Pro-inflammatory chemokine C-C motif ligand 16 (CCL-16) dysregulation in irritable bowel syndrome (IBS): a pilot study.
ABSTRACT: BACKGROUND:Irritable bowel syndrome (IBS) is a serious health problem that affects an estimated 10-15% of people worldwide and has economic consequences in the United States of over $30 billion annually. In the US, IBS affects all races and both sexes, with more females than males (2:1) reporting symptoms consistent with IBS. Although the etiology of this functional gastrointestinal disorder is unknown, literature suggests that a subclinical inflammatory component has a role in the etiologic mechanisms underlying IBS. The aim of this study was to evaluate the gene expression of inflammatory biomarkers in patients with and without IBS and among different IBS phenotypes. METHODS:Irritable bowel syndrome patients (n=12) that met Rome III Criteria for IBS longer than 6months were compared with healthy matched controls (n=12). Peripheral whole blood from fasting participants was collected and RNA was extracted. The expression of 96 inflammatory genes was then analyzed using a custom quantitative real-time PCR array. KEY RESULTS:CCL-16 gene expression was upregulated by 7.46-fold in IBS patients when compared with controls. CCL-16 was overexpressed by over 130-fold in IBS-constipation patients when compared with both controls and IBS-diarrhea patients. CONCLUSIONS & INFERENCES:These results further suggest a subclinical inflammatory component underlying IBS. To better understand the phenotypic differences in IBS it is important to broaden the study of these inflammatory and other biomarkers.
Project description:Sleep disturbances are common, and perhaps are even more prevalent in irritable bowel syndrome (IBS).To determine the effect of measured sleep on IBS symptoms the following day, IBS-specific quality of life (IBS-QOL) and non-GI pain symptoms.IBS patients' sleep patterns were compared to healthy individuals via wrist-mounted actigraphy over 7 days. Daily bowel pain logs (severity, distress; 10-point Likert) stool pattern (Bristol scale) and supporting symptoms (e.g. bloating, urgency; 5-point Likert) were kept. Validated measures, including the GI Symptom Rating Scale-IBS, Visceral Sensitivity Index, Pittsburgh Sleep Quality Index and the IBS-Quality of Life were collected. Mediation analysis explored the relationship between sleep, mood and bowel symptoms.Fifty subjects (38.6 ± 1.0 years old, 44 female; 24 IBS and 26 healthy controls) completed sleep monitoring. IBS patients slept more hours per day (7.7 ± 0.2 vs. 7.1 ± 0.1, P = 0.008), but felt less well-rested. IBS patients demonstrated more waking episodes during sleep (waking episodes; 12.1 vs. 9.3, P < 0.001). Waking episodes predicted worse abdominal pain (P ? 0.01) and GI distress (P < 0.001), but not bowel pattern or accessory IBS symptoms (P > 0.3 for each). Waking episodes negatively correlated with general- and IBS-specific QOL in IBS (r = -0.58 and -0.52, P < 0.001 for each). Disturbed sleep effects on abdominal pain were partially explained by mood as an intermediate.Sleep disturbances are more common in irritable bowel syndrome, and correlate with IBS-related pain, distress and poorer irritable bowel syndrome-related quality of life. Disturbed sleep effects extend beyond the bowel, leading to worse mood and greater somatic pain in patients with the irritable bowel syndrome.
Project description:Patients with irritable bowel syndrome (IBS) exhibit low-grade inflammation and increased gut permeability. Dietary sugar has been shown to contribute to low-grade inflammation and increased gut permeability, and to correlate with gastrointestinal (GI) symptoms. The aim of the present study was to examine the effect of a starch- and sucrose-reduced diet (SSRD) on gastrointestinal (GI) and extra-intestinal symptoms in IBS. One hundred and five IBS patients (82 women, 46.06 ± 13.11 years), with irritable bowel syndrome-symptom severity scale (IBS-SSS) > 175, were randomized to SSRD for 4 weeks or continued ordinary eating habits. The visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 and 4 weeks. After the intervention, one-third of the patients did not fulfill the criteria for IBS/functional gastrointestinal disorder. Half of the participants changed from moderate/severe disease to no/mild disease according to IBS-SSS. Comparisons between the groups showed decreased weight and sweet cravings, and parallel decreases in total IBS-SSS and extra-intestinal IBS-SSS scores, in the intervention group compared to controls (p < 0.001 for all). When calculating separate extra-intestinal symptoms, belching (p = 0.001), muscle/joint pain (p = 0.029), urinary urgency (p = 0.017), and tiredness (p = 0.011) were decreased after introduction of SSRD compared to controls. In conclusion, SSRD improves both GI and extra-intestinal symptoms in IBS.
