Irritable Bowel Syndrome Phenotype Research Articles

Irritable bowel syndrome phenotypes: leading factors of genetics and epigenetics, mechanisms of formation

To develop individualized approaches to the treatment of irritable bowel syndrome (IBS) based on the interaction of genetic and epigenetic factors, to characterize the phenotypes of the disease. According to the formulated concept of the authors, from the cohort of patients with IBS, subgroups were distinguished - "post-infectious IBS" (n=45), "IBS in overweight and obese people" (n=49), "comorbid IBS" (n=75) and "essential IBS" (n=51). In each subgroup the prevalence of candidate gene polymorphisms associated with IBS (COMT, SLC6A4, FTO), nutritional habits, levels of anxiety and depression, secretion of cortisol, serotonin, dopamine and zonulin levels in feces were studied. Patients with "post-infectious IBS" are characterized by the carriage of the S allele of the SLC6A4 gene, the val/val genotype of the COMT gene, the prevalence of diarrhea, a high level of anxiety and frequent refusal of milk and dairy products. The phenotype "IBS in overweight and obese individuals" is characterized by L/L genotypes of the SLC6A4 gene, met/met of the COMT gene and A/A of the FTO gene, constipation, low plasma dopamine levels, signs of depression, frequent episodes of overeating, addiction to fatty and sweet foods, excessive consumption of sugar, lack of vegetables in the diet. The "comorbid IBS phenotype" is characterized by more frequent detection of the val/val genotype of the COMT gene and the carriage of the S allele of the SLC6A4 gene, clinically pronounced anxiety and depression, early onset of the disease, severe course, significant food restrictions and significant increase in epithelial permeability. With the "essential phenotype", there are no bright stigmas of the disease; it is not possible to identify distinctive genetic and epigenetic factors, as well as the leading pathogenetic mechanism. The analysis of genetic and epigenetic factors, the leading mechanisms of the formation and course of IBS allows us to identify additional (except for "postinfectious") phenotypes of the disease: "IBS in overweight and obese people", "comorbid" and "essential".

Prostaglandin I2 suppresses the development of gut-brain axis disorder in irritable bowel syndrome in rats

In this study, we attempted to clarify a role of prostaglandin (PG) I2 and its specific receptor, IP in the pathogenesis of irritable bowel syndrome (IBS) using a maternal separation (MS)-induced IBS model. Administration of beraprost (BPS), a specific IP agonist, improved visceral hypersensitivity and depressive state with decreased serum CRF level in the IBS rats. To clarify the mechanism of the effect of BPS, we performed serum metabolome analysis and 1-methylnicotinamide (1-MNA) was identified as a possible candidate for a clue metabolite of pathogenesis of IBS. The serum 1-MNA levels revealed inverse correlation to the level of visceral sensitivity, and positive correlation to a depression marker, immobilizing time. Administration of 1-MNA induced visceral hypersensitivity and depression with increased levels of serum CRF. Since fecal 1-MNA is known for a marker of dysbiosis, we examined the composition of fecal microbiota by T-RFLP analysis. The proportion of clostridium cluster XI, XIVa and XVIII was significantly changed in MS-induced IBS rats treated with BPS. Fecal microbiota transplant of BPS-treated rats improved visceral hypersensitivity and depression in IBS rats. These results suggest for the first time that PGI2-IP signaling plays an important role in IBS phenotypes such as visceral hypersensitivity and depressive state. BPS modified microbiota, thereby inhibition of 1-MNA-CRF pathway, followed by improvement of MS-induced IBS phenotype. These results suggest that the PGI2-IP signaling could be considered to be a therapeutic option for IBS.

