Pathophysiology Of Irritable Bowel Syndrome Research Articles

Microbiome and Its Role in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is an extremely common and often very debilitating chronic functional gastrointestinal disorder. Despite its prevalence, significant associated healthcare costs, and quality-of-life issues for affected individuals, our understanding of its etiology remained limited. However, it is now evident that microbial factors play key roles in IBS pathophysiology. Acute gastroenteritis following exposure to pathogens can precipitate the development of IBS, and studies have demonstrated changes in the gut microbiome in IBS patients. These changes may explain some of the symptoms of IBS, including visceral hypersensitivity, as gut microbes exert effects on the host immune system and gut barrier function, as well as the brain-gut axis. Microbial differences also appear to underlie the two main functional categories of IBS: diarrhea-predominant IBS (IBS-D) is associated with small intestinal bacterial overgrowth, which can be diagnosed by a positive hydrogen breath test, and constipation-predominant IBS (IBS-C) is associated with increased levels of methanogenic archaea, which can be diagnosed by a positive methane breath test. Mechanistically, the pathogens that cause gastroenteritis and trigger subsequent IBS development produce a common toxin, cytolethal distending toxin B (CdtB), and antibodies raised against CdtB cross-react with the cytoskeletal protein vinculin and impair gut motility, facilitating bacterial overgrowth. In contrast, methane gas slows intestinal contractility, which may facilitate the development of constipation. While antibiotics and dietary manipulations have been used to relieve IBS symptoms, with varying success, elucidating the specific mechanisms by which gut microbes exert their effects on the host may allow the development of targeted treatments that may successfully treat the underlying causes of IBS.

Expression of Neurotrophic Factors, Tight Junction Proteins, and Cytokines According to the Irritable Bowel Syndrome Subtype and Sex.

Background/AimsEmerging evidence shows that the mechanism of irritable bowel syndrome (IBS) is associated with neurotrophic factors and tight junction proteins (TJPs). It is known that there are sex differences in the pathophysiology of IBS. The aim of the present study is to determine expression levels of neurotrophic factors, TJPs, and cytokines according to IBS subtype and sex.MethodsFrom 59 IBS (33 IBS-constipation, 21 IBS-diarrhea, and 5 IBS-mixed) and 36 control patients, colonic mucosa mRNA expression levels of transient receptor potential vanilloid-1 (TRPV1), nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and various TJPs were assessed by real-time polymerase chain reaction. Western blot was performed to determine levels of zonular occludens-1 (ZO-1). Serum levels of cytokines were measured by enzyme-linked immunosorbent assay.ResultsTRPV1, GDNF, and NGF mRNA levels were significantly increased in those with IBS-constipation compared to those in controls (all P < 0.05). However, they showed no significant difference between those with IBS-diarrhea and controls. Expression level of TRPV1 correlated with that of GDNF (r = 0.741, P < 0.001) and NGF (r = 0.935, P < 0.001). ZO-1 RNA expression levels were lower (P = 0.021) in female IBS-diarrhea than those in controls, although they showed no significant differences between male IBS-diarrhea and controls. Serum IL-1β levels in female IBS were significantly higher than those of male IBS, especially in IBS-constipation (P < 0.001).ConclusionOur results suggest that neurotrophic factors and IL-1β are closely related to IBS-constipation and that decrease of ZO-1 is an important factor in female with IBS-diarrhea.

Functional polymorphism of the serotonin reuptake transporter SLC6A4 gene in various clinical variants of irritable bowel syndrome

