Irritable bowel syndrome-specific volatile organic compounds in faecal headspace do not associate with classical symptom-based subtypes

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is diagnosed using symptom-based Rome criteria. These criteria classify IBS patients into four subtypes in accordance to their stool patterns. However, whether this subtyping approach is based on true differences in the underlying biology of IBS patients, is unclear. Volatile organic compounds (VOCs) in the faecal headspace reflect both the gut microbial and host intestinal intraluminal processes and thereby may be used to study pathophysiological differences between IBS and its subtypes. We profiled faecal headspace VOCs in a cohort of 164 patients with IBS and 143 healthy controls using gas chromatography-mass spectrometry. Random forest models were employed to impute missing values and identify discriminatory VOCs to differentiate IBS patients from healthy controls. We corrected for faecal water content using partial least squares regression. Multivariate associations between the obtained volatile profiles and Rome III IBS subtypes were evaluated using regularized MANOVA. A total of 39 VOCs, including short-chain fatty acid esters, neurotransmitter-related metabolites, alcohols, and sulphides, were selected as significantly altered in patients with IBS. Our classification model achieved an area under the curve of 0.82 on both training and independent test sets, demonstrating robust separation between IBS patients and healthy individuals. However, VOC profiles did not associate to Rome III -based IBS subtypes. This study highlights the potential of faecal VOC profiling as a non-invasive tool for studying and characterizing IBS, yet they also reveal a disconnect between metabolic signatures and current stool-based subtypes. While the Rome criteria remain the clinical standard for diagnosis and subtyping of IBS, they offer limited insight into underlying disease mechanisms. Future research should focus on integrating VOC analysis with other omics approaches to refine IBS sub-classification into biologically relevant clusters, which may aid to improve personalized therapeutic strategies.