Pathogenesis Of Irritable Bowel Syndrome Research Articles

Синдром раздраженного кишечника в педиатрической практике. Фокус на детей с предшествующим оперативным вмешательством

This review aims to summarize the existing literature on irritable bowel syndrome (IBS) in children and discuss the evolution of definitions and diagnostic criteria according to the Rome IV Criteria issued in 2016. The article also covers the main theories of IBS pathogenesis, including the role of surgical interventions and changes in the intestinal microbiota. There is an overview of current therapeutic approaches used for IBS treatment in accordance with the variety of etiopathogenetic factors. It has been shown that the use of probiotics, antidepressants, prokinetics, and antispasmodics can become a strategy for the prevention and management of IBS in children. Key words: children, irritable bowel syndrome, functional gastrointestinal disorders

Serum Calcium alteration Correlates With Worsening of Lipid Profile and oxidant/ antioxidant status in women with Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is known to be a heterogeneous disease, characterized by abdominal pain and disorders of intestinal motility. This study aims at investigating if serum calcium levels correlate with lipid values in IBS and the oxidant / antioxidant system as one of the factors proposed in the etiology of IBS. A total of 70 patient’s women with IBS were included in this study. 70 healthy subjects were selected to form the control group. Total cholesterol, triglycerides, calcium, Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-), superoxide (O2), carbonyls proteins (Pc) and malondialdehyde (MDA) and nitric oxide (NO) concentrations were studied in all patients and controls. The characteristics of the study population show that the mean age is 45 ± 3 and 47 ± 4 years for control women and IBS women respectively, as well as women with IBS is overweight Calcium significantly decreased while increasing total cholesterol and triglycerides in women IBS . MDA, carbonyls proteins, NO and O2 concentrations were significantly higher in IBS patients than in controls. The vitamin C, Catalase, SOD and GSH activities patients with IBS were significantly lower than that of controls. These results suggest that alterations in lipid profile, level of calcium and the oxidant/ antioxidant system may play a role in the pathogenesis of IBS.

Increased Expression of Colonic Mucosal Melatonin in Patients with Irritable Bowel Syndrome Correlated with Gut Dysbiosis

Dysregulation of the gut microbiota/gut hormone axis contributes to the pathogenesis of irritable bowel syndrome (IBS). Melatonin plays a beneficial role in gut motility and immunity. However, altered expression of local mucosal melatonin in IBS and its relationship with the gut microbiota remain unclear. Therefore, we aimed to detect the colonic melatonin levels and microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and explore their relationship in germ-free (GF) rats and BON-1 cells. Thirty-two IBS-D patients and twenty-eight healthy controls (HCs) were recruited. Fecal specimens from IBS-D patients and HCs were separately transplanted into GF rats by gavage. The levels of colon mucosal melatonin were assessed by immunohistochemical methods, and fecal microbiota communities were analyzed using 16S rDNA sequencing. The effect of butyrate on melatonin synthesis in BON-1 cells was evaluated by ELISA. Melatonin levels were significantly increased and negatively correlated with visceral hypersensitivity in IBS-D patients. GF rats inoculated with fecal microbiota from IBS-D patients had high colonic melatonin levels. Butyrate-producing Clostridium cluster XIVa species, such as Roseburia species and Lachnospira species, were positively related to colonic mucosal melatonin expression. Butyrate significantly increased melatonin secretion in BON-1 cells. Increased melatonin expression may be an adaptive protective mechanism in the development of IBS-D. Moreover, some Clostridium cluster XIVa species could increase melatonin expression via butyrate production. Modulation of the gut hormone/gut microbiota axis offers a promising target of interest for IBS in the future.

Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term “brain–gut–microbiome axis” has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.