Rationale:Irritable bowel syndrome (IBS) is a multifactorial disease, the genetic aspect of which is being actively studied.Aim:To investigate functional polymorphism of the serotonin reuptake transporter (SERT)SLC6A4gene of various clinical variants of IBS.Materials and methods:We performed a cross-sectional single center study in 79 Caucasian patients with IBS (according to the Rome criteria IV). The patients were divided into two groups: group 1, IBS with diarrhea (IBS-D, n = 45) and group 2, IBS with constipation (IBS-C, n = 34). The control group included 59 Caucasian patients with gastrointestinal disorders without IBS. Polymorphism5-HTTLPRof theSLC6A4gene was assessed in all subjects. In group 1 patients, blood serotonin levels were measured and psychological tests were performed, including Spielberger's State / Trait Anxiety Inventory, quality of life by SF36 and GSRS, Asthenia scale, VAS scores for pain intensity.Results:Thirty-five of 45 (77.8%) patients with IBS-D carried the mutantSallele, which was significantly more frequent than in the IBS-C group (p = 0.002) and in the control group (p = 0.005). There were no statistically significant differences (p = 0.54) in the frequency of detection of the homozygousLLgenotype (normal allele) and the heteroand homozygous mutant alleles (SLandSS) genotype between the IBS-C and control patients. In the IBS-D group, a gender difference for the mutantSSallele of5-HTTLPRwas found, with significantly higher frequency in female patients (p = 0.0147). No significant gender differences in the genotype distribution between the patients with IBS-C and the control group were found. There were also no differences in blood serotonin levels in the IBS patients with various5-HTTLPRtypes (p = 0.086); they were all in the reference range. However, there was a trend towards lower serotonin levels in theLLgenotype carriers compared to those with theSS/SLpolymorphisms. The Gastroenterological inventoryGSRSdemonstrated significantly higher total score for the constipation syndrome in the patients with homozygousLL 5-HTTLPRpolymorphism, compared to that in the patients with theSS/SLgenotype (p = 0.013).Conclusion:The results may be related to lower expression of theSLC6A4gene in the carriers of the mutant allele in the5-HTTLPRpromoter and subsequent decreased rate of serotonin uptake, with resulting stimulation of the gastrointestinal tract. TheSERTpolymorphism of theSLC6A4gene is worth further investigation as a potential candidate gene in the IBS pathophysiology.

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

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.

The effectiveness of diosmectite in the treatment of irritable bowel syndrome with diarrhea

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, changes in the frequency and consistency of stool. These symptoms cannot be explained by structural changes in the intestines. To date, there is no special laboratory test or specific biomarker for the diagnosis of IBS. Thus, IBS is classified as a functional disorder. The diagnosis is established on the basis of characteristic complaints, medical history, a thorough physical examination and additional studies, taking into account the absence of symptoms of an organic disease. Although a large number of studies have been conducted in this area, the pathophysiology of IBS is complex and not fully understood. Multiple factors are believed to contribute to the development of symptoms in patients with IBS. Altered gastrointestinal motility, visceral hypersensitivity, and the interaction between the brain and intestines are important classic concepts in IBS pathophysiology. New studies in this area include mild post-infection inflammation, genetic and immunological factors, altered microbiota, dietary factors, and enteroendocrine cells. Despite significant successes in understanding the pathogenesis of IBS with diarrhea, the treatment of this category of patients presents great difficulties. Few treatments have shown efficacy and safety in IBS with a predominance of diarrhea. The use of diosmectite is proposed as an effective and safe treatment for IBS with diarrhea. Smectalia — a new dosage form of smectite dioctahedral registered in the pharmaceutical market of Ukraine. Due to the spatial structure and its properties, diosmectite protects the intestinal mucosa, helps to reduce diarrhea, flatulence, abdominal pain. The use of diosmectite in patients with IBS with a predominance of diarrhea has shown good efficacy and a high safety profile. The results of the analyzed clinical studies provide the basis for the widespread use of diosmectite in treatment regimens for IBS with diarrhea.

Identification of Gut Microbiota and Metabolites Signature in Patients With Irritable Bowel Syndrome

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.

