Microbiome–Metabolome Signatures for IBS Associated with Altered Serotonin Metabolism

Zlatan Mujagic, MD, PhD

A new investigation identified fecal microbiome-metabolome signatures related to irritable bowel syndrome (IBS) that were associated with altered serotonin metabolism and unfavorable stress responses related to gastrointestinal symptoms (GI).

Investigators described the GI tract and its microbiome as a “potent” metabolic organ system with capabilities beyond nutrient processing and absorption that nevertheless remains incompletely defined.

Additionally, the complexity of potential etiological factors of IBS have burdened investigators in the pursuit of biomarkers and efficacious treatment strategies.

For the present study, Zlatan Mujagic, MD, PhD, Maastricht University Medical Center, and fellow investigators combined analyses of gut microbiota composition and its metabolic capacity using metagenomic sequencing (MGS) to identify profiles of fecal microbiome and metabolome associated with IBS.

The team also studied associations of fecal microbiota composition and evaluated the host-microbiome interaction using metabolic reaction networks integrated with microbiome information.

Mujagic and colleagues enrolled participants form the MIBS cohort, all of whom were between 18-75 years of age and recruited via the outpatient’s gastroenterology-hepatology clinic of MUMC+, a secondary referral center in Maastricht, the Netherlands, and through general practitioners in the area of the hospital.

The study featured detailed descriptions of the inclusion process, collected questionnaires on GI symptoms, psychological factors, diet, medication use, quality of life, visceral hypersensitivity, and biomarkers in faces and blood plasma related to inflammation and neuroendocrine activity.

Participants were tasked with producing a fecal sample at home and bringing it to the hospital within 24 hours. Fecal DNA isolation was then performed via AllPrep DNA/RNA Mini-Kit in addition to mechanical lysis.

The fecal DNA samples were sent to the Broad Institute of Harvard and MIT in Cambridge where library preparation and MGS were performed on the Illumina HiSeq platform.

From there, fecal metabolites were measured using proton nuclear magnetic resonance (H-NMR) spectroscopy and gut microbiome using shotgun metagenomic sequencing (MGS), and data were analyzed using support vector classification and regression and kernel t-SNE.

A total of 142 IBS patients were enrolled in the study followed by 120 healthy controls.

Mujagic and investigators observed that microbiome and metabolome profiles were able to distinguish IBS and healthy controls through an area-under-the-receiver-operator-curve of 77.3% and 79.5%.

No significant differences in predictive ability were seen in microbiome-metabolome data between 3 classical, stool-pattern based, IBS subtypes.

Furthermore, unsupervised clustering indicated distinct subsets of IBS patients based on fecal microbiome-metabolome data.

Investigators believed said clusters could be related to plasma levels of serotonin and its metabolite 5-hydroxyindoleacetate, effects of psychological stress on GI symptoms, onset of IBS after stressful events, medical history of previous abdominal surgery, dietary caloric intake, and IBS symptom duration.

Additionally, the team suggested their results merited replication in independent cohorts and longitudinal analysis.

“These unique observations revealed numerous starting points for new mechanistic research,” the team wrote.

The study, "Integrated fecal microbiome–metabolome signatures reflect stress and serotonin metabolism in irritable bowel syndrome," was published online in Gut Microbiomes.