Фенотип СРК, ассоциированный с ожирением и избыточной массой тела: стратегия индивидуализированной курации больного

One of the most urgent problems of modern healthcare in Russia and worldwide is the increase in the number of people with overweight and obesity. It is generally recognized that overweight and obesity increase the risk of coronary heart disease, hypertension, type 2 diabetes mellitus, cholelithiasis, non-alcoholic fatty liver disease (NAFLD). At the same time, recent data indicate that pathomorphism of other chronic non-infectious diseases was also noted during preserving trend towards an increase in the obesity prevalence, for which the presence of overweight or obesity was not considered a traditional risk factor. Using the example of a clinical case concerning a female patient with a combined course of irritable bowel syndrome (IBS) and NAFLD, the article presents up-to-date information on risk factors and pathogenetic mechanisms of such comorbidity and suggests treatment methods to improve the therapy efficacy for this patient cohort. The presence of common risk factors and pathogenetic mechanisms creates the basis for the formation of comorbidity of IBS and NAFLD, which requires the development of patient-centered management. KEYWORDS: irritable bowel syndrome, non-alcoholic fatty liver disease, metabolic syndrome, intestinal permeability, intestinal microbiota, mebeverin, ademetionine. FOR CITATION: Livzan M.A., Gaus O.V., Fedorin M.M. IBS phenotype associated with obesity and overweight: treatment tactics for patient- centered management. Russian Medical Inquiry. 2023;7(5):323–331 (in Russ.). DOI: 10.32364/2587-6821-2023-7-5-11.

Probióticos en Síndrome de Intestino Irritable: ¿Están listos para la práctica clínica?

Probiotics are used as non-pharmacological therapy for Irritable Bowel Syndrome (IBS). Probiotics have mechanisms of action that can influence the complex pathophysiology of IBS. Evidence of the efficacy and safety of probiotics in IBS is based on various meta-analysis that showed these agents have a limited but superior effect on the management of IBS. The recommendations on the use of probiotics in IBS in the clinical practice guidelines published to date remain controversial. Some recommend the use of probiotics for global symptoms and abdominal pain, while others state that there is low quality evidence for a recommendation. Currently, probiotics are frequently prescribed by doctors for the treatment of patients with IBS. A greater number of high-quality clinical trials are needed to define which probiotic strains are effective in the different IBS phenotypes.

Psychological profiles of irritable bowel syndrome patients with different phenotypes.

Background/Aims Abnormal psychological profiles are frequently found in patients with functional gastrointestinal disorders (FGIDs). The present study aimed to evaluate the psychological profiles of FGID patients with irritable bowel syndrome (IBS), and IBS phenotypes.Methods In 608 FGID patients, including 235 with IBS, have filled a Rome III questionnaire and the French version of the Minnesota Multiphasic Personality Inventory 2. Data analysis was performed using univariate analysis and multivariate logistic regression.Results This study shows that IBS patients have abnormal psychological profiles with more significant symptom exaggeration and decreased test defensiveness than non-IBS patients. They have a significantly higher score for all clinical scales. Logistic regression analysis showed in IBS patients a decrease of body mass index (P= 0.002), and test defensiveness score K (P= 0.001) and an increase of Hypochondriasis (P< 0.001) and Masculinity-Femininity scale (P= 0.018). By comparison with non-IBS patients, IBS-constipation, IBS-diarrhea, and mixed IBS patients have increased Hypochondriasis value and Depression score, mixed IBS patients have higher Psychasthenia score and higher Hypomania score. No item was significantly different in the IBS-unspecified group.Conclusions This study shows that IBS patients have different psychological profiles than other FGID patients and that psychological characteristics are associated with IBS phenotypes except for patients with unsubtyped IBS.