Project description:The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2-3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.
Project description:Dietary advice constitutes one of the first choices of treatment for irritable bowel syndrome (IBS). We have recognized an increased prevalence of sucrase-isomaltase (SI) gene variants in IBS patients, possibly rendering starch- and sucrose-intolerance. The aims were to examine participants' dietary habits at baseline, to correlate habits with gastrointestinal (GI) symptoms and blood levels of minerals and vitamins, and to examine the effect of a starch- and sucrose-reduced diet (SSRD) on GI symptoms. In the study 105 IBS patients (82 women, 46.06 ± 13.11 years), irritable bowel syndrome-symptom severity scale (IBS-SSS)>175, were randomized to SSRD for 2 weeks or continued ordinary eating habits. Blood samples, visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 weeks. Patients with irregular dietary habits exhibited higher IBS-SSS than patients with regular habits (p = 0.029). Women already on a diet had lower ferritin levels than others (p = 0.029). The intervention led to 66.3% of patients being responders, with differences in the change of IBS-SSS (p < 0.001), abdominal pain (p = 0.001), diarrhea (p = 0.002), bloating and flatulence (p = 0.005), psychological well-being (p = 0.048), and intestinal symptoms' influence on daily life (p < 0.001), compared to controls. Decreased intake of cereals and sweets/soft drinks correlated with decreased scores.
Project description:Background and Aims: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. However, the underlying mechanism of IBS is not fully understood. The aim of this study was to investigate potential mechanism and novel biomarkers of IBS through evaluation of the metabolomic and microbiologic profile. Methods: Fecal samples were collected from 15 irritable bowel syndrome patients and 15 healthy controls. By using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) and 16S rDNA amplicon sequencing, fecal metabolites and microbiota of healthy controls and the IBS patients were measured. Results: IBS patients had a significantly differential metabolite profile as compared to healthy controls, and 4 clusters with 31 metabolites, including a group of amino acids and fatty acids, were significantly up-regulated as compared to the healthy controls. In addition, 19 microbes were significantly up-regulated, and 12 microbes were down-regulated in the IBS group, when compared with the healthy controls. Some clusters of fecal metabolites or microorganisms were significantly correlated with the severity of IBS symptoms, such as the frequency of abdominal pain/discomfort and the number of bowel movements. Correlation of the metabolite levels with abundances of microbial genera showed some statistically significant metabolite-microbe associations. Four differentially abundant amino acids clustered together were positively correlated with some microbes, including Lachnospira, Clostridium, and so on. Conclusion: The finding of this study puts a global perspective on metabolomics and microbiota profiling in IBS patients and provides a theoretical basis for future research on pathophysiology of IBS.
Project description:Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.
Project description:Irritable bowel syndrome (IBS) is one the most frequent and common functional gastrointestinal disorders that has a multifactorial etiopathogenesis. Multiple biomarkers have been tested in search for a reliable and specific biomarker, but there is not yet a specific biomarker for IBS. The aim of this study was to evaluate two biomarkers of different putative pathways of the pathogenesis of IBS: the monocyte chemotactic protein-1 (MCP-1) and nitrotyrosine, in order to establish their role as potential biomarkers. We enrolled 42 consecutive IBS patients diagnosed by Rome III criteria and 35 consecutive healthy controls. Serum concentrations for the two biomarkers (MCP-1 and nitrotyrosine) were determined using commercial ELISA kits. Serum levels of MCP-1 were not statistically significantly higher in IBS patients than in controls (204±130 vs. 174±73 pg/ml; P=0.311). Nitrotyrosine levels were statistically significantly lower in IBS patients than in controls (30±12 vs. 353±14 nM; P=0.050). MCP-1 levels were higher in IBS patients with metabolic syndrome versus IBS patients without metabolic syndrome (239±153 vs. 168±120 pg/ml; P=0.948) and in controls with metabolic syndrome (174±56 pg/ml). MCP-1 serum levels were statistically significantly higher in IBS patients with metabolic syndrome than in controls (239±153 vs. 157±89 pg/ml; P=0.037), suggesting multiple factors being involved, particularly the diet and its relation with the metabolic syndrome, and it suggests that MCP-1 could be a marker of subclinical atherosclerosis. Low-grade inflammation might be related to oxidative stress, which plays an underestimated role in the pathogenesis of IBS.
