代谢组学和肠道微生物群与克罗恩病对 TNF 治疗的原发性反应相关。

Metabonomics and the Gut Microbiome Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease.

机构信息

St Vincent's Hospital, Inflammatory Bowel Disease, Melbourne, VIC, Australia.

St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK.

出版信息

J Crohns Colitis. 2020 Sep 7;14(8):1090-1102. doi: 10.1093/ecco-jcc/jjaa039.

DOI:10.1093/ecco-jcc/jjaa039

PMID:32119090

Abstract

BACKGROUND AND AIMS

Anti-tumour necrosis factor [anti-TNF] therapy is indicated for treatment of moderate to severe inflammatory bowel disease [IBD], but has a primary non-response rate of around 30%. We aim to use metabonomic and metataxonomic profiling to identify predictive biomarkers of anti-TNF response in Crohn's disease.

METHODS

Patients with luminal Crohn's disease, commencing anti-TNF therapy, were recruited with urine, faeces, and serum samples being collected at baseline and 3-monthly. Primary response was defined according to a combination of clinical and objective markers of inflammation. Samples were measured using three UPLC-MS assays: lipid, bile acid, and Hydrophillic Interaction Liquid Chromatography [HILIC] profiling with 16S rRNA gene sequencing of faeces.

RESULTS

Samples were collected from 76 Crohn's disease patients who were anti-TNF naïve and from 13 healthy controls. There were 11 responders, 37 non-responders, and 28 partial responders in anti-TNF-treated Crohn's patients. Histidine and cysteine were identified as biomarkers of response from polar metabolite profiling [HILIC] of serum and urine. Lipid profiling of serum and faeces found phosphocholines, ceramides, sphingomyelins, and triglycerides, and bile acid profiling identified primary bile acids to be associated with non-response to anti-TNF therapy, with higher levels of phase 2 conjugates in non-responders. Receiver operating curves for treatment response demonstrated 0.94 +/ -0.10 [faecal lipid], 0.81 +/- 0.17 [faecal bile acid], and 0.74 +/- 0.15 [serum bile acid] predictive ability for anti-TNF response in Crohn's disease.

CONCLUSIONS

This prospective, longitudinal cohort study of metabonomic and 16S rRNA gene sequencing analysis demonstrates that a range of metabolic biomarkers involving lipid, bile acid, and amino acid pathways may contribute to prediction of response to anti-TNF therapy in Crohn's disease.

PODCAST

This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

摘要

背景和目的

抗肿瘤坏死因子 [anti-TNF] 疗法适用于治疗中重度炎症性肠病 [IBD]，但其原发性无反应率约为 30%。我们旨在使用代谢组学和代谢分类组学分析来确定克罗恩病抗 TNF 反应的预测生物标志物。

方法

招募开始接受抗 TNF 治疗的腔克罗恩病患者，采集基线和 3 个月时的尿液、粪便和血清样本。根据炎症的临床和客观标志物的组合来定义主要反应。使用三种 UPLC-MS 测定法测量样品：粪便的脂质、胆汁酸和亲水相互作用液相色谱 [HILIC] 图谱以及 16S rRNA 基因测序。

结果

共收集了 76 例抗 TNF 初治克罗恩病患者和 13 例健康对照者的样本。在接受抗 TNF 治疗的克罗恩病患者中，有 11 例应答者、37 例无应答者和 28 例部分应答者。血清和尿液的极性代谢物谱 [HILIC] 鉴定出组氨酸和半胱氨酸是反应的生物标志物。血清和粪便的脂质谱发现磷酸胆碱、神经酰胺、神经鞘磷脂和甘油三酯，胆汁酸谱确定初级胆汁酸与抗 TNF 治疗无反应相关，无反应者中相 2 结合物水平较高。治疗反应的接收者操作曲线显示，在克罗恩病中，抗 TNF 反应的预测能力分别为 0.94 +/- 0.10 [粪便脂质]、0.81 +/- 0.17 [粪便胆汁酸]和 0.74 +/- 0.15 [血清胆汁酸]。