Assessing the ecological role of yeasts in the human gut

Background: The influence of gut microorganisms in health and disease is well documented, however, the role of yeasts has not been as widely studied as bacteria, despite associations with gastrointestinal disorders, such as Irritable Bowel Syndrome (IBS). For instance, Candida albicans is an opportunistic pathogen that has been linked to gastrointestinal symptoms. Methods: Urine, stool and blood samples will be collected from 40 healthy controls, 40 IBS and 40 inflammatory bowel disease (IBD) patients for microbial and metabolic analysis using primarily flow cytometry-fluorescence in situ hybridisation (FC-FISH) and proton nuclear magnetic resonance (1H-NMR) spectroscopy, respectively. Calprotectin and anti-Saccharomyces cerevisiae antibodies (ASCA) levels will assess gastrointestinal inflammation. Statistical analysis will identify yeasts and their metabolites associated with the cohorts of interest. Preliminary results: Preliminary tests to assess the presence and functionality of yeasts in healthy and IBS faecal samples using in vitro batch culture fermentation highlighted significant metabolic differences between the phenotypes: Trimethylamine (TMA), short chain fatty acids (SCFA) and ethanol predominantly distinguished in the IBS metabolic profile, compared to gamma-amino-N-butyrate (GABA) in the healthy donor. The addition of C. albicans shifted the healthy phenotype to resemble the IBS donor, whereas nystatin shifted the IBS phenotype towards the healthy metabolic profile. Conclusion: This study will further define the preliminary results that indicate the implication of yeasts in IBS pathogenesis. Understanding the role of yeasts within the healthy and diseased human gut is necessary to develop targeted therapies to improve patient’s quality of lives and relieve burdens on the economy and healthcare systems.

511 High Risk of Ionizing Radiation Exposure Among Patients With Irritable Bowel in the United States

INTRODUCTION: Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder. While ionizing radiation exposure, and its associated cancer risk, is well-studied in other GI disorders, there is a paucity of data in the IBS population. METHODS: After IRB approval, a retrospective cohort study at a tertiary care referral center was conducted. Radiologic studies performed between Jan 2008-Dec 2017 on patients diagnosed with IBS were retrospectively evaluated. Data from patients whose primary care physician and gastroenterologist were in our healthcare system were included. Analyses was performed by chi square and Mann Kendall trend test and multivariable logistic regression was applied to assess independent associations. Percentage of participants receiving more than a cumulative dosage of 50 mSv (consensus threshold for high cancer risk) in the study period was calculated RESULTS: The mean age of participants was 40.83 years (SD: 12.12 years). 35.24% participants had a smoking history. A vast majority of participants were female (77.53%) and 55.95% of participants had a co-morbid psychiatric diagnosis. Most participants (85.46%) were on pain medications in the outpatient setting. 16 patients (7%) did not undergo any radiological study during the study period. 56 patients (24.67%) received greater than 50 mSv of cumulative effective radiation dosage during the 10-year study period. Mean yearly effective radiation dosage was 3.75 mSv per year (SD: 5.67). Mean cumulative effective radiation dosage during the study period was 37.45 mSv. A mean dosage of 27.87 mSv was attributable to studies involving the abdomen. Participants received a mean dosage of 17.59 mSv before and 19.86 mSv after the definitive diagnosis by the digestive disease clinic. Female gender, comorbid depression and anxiety, and diarrhea predominant IBS phenotype was significantly associated with an increased risk of radiation exposure (P &lt; 0.05). Mann Kendall trend test did not reveal any change in average ionizing radiation exposure in patients during the study period (P &gt; 0.05). CONCLUSION: Previous limited data from Europe hinted at a low risk of radiation exposure in IBS but we finds that, contrary to popular belief, a significant proportion of IBS patients are exposed to high levels of ionizing radiation, which potentially poses a significant cancer risk. Nationwide cohort studies are needed to assess this risk and quality improvement initiatives are needed to decrease radiation exposure in this relatively young population.

Lipid and Metabolite Profiles in Human Plasma and Associations with the Microbiome and Functional Gastrointestinal Disorders (P20-033-19)

