EBioMedicine. 2024 Aug 21:107:105282. doi: 10.1016/j.ebiom.2024.105282. Online ahead of print.

Thomas Edward Conley ¹, Rachael Slater ², Stephen Moss ³, David Colin Bulmer ⁴, Juan de la Revilla Negro ⁵, Umer Zeeshan Ijaz ⁶, David Mark Pritchard ⁷, Miles Parkes ³, Chris Probert ⁷

Author information

¹University of Liverpool Institute of Systems, Molecular and Integrative Biology, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Department of Gastroenterology, Liverpool, UK. Electronic address: tconley@liverpool.ac.uk.

²University of Liverpool Institute of Systems, Molecular and Integrative Biology, Liverpool, UK.

³Cambridge University Hospitals NHS Foundation Trust, Department of Gastroenterology, Cambridge, UK; University of Cambridge Department of Medicine, Gastroenterology and Hepatology, Cambridge, Cambridgeshire, UK.

⁴University of Cambridge Department of Pharmacology, Cambridge, Cambridgeshire, UK.

⁵Cambridge University Hospitals NHS Foundation Trust, Department of Gastroenterology, Cambridge, UK.

⁶University of Glasgow, Mazumdar-Shaw Advanced Research Centre, Glasgow, UK.

⁷University of Liverpool Institute of Systems, Molecular and Integrative Biology, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Department of Gastroenterology, Liverpool, UK.

Abstract

Background: Irritable bowel syndrome (IBS) is a common and debilitating disorder manifesting with abdominal pain and bowel dysfunction. A mainstay of treatment is dietary modification, including restriction of FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols). A greater response to a low FODMAP diet has been reported in those with a distinct IBS microbiome termed IBS-P. We investigated whether this is linked to specific changes in the metabolome in IBS-P.

Methods: Solid phase microextraction gas chromatography-mass spectrometry was used to examine the faecal headspace of 56 IBS cases (each paired with a non-IBS household control) at baseline, and after four-weeks of a low FODMAP diet (39 pairs). 50% cases had the IBS-P microbial subtype, while the others had a microbiome that more resembled healthy controls (termed IBS-H). Clinical response to restriction of FODMAPs was measured with the IBS-symptom severity scale, from which a pain sub score was calculated.

Findings: Two distinct metabotypes were identified and mapped onto the microbial subtypes. IBS-P was characterised by a fermentative metabolic profile rich in short chain fatty acids (SCFAs). After FODMAP restriction significant reductions in SCFAs were observed in IBS-P. SCFA levels did not change significantly in the IBS-H group. The magnitude of pain and overall symptom improvement were significantly greater in IBS-P compared to IBS-H (p = 0.016 and p = 0.026, respectively). Using just five metabolites, a biomarker model could predict microbial subtype with accuracy (AUROC 0.797, sensitivity 78.6% (95% CI: 0.78-0.94), specificity 71.4% (95% CI: 0.55-0.88).

Interpretation: A metabotype high in SCFAs can be manipulated by restricting fermentable carbohydrate, and is associated with an enhanced clinical response to this dietary restriction. This implies that SCFAs harbour pro-nociceptive potential when produced in a specific IBS niche. By ascertaining metabotype, microbial subtype can be predicted with accuracy. This could allow targeted FODMAP restriction in those seemingly primed to respond best.

Funding: This research was co-funded by Addenbrooke's Charitable Trust, Cambridge University Hospitals and the Wellcome Sanger Institute, and supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).