Analysis of brain networks and fecal metabolites reveals brain\u2013gut alterations in premenopausal females with irritable bowel syndrome

Alterations in brain–gut–microbiome (BGM) interactions have been implicated in the pathogenesis of irritable bowel syndrome (IBS). Here, we apply a systems biology approach, leveraging neuroimaging and fecal metabolite data, to characterize BGM interactions that are driving IBS pathophysiology. Fecal samples and resting state fMRI images were obtained from 138 female subjects (99 IBS, 39 healthy controls (HCs)). Partial least-squares discriminant analysis (PLS-DA) was conducted to explore group differences, and partial correlation analysis explored significantly changed metabolites and neuroimaging data. All correlational tests were performed controlling for age, body mass index, and diet; results are reported after FDR correction, with q < 0.05 as significant. Compared to HCs, IBS showed increased connectivity of the putamen with regions of the default mode and somatosensory networks. Metabolite pathways involved in nucleic acid and amino acid metabolism differentiated the two groups. Only a subset of metabolites, primarily amino acids, were associated with IBS-specific brain changes, including tryptophan, glutamate, and histidine. Histidine was the only metabolite positively associated with both IBS-specific alterations in brain connectivity. Our findings suggest a role for several amino acid metabolites in modulating brain function in IBS. These metabolites may alter brain connectivity directly, by crossing the blood–brain-barrier, or indirectly through peripheral mechanisms. This is the first study to integrate both neuroimaging and fecal metabolite data supporting the BGM model of IBS, building the foundation for future mechanistic studies on the influence of gut microbial metabolites on brain function in IBS.

Inhibition of miRNA-29a regulates intestinal barrier function in diarrhea-predominant irritable bowel syndrome by upregulating ZO-1 and CLDN1.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic functional gastrointestinal disorder. MicroRNAs (miRNAs) have been identified to be involved in different physiological and pathological processes. In this study, the role of miRNA-29a in the potential mechanism underlying the function of the intestinal mucosal barrier in IBS-D was analyzed. Human intestinal mucosal epithelia from patients with IBS-D (diagnosed as meeting the Rome IV criteria) and healthy volunteers were collected. An IBS-D mouse model was established via induction with trinitro-benzene-sulfonic acid (TNBS), and the mice were injected with miRNA-29a inhibitor. Using transmission electron microscopy (TEM), the epithelial ultrastructure of the human intestinal mucosa was examined. Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, the expression level of miRNA-29a was assessed. ELISA was used to analyze the activity of D-lactate (D-LA) and diamine oxidase (DAO). Through immunohistochemistry, RT-qPCR and western blotting, the expression of tight junction protein ZO-1 (ZO-1) and claudin-1 (CLDN1) was examined. In the human intestinal mucosal epithelia from patients with IBS-D, miRNA-29a was upregulated, ZO-1 and CLDN1 were downregulated, and the junctional complex (JC) was faint and discontinuous. In the IBS-D mouse model, treatment with miRNA-29a inhibitor downregulated D-LA and DAO activity, and increased the expression of ZO-1 and CLDN1 in the intestinal mucosal epithelium. In conclusion, the present study revealed that miRNA-29a is involved in the pathogenesis of IBS-D, probably by downregulating ZO-1 and CLDN1 expression, suggesting that miRNA-29a is likely to be an important regulator of intestinal barrier function and could be a possible therapeutic target for IBS-D.

S0483 Cytokine Gene Polymorphisms in Irritable Bowel Syndrome vs Inflammatory Bowel Disease: A Network Meta-Analysis

INTRODUCTION: Cytokines are imbalanced in irritable bowel syndrome (IBS) and polymorphisms of cytokine-encoding genes may alter the risk of developing IBS. Whether IBS and inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are separate entities or are on a spectrum with overlap is a question which has not been sufficiently explored. This study aimed to understand whether cytokine gene polymorphisms which are observed in IBS are also associated with IBD. METHODS: We designed a network meta-analysis to compare the distribution of three cytokine gene polymorphisms that have been more frequently studied in IBS and IBD: IL-10 (-1082GA), IL6 (-174GC), and TNF-α (-308GA). PubMed and Embase were searched for studies on the distribution of these polymorphisms in IBS and IBD vs. control. NetMetaXL (CADTH, Ottawa, Canada) was used for conducting this Bayesian network meta-analysis. Vague prior <0.5 suggested lower heterogeneity where fixed effects model was used. Odds ratio (OR) with 95% credible intervals [95% Cr.I.]. was used for the comparisons. RESULTS: Ten studies on IBS vs. controls, one on IBS vs. IBD vs. controls, and thirty-nine comparing IBD vs. controls, were included. The high producer IL-10 (-1082GG) genotype was less frequent in IBS vs. the three other groups: Controls 0.66 [0.50–0.88], UC 0.66 [0.47–0.91], and CD 0.72 [0.52–0.98]; while the intermediate producer IL-10 (-1082GA) was more frequently observed in IBS vs. Controls and UC. When comparing the low producer IL-10 (-1082AA) genotype in IBS with either IBD groups or Controls, no significant difference was observed, while CD had a lower frequency of IL-10 (-1082AA) vs. Controls. The high producer TNF-α (-308AA) was similarly distributed in IBS vs. other groups and was less frequent in Controls vs. UC: 0.68 [0.46–0.99]. TNF-α (-308 GG and GA) was similar among the study groups. IL6 (-174GC) was less frequent in IBS vs. CD: 0.73 [0.55–0.98]; and in UC vs. CD: 0.69 [0.53–0.89]. The high producer IL6 (-174GG) was less frequent in CD vs. UC: 0.73 [0.56–0.95]; while no difference was observed in IBS vs. other groups. CONCLUSION: IL-10 (-1082GA) has a more prominent role than TNF-α (-308GA) and IL6 (-174GC) in the pathogenesis of IBS and may distinguish IBS from IBD. There is a shift toward high producer pro-inflammatory TNF-α (-308AA) and IL6 (-174GG) in UC, distinguishing it from the other groups.

