Integrated faecal microbiome-metabolome signatures reflect stress and serotonin metabolism in Irritable Bowel Syndrome

Aims: To study the microbiome-gut-brain axis we aimed to identify profiles of fecal microbiota and metabolites associated with irritable bowel syndrome (IBS) and to specific phenotypes of IBS, and used metabolic reaction networks integrated with microbiota data to study the host-microbiome interaction. Methods: Extensively phenotyped IBS patients (Rome III) and healthy controls (HC) were included in this cross-sectional analysis. Fecal metabolites were measured using proton-Nuclear-Magnetic-Resonance (1H-NMR) spectroscopy. Gut microbiome was assessed by shot-gun-metagenomic-sequencing (MGS). Data were analyzed using Support-Vector-Machines for classification and regression, and kernel t-SNE to obtain unsupervised clustering of IBS for comparison with biological and clinical metadata. Results: 314 subjects were included: 181 IBS, 133 HC. Fecal microbiome-metabolome profiles were associated to IBS and HC. These groups could be distinguished by metabolic phenotyping with an area-under-the-curve (AUC) of 79.5%, and by metagenomics data, with best AUC 77.3%, using microbial family taxonomic rank. This could substantially be improved by combining microbiota and metabolites; AUC 83.6% (Figure 1). There were no significant differences in predictive ability between three IBS subtypes based on predominant stool pattern when considering the microbiome-metabolome data. However, unsupervised clustering shows distinct subsets of IBS patients based on fecal microbiome and metabolome, associated to effects of psychological stress on gastrointestinal symptoms, onset of IBS after stressful events, levels of serotonin and its metabolite 5-hydroxyindoleacetate, medical history of previous abdominal surgery, dietary caloric intake and duration of IBS symptoms. Furthermore, metabolic reaction networks integrated with microbiota data provided insight in metabolic pathways. Conclusions: Fecal microbiome-metabolome signatures for IBS were associated with altered serotonin metabolism and unfavorable stress response related to gastrointestinal symptoms. Host-microbiome interactions were reflected by pathways in metabolic reaction networks integrated with microbiota data. This supports the microbiota-gut-brain link in the pathogenesis of IBS.