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

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

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.

Keywords: Crohn’s disease; metabolomics; microbiota.

MeSH terms

  • Adalimumab* / administration & dosage
  • Adalimumab* / adverse effects
  • Adult
  • Bile Acids and Salts / analysis*
  • Biomarkers, Pharmacological / analysis
  • Crohn Disease* / diagnosis
  • Crohn Disease* / drug therapy
  • Crohn Disease* / epidemiology
  • Crohn Disease* / immunology
  • Cysteine / analysis*
  • Feces
  • Female
  • Histidine / analysis*
  • Humans
  • Inflammation* / blood
  • Inflammation* / diagnosis
  • Inflammation* / urine
  • Infliximab* / administration & dosage
  • Infliximab* / adverse effects
  • Lipid Metabolism / drug effects*
  • London
  • Longitudinal Studies
  • Male
  • Metabolomics / methods
  • Predictive Value of Tests
  • RNA, Ribosomal, 16S / analysis*
  • Tumor Necrosis Factor Inhibitors / administration & dosage
  • Tumor Necrosis Factor Inhibitors / adverse effects

Substances

  • Bile Acids and Salts
  • Biomarkers, Pharmacological
  • RNA, Ribosomal, 16S
  • Tumor Necrosis Factor Inhibitors
  • Histidine
  • Infliximab
  • Adalimumab
  • Cysteine