Shugan Decoction Alleviates Colonic Dysmotility in Female SERT-Knockout Rats by Decreasing M3 Receptor Expression.

BackgroundIrritable bowel syndrome (IBS) is a functional gut disease characterized by visceral hypersensitivity and gut motor dysfunction. Serotonin (5-hydroxytryptamine, 5-HT) is an important enteric neurotransmitter. High levels of 5-HT aggravate IBS symptoms. The serotonin reuptake transporter (SERT) is a membrane-embedded transporter involved in IBS pathogenesis that plays an important role in regulating 5-HT signaling.AimWe investigated whether gut motor function was altered in SERT-knockout (SERT-KO) rats. Additionally, we sought to determine whether Shugan decoction (SGD), a clinically experienced prescription for the treatment of IBS, exerts regulatory effects on intestinal motility in SERT-KO rats, and attempted to identify the mechanisms involved.MethodSERT-KO rats were produced by transcription activator-like effector nuclease (TALEN) technology. Fecal pellet output was measured for ten consecutive days to estimate distal colonic motility. Small intestinal motility was measured by charcoal-meal experiments. The colonic and small intestinal muscle contractile activities were measured by organ bath study. Western blot was used to analyze the muscarinic receptor expression in colon tissue.ResultCompared with that in wild-type (WT) rats, the defecation amount, amplitude of spontaneous contraction, and the tension of ACh-induced contraction of colonic longitudinal smooth muscle in SERT-KO rats were significantly increased. The expression of muscarinic receptor subtype-3 (M3R) in the colons of SERT-KO rats was also elevated. SGD can decrease defecation of SERT-KO rats. Moreover, SGD reduced the amplitude of spontaneous contraction, the frequency and tension of ACh-induced contraction of colonic longitudinal smooth muscle, and the expression of M3R in the colon in SERT-KO rats.ConclusionsSERT-KO rats showed increased defecation accompanied by enhanced colonic motility and M3R expression. The findings suggest that SGD modifies colonic dysmotility and reduces defecation in SERT-KO rats by down-regulating M3R expression in the colon.

Vitamin D receptor is overexpressed in the duodenum of patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, and bile acids are thought to be associated with the pathogenesis of IBS. Bile acid receptors are expressed on intestinal epithelial cells. However, no study has assessed bile acid receptor proteins in IBS. Therefore, we examined the intestinal mucosal expression of bile acid receptors in patients with IBS. Intestinal biopsies were performed in patients with IBS and controls. Mast cells, vitamin D receptor (VDR), and somatostatin were stained with specific antibodies. Levels of VDR, farnesoid X receptor (FXR), takeda-G-protein-receptor-5 (TGR5), claudins, and transient-receptor-potential-cation-channel-subfamily-V-member 6 (TRPV6) were assessed by western blotting. 3Mast cell counts in the second part of the duodenum were significantly higher in patients with IBS than in controls. VDR protein levels were significantly elevated in the duodenum and terminal ileum of patients with IBS compared with controls, although this difference was not seen in the cecum or rectum. FXR and TGR5 protein levels did not differ in any part of the intestine. VDR-positive cryptal epithelia in IBS were distributed not only at basal crypt but also along the upper part of the basal crypt epithelial cells. In contrast, the pattern of gut somatostatin-positive cells, claudins, and TRPV6 levels did not differ. The number of mast cells in the duodenum was significantly increased, and the protein expression levels of VDR, but not those of FXR or TGR5, were elevated in the duodenal epithelial crypt in patients with IBS.