5-HT6 receptor antagonism reduces defecation in rat: A potential treatment strategy for irritable bowel syndrome with diarrhea

Whereas the potential role of serotonin for the pathophysiology of irritable bowel syndrome (IBS) has since long been discussed, the possibility that 5-hydroxytryptamine 6 (5-HT6) receptors may serve as targets for the treatment of this condition has as yet not been explored. The aim of the current study was to assess to what extent defecation in rats is influenced by manipulation of 5-HT6 receptors. Reduced defecation following SB-399885 was observed in non-stressed animals assessed for 7 h after drug administration. While not impacting context-conditioned freezing, three 5-HT6 receptor antagonists (SB-399885, SB-271046 and SB-258585) also markedly reduced the number of faecal boli produced by rats exposed to context-conditioned fear. In contrast, a 5-HT6 receptor agonist, WAY-208466, influenced defecation neither in unstressed animals nor in rats experiencing conditioned fear stress. A clinical study on the possible effect of a 5-HT6 receptor antagonist in IBS with diarrhea appears warranted.

Mast cells are increased in the small intestinal mucosa of patients with irritable bowel syndrome: A systematic review and meta‐analysis

Colonic mast cells have been proposed to be related to the pathophysiology of irritable bowel syndrome (IBS). Whether mast cell counts are altered in the small intestine, a less-explored region in patients with IBS is not completely clear. PubMed and EMBASE were searched for case-control studies on mast cell count/density in the small intestine of patients with IBS vs controls through February 2019. Mast cell counts were separately analyzed in the duodenum, jejunum, and ileum. Data were pooled using the standardized mean difference (SMD) method. When zero was not within the 95% confidence interval (CI), the SMD was considered significant. Data from 344 patients with IBS and 229 healthy controls from three studies in the duodenum, six in the jejunum, and five in the ileum were pooled in this meta-analysis. The number of mast cells was significantly higher in the ileum (SMD: 1.78 [95% CI: 0.89, 2.66]) of patients with IBS. Mast cell counts were not significantly different in the duodenum (SMD:0.81 [-0.06, 1.67]) or the jejunum (SMD:0.58 [-0.03, 1.19]) of patients with IBS vs healthy controls. Mast cells are increased in the small intestine of IBS vs controls, mainly in the ileum. Future studies should address whether such findings are IBS subtype or gender-dependent. Methodological variations, single-center bias, and the limited number of studies included in this meta-analysis may affect the final results.

Is fecal calprotectin always normal in children with irritable bowel syndrome?

Background/AimsFecal calprotectin (FC) is a marker of intraluminal intestinal inflammation. Intestinal inflammation may contribute to the pathophysiology of irritable bowel syndrome (IBS). This study evaluated FC levels in children with IBS and differences in FC levels in children stratified by IBS subtype and healthy controls (HCs).MethodsA total of 157 children with IBS and 56 HCs aged 4–16 years (119 boys, 94 girls, mean age of 9.48 years) were included in this prospective study. Children with IBS were diagnosed using the Rome III criteria and classified into 4 subtypes: IBS with constipation (IBS-C, n=37), IBS with diarrhea (IBS-D, n=54), IBS with alternating constipation and diarrhea (IBS-M, n=49), and IBS unsubtyped (IBS-U, n=17); postinfectious IBS (PI-IBS) was also considered. The FC concentration in stool samples was analyzed using an enzyme-linked immunosorbent assay. All participants answered a questionnaire regarding several demographic and clinical characteristics.ResultsChildren with IBS had significantly higher levels of FC than the HCs (88.71 μg/g vs. 17.77 μg/g). Among the 4 IBS subtypes, the FC concentration was highest in children with IBS-D, followed by those with IBS-M, IBS-C, and IBS-U (169.94 μg/g vs. 45.04, 31.22, and 33.52 μg/g, respectively), and these differences were statistically significant. For PI-IBS, 90% of cases were in the IBS-D group.ConclusionsThe FC level was significantly higher in children with IBS than in HCs and differed depending on the IBS subtype, supporting the notion that IBS is a type of low-grade bowel inflammation.

Diet in Irritable Bowel Syndrome (IBS): Interaction with Gut Microbiota and Gut Hormones.