ObjectivesMetabolomic profiling of plasma provides a biochemical fingerprint of the circulating metabolites from the host and microbiome, and may assist with understanding mechanisms underlying functional gastrointestinal (GI) disorders such as Irritable Bowel Syndrome (IBS). In a case-control study, we aimed to identify microbial and host factors in plasma to provide mechanistic insights into functional GI disorders and increase the predictability of phenotypes for use in nutrition intervention studies. MethodsPlasma samples from 246 individuals with functional GI disorders (cases) or asymptomatic (controls), consisting of 93 healthy controls, 54 with functional constipation (C) or IBS-C, 60 with functional diarrhoea (D) or IBS-D, and 39 diagnosed as IBS-mixed or awaiting diagnosis. Plasma was subjected to biphasic extraction and global metabolite profiling was performed using three separate untargeted liquid chromatography high resolution mass spectrometry analysis (LC-MS) methods (polar, semi-polar and non-polar chromatography). ResultsPlasma metabolomic profiles differed considerably between the IBS phenotypes and those of the control subjects. Multivariate partial least squares discriminant analysis of 428 annotated lipid species highlighted significant differences (P < 0.001) between IBS-C and healthy control subjects. Univariate analysis revealed significant differences in the concentrations of 48 lipid species (P < 0.05) between the two groups, including elevated concentrations of many sphingolipids and phospholipids in the IBS-C group. Biochemical network analysis also revealed major perturbations in amino acid, bile acid and lipid metabolism, and highlighted key metabolic pathways included microbial related pathways. ConclusionsPerturbations of plasma lipid concentrations in the IBS subjects suggest changes may occur with both host and microbial lipid metabolism. Future efforts to investigate these links will utilize a systems biology approach integrating metabolomic and fecal metagenomic datasets to further identify key pathways and biomarkers that characterize functional GI disorders and how nutrition can improve GI health and function. Funding SourcesFunded by the New Zealand National Science Challenge High-Value Nutrition program.

Identifying biomarkers relevant to functional gastrointestinal disorders using a systems biology approach

The links between food, gastrointestinal (GI) function and comfort, and brain function are at the forefront of nutritional research. A key part of the gut‐brain axis (GBA) is the GI microbiota. Animal studies show that normal development of the enteric and central nervous systems depends on microbial colonisation, which also modulates neurotransmitter abundance and activity, expression of genes linked to anxiety and synaptic plasticity, and prefrontal cortex myelination. Furthermore, GI bacteria can stimulate secretion of the neurotransmitter serotonin from enterocytes and some microbial tryptophan‐derived metabolites have neuroprotective and immune benefits. Irritable Bowel Syndrome (IBS) is a functional GI disorder characterised by chronic or recurrent abdominal discomfort mostly associated with changes in GI habit in the absence of a detectable organic cause. Several central and peripheral mechanisms initiate perturbations in GI motor and sensory functions and lead to IBS symptoms. Peripheral molecules, and associated pathway dysfunctions and altered tissue abundance or expression, are important to better define IBS and ultimately GI function and comfort. Global metabolite profiling across multiple sample types can provide biochemical fingerprints which can assist with understanding the underlying mechanisms. In a case‐control study, we aimed to identify microbial and host factors in plasma that provide mechanistic insights into functional GI disorders and increase the predictability of phenotypes for use in nutrition intervention studies. Individuals with functional GI symptoms (cases) or asymptomatic (controls) undergoing colonoscopy were recruited at Christchurch hospital and a subset of 102 plasma samples and 70 breath samples were measured. Plasma samples were subjected to biphasic extraction and liquid chromatography mass spectrometry analysis (LCMS) while breath volatiles were captured on carbon sorbent and subsequently analysed by gas chromatography MS (GCMS). LCMS analysis detected 491 polar, 458 semi‐polar and 768 non‐polar (lipids) metabolite features in plasma, while GCMS profiling yielded 37 volatile components in the breath. Significant partial least square discriminant analysis models were generated for all three LCMS plasma analyses (polar P=7.7e−5, Q2=0.46; semi‐polar P=5.5e−9, Q2=0.61; non‐polar P=4.5e−7, Q2=0.52) between the IBS phenotypes and the control subjects, with major perturbations observed in amino acid, bile acid and lipid metabolism. Breath volatile profiles revealed weak separations between the IBS phenotypes. The next steps include applying a systems biology approach using metabolomics (breath, plasma, faeces) and microbiota datasets of a larger cohort size to identify key pathways and biomarkers. Together with functional outcomes, these host‐microbial factors will provide new knowledge that can support the development of added‐value foods for improving GI function and comfort.Support or Funding InformationThis research was funded by the New Zealand Ministry of Business, Innovation and Employment as part of the High‐Value Nutrition National Science ChallengeThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Current insights into the innate immune system dysfunction in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients’ quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.

Childhood bladder and bowel dysfunction predicts irritable bowel syndrome phenotype in adult interstitial cystitis/bladder pain syndrome patients.