Diet therapy for irritable bowel syndrome

The review provides present information on the pathogenesis of irritable bowel syndrome (IBS), the relationship of endogenous and exogenous factors with the development of IBS-symptoms, questions of diet therapy are discussed, diets traditionally prescribed in IBS treatment and diets, such as FODMAP and gluten-free diet, which are the most promising and have a positive effect on the symptoms of IBS.

Epigenetic Mechanisms in Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a brain-gut axis disorder characterized by abdominal pain and altered bowel habits. IBS is a multifactorial, stress-sensitive disorder with evidence for familial clustering attributed to genetic or shared environmental factors. However, there are weak genetic associations reported with IBS and a lack of evidence to suggest that major genetic factor(s) contribute to IBS pathophysiology. Studies on animal models of stress, including early life stress, suggest a role for environmental factors, specifically, stress associated with dysregulation of corticotropin releasing factor and hypothalamus-pituitary-adrenal (HPA) axis pathways in the pathophysiology of IBS. Recent evidence suggests that epigenetic mechanisms, which constitute molecular changes not driven by a change in gene sequence, can mediate environmental effects on central and peripheral function. Epigenetic alterations including DNA methylation changes, histone modifications, and differential expression of non-coding RNAs (microRNA [miRNA] and long non-coding RNA) have been associated with several diseases. The objective of this review is to elucidate the molecular factors in the pathophysiology of IBS with an emphasis on epigenetic mechanisms. Emerging evidence for epigenetic changes in IBS includes changes in DNA methylation in animal models of IBS and patients with IBS, and various miRNAs that have been associated with IBS and endophenotypes, such as increased visceral sensitivity and intestinal permeability. DNA methylation, in particular, is an emerging field in the realm of complex diseases and a promising mechanism which can provide important insights into IBS pathogenesis and identify potential targets for treatment.

Efficacy of Probiotics for Prevention of Small Intestinal Bacterial Overgrowth (SIBO) Recurrence among Patients with Irritable Bowel Syndrome (IBS)

Introduction and study aim: IBS is the most common functional disorder of gastrointestinal (GI) tract. It is shown that intestinal microbiota plays an important role in the pathogenesis of Irritable Bowel Syndrome (IBS). Recent studies have been shown that probiotics could be effective in the improvement of IBS symptoms by changing gut normal microflora. In this study we investigated the probiotics’ efficacy in prevention of small intestinal bacterial overgrowth (SIBO) recurrence among patients with IBS. Patients and Methods: In a double blind clinical trial, patients with IBS and SIBO who were diagnosed based on positive Hydrogen breath test, initially received antibiotics for a period of 10 days and then randomly divided into 2 groups (Mutaflor probiotic and placebo) after confirmation of negative Hydrogen breath test. After 3 months treatment, breath tests were repeated and frequency of SIBO recurrence was compared between 2 groups. Results: Among 172 patients with IBS and SIBO, 159 cases included the study and after antibiotic treatment and negative breath tests, eventually 156 patients were analyzed. Both groups had similar demographic characters such as age, sex, IBS type and PPI consumption. Frequency of SIBO recurrence were significantly lower in the probiotic group than the placebo group (P=0.033). Frequency rate of constipation and mixed type of IBS were almost similar in both groups (P>0.05) and only there was a significant difference in SIBO frequency between 2 groups as diarrhea dominant IBS (P<0.05). Conclusion: Our study showed that Mutaflor probiotic has beneficial effects on reduction of SIBO recurrence among IBS patients and could be successfully used for treatment of these patients.

Fusobacterium nucleatum Causes Microbial Dysbiosis and Exacerbates Visceral Hypersensitivity in a Colonization-Independent Manner.