Diet plays an important role not only in the pathophysiology of irritable bowel syndrome (IBS), but also as a tool that improves symptoms and quality of life. The effects of diet seem to be a result of an interaction with the gut bacteria and the gut endocrine cells. The density of gut endocrine cells is low in IBS patients, and it is believed that this abnormality is the direct cause of the symptoms seen in IBS patients. The low density of gut endocrine cells is probably caused by a low number of stem cells and low differentiation progeny toward endocrine cells. A low fermentable oligo-, di-, monosaccharide, and polyol (FODMAP) diet and fecal microbiota transplantation (FMT) restore the gut endocrine cells to the level of healthy subjects. It has been suggested that our diet acts as a prebiotic that favors the growth of a certain types of bacteria. Diet also acts as a substrate for gut bacteria fermentation, which results in several by-products. These by-products might act on the stem cells in such a way that the gut stem cells decrease, and consequently, endocrine cell numbers decrease. Changing to a low-FODMAP diet or changing the gut bacteria through FMT improves IBS symptoms and restores the density of endocrine cells.

Therapeutic Effect of Amitriptyline in Patients Suffering from Irritable Bowel Syndrome

Patients suffering from irritable bowel syndrome (IBS) form a part of the most frequent visitors in GP and gastroenterologist. Pathophysiology of irritable bowel syndrome consists of abnormal bowel motility including the pathological gastro-colic reflex with an abnormal character of stool consistency

Impact of occupational stress on irritable bowel syndrome pathophysiology and potential management in active duty noncombat Greek military personnel: a multicenter prospective survey.

Irritable bowel syndrome (IBS) is one of the gut-brain axis interaction disorders. It has global distribution with varying prevalence and particular financial and psychological consequences. IBS has been associated with stress and anxiety, conditions that are usually prevalent in the army. There are scarce data investigating the impact of IBS on noncombat active duty military without reports of Greek military or stress in the occupational environment. The main exclusion criteria in our noncombat military multicenter prospective survey were gastrointestinal pathologies, malignancies, hematochezia, recent infections and antibiotics prescription, and pregnancy. Questionnaires included a synthesis of baseline information, lifestyle, and diet, psychological and stress-investigating scales and the IBS diagnosis checklist. Hospital Anxiety and Depression Scale and Rome IV criteria were utilized. Among 1605 participants included finally, the prevalence of IBS was 8% and 131 cases were identified. Women were more vulnerable to IBS, although male sex was prevalent at a ratio of 3.5 : 1 (male:female) in the entire sample. The mean age of all participants was 23.85 years; most of the IBS patients were older than thirty. Abnormal anxiety scores and high levels of occupational stress were related to an IBS diagnosis. This prospective multicenter survey showed, for the first time, the potential impact of occupational stress on IBS in active duty noncombat Greek Military personnel. The diagnosis of IBS by questionnaire is a quick, affordable way that can upgrade, by its management, the quality of life and relieve from the military burden. Our results are comparable with previous studies, although large-scale epidemiological studies are required for the confirmation of a possible causative relationship.

Does Irritable Bowel Syndrome Exist? Identifiable and Treatable Causes of Associated Symptoms Suggest It May Not

Significant shortcomings in irritable bowel syndrome (IBS) diagnosis and treatment may arise from IBS being an “umbrella” diagnosis that clusters several underlying identifiable and treatable causes for the same symptom presentation into one classification. This view is compatible with the emerging understanding that the pathophysiology of IBS is heterogeneous with varied disease mechanisms responsible for the central pathological features. Collectively, these converging views of the pathophysiology, assessment and management of IBS render the traditional diagnosis and treatment of IBS less relevant; in fact, they suggest that IBS is not a disease entity per se and posit the question “does IBS exist?” The aim of this narrative review is to explore identifiable and treatable causes of digestive symptoms, including lifestyle, environmental and nutritional factors, as well as underlying functional imbalances, that may be misinterpreted as being IBS.

