Abstract
Irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders characterized by chronic and/or recurrent symptoms of abdominal pain and irregular defecation. Changed gut microbiota has been proposed to mediate IBS; however, contradictory results exist, and IBS-specific microbiota, metabolites, and their interactions remain poorly understood. To address this issue, we performed metabolomic and metagenomic profiling of stool and serum samples based on discovery (n = 330) and validation (n = 101) cohorts. Fecal metagenomic data showed moderate dysbiosis compared with other diseases, in contrast, serum metabolites showed significant differences with greater power to distinguish IBS patients from healthy controls. Specifically, 726 differentially abundant serum metabolites were identified, including a cluster of fatty acyl-CoAs enriched in IBS. We further identified 522 robust associations between differentially abundant gut bacteria and fecal metabolites, of which three species including Odoribacter splanchnicus, Escherichia coli, and Ruminococcus gnavus were strongly associated with the low abundance of dihydropteroic acid. Moreover, dysregulated tryptophan/serotonin metabolism was found to be correlated with the severity of IBS depression in both fecal and serum metabolomes, characterized by a shift in tryptophan metabolism towards kynurenine production. Collectively, our study revealed serum/fecal metabolome alterations and their relationship with gut microbiome, highlighted the massive alterations of serum metabolites, which empower to recognize IBS patients, suggested potential roles of metabolic dysregulation in IBS pathogenesis, and offered new clues to understand IBS depression comorbidity. Our study provided a valuable resource for future studies, and would facilitate potential clinical applications of IBS featured microbiota and/or metabolites.
Highlights
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder that affects around 11% of the population globally [1]
The elevated glycolysis VI pathway may suggest abnormalities in energy metabolism involved in IBS; while the elevated synthesis stearate, androgen, and L-tyrosine pathways may increase the sensitivity of tyrosine receptor kinase receptors, associating with adjustment of neuronal transmission strength [38]
The biosynthesis of L-lysine represented a functional pathway that enriched in healthy controls but downregulated in IBS patients, and it was reported to act as a partial serotonin receptor 4 antagonist and inhibit serotonin-mediated intestinal pathologies and anxiety [39]
Summary
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder that affects around 11% of the population globally [1]. The 24 intrinsic factors contained: Gender, Age, BMI, Subtype (including IBS-D, IBS-C, IBS-M, and IBS-U), Serum TBA (Serum Total Bile Acids (TBAs), umol/g), Fecal TBA (Fecal TBAs, umol/g), ALP (Alkaline phosphatase, u/L), ALT (Alanine transaminase, u/L), AST(Aspartate transaminase, u/L), Urea (mmol/L), Creatinine (umol/L), TC (Serum total cholesterol, mmol/L), Fasting glucose (mmol/L), TG (Triglyceride, mmol/ L), C4 (serum 7α-hydroxy-4-cholesten-3-one, ng/mL), FGF19 (serum fibroblast growth factor 19, pg/mL), Stool Freq (stool frequency per day), impaired bile acid synthetic regulation with excessive bile acid excretion contributed by the Clostridia-rich microbiota that is associated with the severity of diarrheal symptoms in IBS-D patients [11] These results indicate a potential role of microbiota and microbiota-related byproducts in IBS, but the alterations of fecal and serum metabolites and their interactions with gut microbiota are not well established and interpreted.
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