Altered profiles of fecal metabolites correlate with visceral hypersensitivity and may contribute to symptom severity of diarrhea-predominant irritable bowel syndrome

Abstract

BACKGROUNDFecal metabolites are associated with gut visceral sensitivity, mucosal immune function and intestinal barrier function, all of which have critical roles in the pathogenesis of irritable bowel syndrome (IBS). However, the metabolic profile and pathophysiology of IBS are still unclear. We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea (IBS-D).AIMTo investigate the fecal metabolite composition and the role of metabolites in IBS-D pathophysiology.METHODSThirty IBS-D patients and 15 age- and sex-matched healthy controls (HCs) underwent clinical and psychological assessments, including the IBS Symptom Severity System (IBS-SSS), an Italian modified version of the Bowel Disease Questionnaire, the Bristol Stool Form Scale (BSFS), the Hospital Anxiety and Depression Scale, and the Visceral Sensitivity Index. Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator. Fecal metabolites, including amino acids and organic acids, were measured by targeted metabolomics approaches. Correlation analyses between these parameters were performed.RESULTSThe patients presented with increased stool water content, more psychological symptoms and increased visceral hypersensitivity compared with the controls. In fecal metabolites, His [IBS-D: 0.0642 (0.0388, 0.1484), HC: 0.2636 (0.0780, 0.3966), P = 0.012], Ala [IBS-D: 0.5095 (0.2826, 0.9183), HC: 1.0118 (0.6135, 1.4335), P = 0.041], Tyr [IBS-D: 0.1024 (0.0173, 0.4527), HC: 0.5665 (0.2436, 1.3447), P = 0.018], Phe [IBS-D: 0.1511 (0.0775, 0.3248), HC: 0.3967 (0.1388, 0.7550), P = 0.028], and Trp [IBS-D: 0.0323 (0.0001, 0.0826), HC: 0.0834 (0.0170, 0.1759), P = 0.046] were decreased in IBS-D patients, but isohexanoate [IBS-D: 0.0127 (0.0060, 0.0246), HC: 0.0070 (0.0023, 0.0106), P = 0.028] was significantly increased. Only Tyr was mildly correlated with BSFS scores in all subjects (r = -0.347, P = 0.019). A possible potential biomarker panel was identified to correlate with IBS-SSS score (R2Adjusted = 0.693, P < 0.001). In this regression model, the levels of Tyr, Val, hexanoate, fumarate, and pyruvate were significantly associated with the symptom severity of IBS-D. Furthermore, visceral sensation, including abdominal pain and visceral hypersensitivity, was correlated with isovalerate, valerate and isohexanoate.CONCLUSIONAltered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D via increasing visceral sensitivity.

Metabolic Profiling of Plasma in Patients with Irritable Bowel Syndrome after a 4-Week Starch- and Sucrose-Reduced Diet

“…Reduced amounts of acylcarnitines were associated with a high degree of constipation for IBS patients, supported by previous research linking carnitine deficiency to constipation [ 29 ]. Although clear differences in metabolite concentrations were observed between the two groups, metabolite concentrations could not be correlated with reductions in IBS symptoms, in contrast to the correlation between metabolite concentrations and GI symptoms as have been found in previous cross-sectional studies [ 8 , 9 , 10 ]. In addition, variation in the intervention group was expected as some patients with IBS experience worse symptoms of fat, fiber, and dairy products [ 30 ], food items that were more ingested during the SSRD regime [ 3 , 22 ].…”

“…One of the most important treatments is dietary advice with less intake of fermentable carbohydrates [ 2 , 3 ]. In the last years, several studies have found altered metabolite profiles in IBS patients in feces [ 4 , 5 , 6 ] or serum [ 7 ], which correlated with the severity of symptoms and visceral hypersensitivity [ 8 , 9 , 10 ]. Further, metabolite signatures (metabolomics) have been associated with several central sensitivity pain syndromes, including IBS [ 11 ].…”

A Distinct Faecal Microbiota and Metabolite Profile Linked to Bowel Habits in Patients with Irritable Bowel Syndrome

“…During the last decade, numerous studies have addressed the role of gut microbiota in IBS pathophysiology [13][14][15][16]. More recently, reports focusing on intestinal metabolites [17,18], alongside studies integrating the gut microbiome and metabolome [22,24,25], as Significantly enriched biological functions predicted to be associated with changes in metabolites in patients with IBS compared to healthy subjects. The bar plot represents 22 biological functions predicted to be altered in IBS patients with significant activation Z-score > 2 or < −2 identified by IPA core analysis.…”

“…Recent studies have described an altered composition of gut microbiota and metabolites in several diseases of the GI tract such as colorectal cancer and inflammatory bowel disease [11,12]. In addition, IBS has been linked to an unbalanced gut microbiota profile [13][14][15][16] and possibly also to an altered metabolite profile [17,18], with links to GI [17,19] and psychological symptoms [20], at least in subsets of patients. There are also contradictory reports of lower, as well as higher, concentrations of faecal short-chain fatty acids in IBS with diarrhoea (IBS-D) as compared to healthy subjects [21].…”

Microbial and metabolomic profiles in correlation with depression and anxiety co-morbidities in diarrhoea-predominant IBS patients

“…Earlier targeted metabolomics studies primarily focused on several categories of metabolites, including SCFAs, amino acids, bile acids, etc. [26,45]. In contrast, non-targeted metabolomics approaches under development collected more detailed and global metabolic profiling data concerning metabolic homeostasis and aberrance [14,19,46,47].…”