Many clinicians have suggested that a history of bladder and bowel dysfunction (BBD) in childhood predisposes to the development of interstitial cystitis/bladder pain syndrome (IC/BPS) or irritable bowel syndrome (IBS) in adulthood. We hypothesized that BBD symptoms in childhood would predict the IBS-associated phenotype in adult IC/BPS patients. Consecutive female patients (n=190) with a diagnosis of IC/BPS were administered a modified form of a clinical BBD questionnaire (BBDQ) to capture childhood BBD-like symptoms, as well as Interstitial Cystitis Symptoms Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Pelvic Pain and Urgency/Frequency (PUF) questionnaires and UPOINT categorization. Patients were stratified to IBS-positive or IBS-negative according to clinical assessment of IBS-like symptoms. The 127 patients (67%) identified with IBS-like symptoms recalled significantly higher BBDQ scores than the 63 patients (33%) who were IBS-negative (2.8 vs. 2.3; p=0.05). The IBS-positive patients also reported a higher number of UPOINT domains than their non-IBS counterparts (3.8 vs. 2.9; p=0.0001), while their PUF total scores were significantly higher (13.6 vs. 12.3; p=0.04). IBS-positive patients more often recalled that in childhood they did not have a daily bowel movement (BM) (p=0.04) and had "to push for a BM" (p=0.009). In childhood, they "urinated only once or twice per day" (p=0.03) and recalled "painful urination" more than those without IBS (p=0.03). There were no significant differences between the groups in answers to the other five questions of the BBDQ. Our symptom recollection survey was able to predict the IBS phenotype of IC/BPS based on a childhood BBDQ. Further prospective studies are needed to further evaluate these novel findings.

Faecal biomarker patterns in patients with symptoms of irritable bowel syndrome

ObjectiveTo determine rates of faecal biomarker results capable of suggesting potentially treatable causes of irritable bowel syndrome (IBS) symptomatology in a population of patients with symptoms of IBS who meet...

Molecular basis of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a functional disorder characterized by abdominal pain, discomfort and bloating. The pathophysiology of IBS is poorly understood, but the presence of psychosocial basis is now known. There is an increasing number of publications supporting the role of genetics in IBS. Most of the variations are found in genes associated with the brain-gut axis, revealing the strong correlation of brain-gut axis and IBS. miRNAs, which play critical roles in physiological processes, are not well studied in IBS. However, so far there is found an involvement of alterations in miRNA expression or sequence, in IBS symptoms. IBS phenotype is affected by epigenetic alteration and environment. Changes in DNA and histone methylation are observed in patients who suffered childhood trauma or abuse, resulting in altered gene expression, such as the glucocorticoid receptor gene. Finally, diet is another factor associated with IBS, which may contribute to symptom onset. Certain foods may affect on bacterial metabolism and epigenetic modifications, predisposing to IBS.

Susceptibility to stress-induced visceral sensitivity: a bad legacy for next generations

Despite high prevalence, the precise irritable bowel syndrome (IBS) pathophysiology remains poorly understood likely due to the heterogeneity of IBS populations and the multifactorial etiology of this disorder. Among risk factors, genetic predisposition and early life trauma have been reported. In this context, the debate on genetic or environmental influences in the IBS pathogenesis is still open. The study by van der Wijngaard etal., reporting for the first time that susceptibility to stress-induced visceral hypersensitivity in maternally separated rats can be transferred to the next generation without any further exposure of F2 individuals to maternal separation, supports the importance of environmental influence in the IBS phenotype. Epigenetic mechanisms such as hypermethylation in the promoter region of the glucocorticoid receptor gene mediating the long-term and transgenerational behavioral effects of maternal care on the development have been shown in some but not in all studies. Van der Wijngaard etal. incriminated maternal care in the transmitted susceptibility to stress-induced visceral hypersensitivity, but not changes in glucocorticoid receptor protein expression in the brain. This finding opens a broad field of future directions aimed at evaluating the mechanisms involved in the transmission across generations of the digestive features of IBS, including, for example, on the role of gut microbiota changes in vertical transmission or epigenetic modifications of intestinal mast cells and the junctional region of intestinal epithelial cells in vertical transfer.