Faecal microbiota transplantation for IBS: still a long way to go

The pathophysiology of irritable bowel syndrome (IBS) remains unclear, and therefore currently available treatments are only modestly effective.1 The possibility that the gut microbiota might have a role in generating the symptoms of IBS has gained prominence, given that IBS is more common after a gastrointestinal infection.2 Furthermore, a systematic review of case-control studies suggested that the composition of the gut microbiota differs between patients with IBS and healthy controls.3 All studies found differences between cases and controls, although the nature of these differences was inconsistent, and therefore no definitive conclusion can be reached as to whether any species might be harmful or protective.

Multi-omics Analysis of Gut Microbiota and Metabolites in Rats With Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a common gastrointestinal dysfunctional disease. The pathophysiology of IBS is, however, largely unknown. This study aimed to determine whether evaluation of fecal metabolite and microbiota profiles may offer an opportunity to identify a novel pathophysiological target for IBS, and to reveal possible gut microbe–metabolite associations. By using gas chromatography coupled to time-of-flight mass spectrometry (GC-TOFMS) and 16S rRNA gene sequencing, we measured fecal metabolites and microbiota of the control and water avoidance stress (WAS)-induced IBS rats. We found a significantly differential metabolite profile between the IBS and control groups; a cluster of metabolites was also found to be significantly associated with the amount of defecations. Moreover, the WAS group exhibited a decreased alpha diversity of the microbial population as compared to the control group. However, the characteristics of gut microbiota could not differentiate the IBS group from the control group. Correlation of the metabolite level with the number of microbial genera showed no significant association between the control and IBS groups. This study provides a global perspective on metabolomics and microbiota profiling in WAS-induced IBS model and a theoretical basis for research on the pathophysiology of IBS.

PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons.

Glucagon-like peptide (GLP-1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper-activation of the hypothalamic-pituitary-adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP-1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP-1 receptor agonist, exendin-4 (Ex-4). Colonic contractile activity was assessed using organ bath physiological recordings. Ex-4 induced an elevation of intracellular calcium arising from store release and influx via voltage-gated calcium channels. Ex-4 activated both ERK-MAPK and PI 3-kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin-releasing factor (CRF) potentiated the neuronal response to Ex-4, and the functional effects of Ex-4 on colonic circular muscle activity were not altered. Ex-4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex-4 were dependent upon activation of PI 3-kinase and ERK-MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.

Metabolomics reveals elevated urinary excretion of collagen degradation and epithelial cell turnover products in irritable bowel syndrome patients.

Irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal (GI) disorder in developed countries, is characterized by chronic abdominal pain, and altered bowel habits. Accurate and timely diagnosis is challenging as it relies on symptoms and an evolving set of exclusion criteria to distinguish it from other related GI disorders reflecting a complex etiology that remains poorly understood. Herein, nontargeted metabolite profiling of repeat urine specimens collected from a cohort of IBS patients (n = 42) was compared to healthy controls (n = 20) to gain insights into the underlying pathophysiology. An integrated data workflow for characterization of the urine metabolome with stringent quality control was developed to authenticate reliably measured (CV < 30%) and frequently detected (> 75%) metabolites using multisegment injection-capillary electrophoresis-mass spectrometry. Complementary statistical methods were then used to rank differentially excreted urinary metabolites after normalization to osmolality that were subsequently identified by high resolution tandem mass spectrometry and their electrophoretic migration behavior. Our work revealed ten consistently elevated urinary metabolites in repeat samples collected from IBS patients at two different time points (q < 0.05 after age and Benjamini-Hochberg/FDR adjustment), which were associated with greater collagen degradation and intestinal mucosal turn-over processes likely due to low-grade inflammation. IBS-specific metabolites identified in urine included a series of hydroxylysine metabolites (O-glycosylgalactosyl-hydroxylysine, O-galactosyl-hydroxylysine, lysine), mannopyranosy-L-tryptophan, imidazole propionate, glutamine, serine, ornithine, dimethylglycine and dimethylguanosine. A major limitation in this retrospective case-control study was significant co-morbidity of IBS patients with other illnesses, including depression and prescribed medications as compared to healthy controls. This work provides new mechanistic insights into the pathophysiology of IBS while also offering a convenient way to monitor patient disease progression and treatment responses to therapy based on a panel of urinary metabolites that avoids invasive blood sampling, colonoscopy and/or tissue biopsies.

