthermore, we identified four distinct microbial community states (MCSs) within our cohort, confirmed their existence in an independent UC cohort, and demonstrated their coassociation with both patient ethnicity and disease severity. Each MCS was uniquely enriched for specific amino acid, carbohydrate, and lipid metabolism pathways and exhibited significant luminal enrichment of the metabolic products of these pathways. Using a novel ex vivo human dendritic cell and T-cell coculture assay, we showed that exposure to fecal water from UC patients caused significant Th2 skewing in CD4+ T-cell populations compared to that of healthy participants. In addition, fecal water from patients in whom their MCS was associated with the highest level of disease severity induced the most dramatic Th2 skewing. Combined with future investigations, these observations could lead to the identification of highly resolved UC subsets based on defined microbial gradients or discrete microbial features that may be exploited for the development of novel, more effective therapies. Despite years of research, the etiology of UC remains enigmatic. Diagnosis is difficult and the patient population heterogeneous, which represents a significant barrier to the development of more effective, tailored therapy. In this study, we demonstrate the clinical utility of the gut microbiome in stratifying UC patients by identifying the existence of four distinct interkingdom pathogenic microbiotas within the UC patient population that are compositionally and metabolically distinct, covary with clinical markers of disease severity, and drive discrete CD4+ T-cell expansions ex vivo. These findings offer new insight into the potential value of the gut microbiome as a tool for subdividing UC patients, opening avenues to the development of more personalized treatment plans and targeted therapies.