Corticotropin-Releasing Hormone Receptor 1 Gene Variants in Irritable Bowel Syndrome

BackgroundCorticotropin-releasing hormone (CRH) acts mainly via the CRH receptor 1 (CRH-R1) and plays a crucial role in the stress-induced pathophysiology of irritable bowel syndrome (IBS). Several studies have demonstrated that variants of the CRH-R1 gene carry a potential risk for depression, but evidence for an association between CRH-R1 genotypes and IBS is lacking. We tested the hypothesis that genetic polymorphisms and haplotypes of CRH-R1 moderate the IBS phenotype and negative emotion in IBS patients.MethodsA total of 103 patients with IBS and 142 healthy controls participated in the study. Three single-nucleotide polymorphisms of the CRH-R1 gene (rs7209436, rs242924, and rs110402) were genotyped. Subjects' emotional states were evaluated using the Perceived-Stress Scale, the State-Trait Anxiety Inventory, and the Self-rating Depression Scale.ResultsThe TT genotype of rs7209436 (P = 0.01) and rs242924 (P = 0.02) was significantly more common in patients with IBS than in controls. Total sample analysis showed significant association between bowel pattern (normal, diarrhea, constipation, or mixed symptoms) and the T allele of rs7209436 (P = 0.008), T allele of rs242924 (P = 0.019), A allele of rs110402 (P = 0.047), and TAT haplocopies (P = 0.048). Negative emotion was not associated with the examined CRH-R1 SNPs.ConclusionThese findings suggest that genetic polymorphisms and the CRH-R1 haplotypes moderate IBS and related bowel patterns. There was no clear association between CRH-R1 genotypes and negative emotion accompanying IBS. Further studies on the CRH system are therefore warranted.

Pro-inflammatory chemokine C-C motif ligand 16 (CCL-16) dysregulation in irritable bowel syndrome (IBS): a pilot study

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 6 months 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.

5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene and irritable bowel syndrome: effect of bowel habit and sex

Conflicting data exist on the association between functional polymorphisms in the serotonin reuptake transporter (SERT) gene (SLC6A4) and irritable bowel syndrome (IBS). This may be partly because of small participant numbers and varying ethnic origin and sex within the cohorts studied. To reassess the potential association between the SERT polymorphisms 5-HTTLPR and STin2 in both male and female IBS patients with diarrhoea (IBS-D) and constipation (IBS-C) compared with healthy volunteers. In this case-control study, 196 Caucasian Rome II IBS patients [97 IBS-D (aged 18-66 years; 67 female) and 99 IBS-C (aged 18-65 years; 95 female)] and 92 Caucasian healthy volunteers (aged 18-63 years; 60 female) from the UK had genomic DNA extracted from peripheral blood and the 5-HTTLPR and STin2 polymorphisms genotyped. The frequency of the 5-HTTLPR (ss) genotype was slightly lower in both IBS-D (16.5%) and IBS-C (14.3%) patients compared with controls (23.9%), although not significantly (P<or=0.191). This seemed to be related to a reduction in the frequency of the 5-HTTLPR (ss) genotype in male patients, particularly those with IBS-D [IBS-D 10%, IBS-C 25%, controls 37.5%; P=0.01 for IBS-D vs. controls; odds ratio (95% confidence interval) for 5-HTTLPR (ss) vs. 5-HTTLPR (non-ss)=0.185 (0.046-0.744)] than in female patients (IBS-D 19.4%, IBS-C 13.8%, controls 16.7%). There were no differences in the frequencies of either the 5-HTTLPR (ll) or (ls), or STin2 genotypes between any of the three groups. Our finding that male IBS-D patients have a reduced frequency of the 5-HTTLPR (ss) genotype contradicts three earlier studies of a similar size, which did not take sex into account. Therefore, replication studies in even larger cohorts, stratifying for sex and endophenotypes, after assessing physiological and psychological traits, are required to unravel the contribution of SERT polymorphisms to the IBS phenotype.