Elimination of Fermentable Carbohydrates to Reduce Gastrointestinal Symptoms in Pediatric Patients With Irritable Bowel Syndrome: A Narrative Review.

Irritable bowel syndrome (IBS) is classified as a functional gastrointestinal (GI) disorder characterized by abdominal pain, bloating, and changes in bowel function. Although the pathophysiology of IBS is incompletely understood, fermentable carbohydrates are implicated as a potential cause of symptoms. An elimination diet, such as a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet, represents a potential intervention for reducing GI symptoms in patients with IBS. The role of fermentable carbohydrates in symptom onset is well studied in adult patients with IBS; however, less research exists in the pediatric population. This review sought to explore evidence for the role of dietary fermentable carbohydrate elimination to reduce GI symptoms (abdominal pain, stool changes, abdominal bloating) in children and adolescents (4-19 years of age) diagnosed with IBS based on Rome III or IV criteria. Five studies of neutral to positive quality rating were identified and analyzed using the Academy of Nutrition and Dietetics Evidence Analysis Process. These studies demonstrate that dietary elimination of fermentable carbohydrates, such as through a low-FODMAP diet, reduces the severity of 1 or more GI symptoms in about one-quarter to one-half of pediatric patients with IBS. Patients without improvement are considered "nonresponders" and may require an alternative intervention. More research is needed to establish the best way to identify patients who would respond to elimination diets vs other IBS treatment strategies.

Dehydroepiandrosterone sulfate improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)- or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dose-dependent manner. It also blocked repeated WAS- or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γ-aminobutyric acid (GABA)A receptor antagonist, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2 receptor antagonist. However, domperidone, a peripheral dopamine D2 receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2 and peripheral CRF2 signaling. DHEA-S may be useful for IBS treating.

Evidence for an association of gut microbial Clostridia with brain functional connectivity and gastrointestinal sensorimotor function in patients with irritable bowel syndrome, based on tripartite network analysis

Background and aimsEvidence from preclinical and clinical studies suggests that interactions among the brain, gut, and microbiota may affect the pathophysiology of irritable bowel syndrome (IBS). As disruptions in central and peripheral serotonergic signaling pathways have been found in patients with IBS, we explored the hypothesis that the abundance of serotonin-modulating microbes of the order Clostridiales is associated with functional connectivity of somatosensory brain regions and gastrointestinal (GI) sensorimotor function.MethodsWe performed a prospective study of 65 patients with IBS and 21 healthy individuals (controls) recruited from 2011 through 2013 at a secondary/tertiary care outpatient clinic in Sweden. Study participants underwent functional brain imaging, rectal balloon distension, a nutrient and lactulose challenge test, and assessment of oroanal transit time within a month. They also submitted stool samples, which were analyzed by 16S ribosomal RNA gene sequencing. A tripartite network analysis based on graph theory was used to investigate the interactions among bacteria in the order Clostridiales, connectivity of brain regions in the somatosensory network, and GI sensorimotor function.ResultsWe found associations between GI sensorimotor function and gut microbes in stool samples from controls, but not in samples from IBS patients. The largest differences between controls and patients with IBS were observed in the Lachnospiraceae incertae sedis, Clostridium XIVa, and Coprococcus subnetworks. We found connectivity of subcortical (thalamus, caudate, and putamen) and cortical (primary and secondary somatosensory cortices) regions to be involved in mediating interactions among these networks.ConclusionsIn a comparison of patients with IBS and controls, we observed disruptions in the interactions between the brain, gut, and gut microbial metabolites in patients with IBS—these involve mainly subcortical but also cortical regions of brain. These disruptions may contribute to altered perception of pain in patients with IBS and may be mediated by microbial modulation of the gut serotonergic system.