Project description:According to the latest gastrointestinal disorders diagnostic criteria (ROME IV), the irritable bowel syndrome (IBS) is mainly characterized by the presence of abdominal pain and changes in intestinal transit. However, both sleep impairments and oxidative status changes (in patients' sera, mucosal level, and other body fluids) were reported IBS. Thus, in this study, we aimed to evaluate several aspects regarding the oxidative stress status in patients' tears as well as sleep disturbances by comparison with the intensity of IBS symptoms, as assessed by the visual analogue scale for irritable bowel syndrome (VAS-IBS). Ten IBS patients and fourteen healthy sex- and age-matched volunteers were recruited from the Oftaprof Ophthalmological Clinic (Ia?i, Romania). Visual analogue scale for irritable bowel syndrome and the Pittsburgh Sleep Quality Index (PSQI) questionnaires were administered to all the patients. Tear samples were collected using the Schirmer test procedure and were subjected to biochemical analysis-superoxide dismutase and glutathione peroxidase activities, malondialdehyde, and total soluble proteins levels were determined. Standard statistical analysis was applied. We found significant differences in oxidative stress marker dynamics in IBS patients as compared to healthy age- and sex-matched controls: increased superoxide dismutase activity (p = 0.02), increased malondialdehyde (p = 0.007), and total soluble proteins levels (p = 0.019). We found no significant differences in tear glutathione peroxidase activity in IBS patients as compared to healthy age- and sex-matched controls (p = 0.55). Furthermore, we observed that the oxidative stress tear markers are correlated with gastrointestinal symptoms severity (as evaluated by VAS-IBS) but not correlated to the sleep quality index and items (as evaluated by PSQI), with significant differences according to patient sex and IBS subtype stratification. In this way, this study brings additional evidence of the oxidative stress role in IBS pathology alongside the evaluation of tear fluid molecular dynamics in IBS for the first time in our best knowledge.
Project description:Mitochondrial dysfunction has been implicated in various functional disorders that are co-morbid to irritable bowel syndrome (IBS) such as migraine, depression and chronic fatigue syndrome. The aim of the current case-control pilot study was to determine if functional symptoms in IBS show a maternal inheritance bias, and if the degree of this maternal inheritance is related to mitochondrial DNA (mtDNA) polymorphisms.Pedigrees were obtained from 308 adult IBS patients, 102 healthy controls, and 36 controls with inflammatory bowel disease (IBD), all from Caucasian heritage, to determine probable maternal inheritance. Two mtDNA polymorphisms (16519T and 3010A), which have previously been implicated in other functional disorders, were assayed in mtDNA haplogroup H IBS subjects and compared to genetic data from 344 published haplogroup H controls.Probable maternal inheritance was found in 17.5 % IBS, 2 % healthy controls and 0 % IBD controls (p < .0001). No difference was found between IBS and control for 3010A, and a trend was found for 16519T (p = 0.05). IBS with maternal inheritance were significantly more likely to have the 16519T than controls (OR 5.8; 95 % CI 1.5-23.1) or IBS without maternal inheritance (OR 5.2; 95 % CI 1.2-22.6).This small pilot study shows that a significant minority (1/6) of IBS patients have pedigrees suggestive of maternal inheritance. The mtDNA polymorphism 16519T, which has been previously implicated in other functional disorders, is also associated with IBS patients who display maternal inheritance. These findings suggest that mtDNA-related mitochondrial dysfunction may constitute a sub-group within IBS. Future replication studies in larger samples are needed.
Project description:IBS: Patients who have undergone a diagnostic program for gastrointestinal symptoms and where the diagnosis irritable bowel syndrome was reached. UC: Patients with well-diagnosed ulcerative colitis