Background: Microbial dysbiosis is closely associated with visceral hypersensitivity and is involved in the pathogenesis of irritable bowel syndrome (IBS), but the specific strains that play a key role have yet to be identified. Previous bioinformatic studies have demonstrated that Fusobacterium is a shared microbial feature between IBS patients and maternal separation (MS)-stressed rats. In this study, we assessed the potential role of Fusobacterium nucleatum (F. nucleatum) in the pathogenesis of IBS.Methods: Fecal samples of patients with diarrhea predominant-IBS (IBS-D) and healthy controls were obtained. An MS rat model was established to receive gavage of either F. nucleatum or normal saline. Visceral sensitivity was evaluated through colorectal distension test, and fecal microbiota was analyzed by 16S rRNA gene sequencing. F. nucleatum-specific IgA levels in fecal supernatants were assessed by western blotting. The antigen reacted with the specific IgA of F. nucleatum was identified by mass spectrometry and the construction of a recombinant Escherichia coli BL21 (DE3).Results: IBS-D patients showed a lower Shannon index and a higher abundance of Fusobacterium. The F. nucleatum-gavage was shown to exacerbate visceral hypersensitivity in MS rats, with both the F. nucleatum-gavage and MS causing a decreased Shannon index and a clear segregation of fecal microbiota. In addition, specific IgA against F. nucleatum was detected in fecal supernatants of both the F. nucleatum-gavaged rats and the IBS-D patients. The FomA protein, which is a major outer membrane protein of F. nucleatum, was confirmed to react with the specific IgA of F. nucleatum in fecal supernatants.Conclusion: Fusobacterium increased significantly in IBS-D patients, and F. nucleatum was involved in the pathogenesis of IBS by causing microbial dysbiosis and exacerbating visceral hypersensitivity in a colonization-independent manner. Meanwhile, F. nucleatum was found to induce an increase in specific secretory IgA through FomA.

Short-course Rifaximin therapy efficacy and lactulose hydrogen breath test in Chinese patients with diarrhea-predominant irritable bowel syndrome

BackgroundGut microbiota alterations including small intestinal bacterial overgrowth (SIBO) might play a role in pathogenesis of irritable bowel syndrome (IBS). Rifaximin could effectively and safely improve IBS symptoms. The aim of this study was to investigate the effect of rifaximin on Gastrointestinal (GI) symptoms, quality of life (QOL) and SIBO eradication in Chinese IBS-D patients.MethodsThis study included 78 IBS-D patients defined by the Rome IV criteria. Patients received 400 mg rifaximin twice daily for 2 weeks and 10-week follow-up. GI symptoms were assessed at week 0, 2, 4, 8 and 12. QOL and lactulose hydrogen breath test (LHBT) results were estimated at week 0 and 4.ResultsAll participants showed significant improvements in GI symptom subdomains after rifaximin treatment (all P < 0.05), which could maintain at least 10 weeks of follow-up. Additionally, QOL scores were increased with concomitant improvement of clinical symptoms (all P < 0.05). The 45 rifaximin-responsive patients (57.7%) achieved significantly greater GI-symptom improvement than non-responders (all P < 0.05). No GI symptoms were associated with SIBO (all P > 0.05). SIBO normalization after rifaximin treatment measured by LHBT was found in 44.4% (20/45) of patients with SIBO before treatment.ConclusionA short course (2 weeks) of rifaximin improved GI symptoms and QOL in Chinese IBS-D patients whether they had SIBO or not. However, the efficacy of rifaximin could not be explained by the successful eradication of SIBO. Further studies on the therapeutic mechanisms of rifaximin in IBS are urgently needed.

Viral metagenomic analysis of fecal samples reveals an enteric virome signature in irritable bowel syndrome

BackgroundChanges in the enteric microbiota have been suggested to contribute to gastrointestinal diseases, including irritable bowel syndrome. Most of the published work is on bacterial dysbiosis with meager data on the role of the virome in irritable bowel syndrome and other gastrointestinal diseases. In the current study, we therefore aimed to investigate the viral community composition of the gut and test for potential dysbiosis linked to irritable bowel syndrome.ResultsA metagenomics analysis on fecal samples of 50 individuals — 30 of whom met the Rome IV criteria for IBS and 20 healthy controls— was conducted. There was a noticeable alteration in viral taxa observed in association with irritable bowel syndrome when compared to healthy individuals — where some eukaryotic viral taxa noticeably prevail over others. We observed a significant decrease in the diversity and abundance of enteric virome particularly in eukaryotic viruses of Megavirales in patients with irritable bowel syndrome.ConclusionsThese findings shed light on a new hypothesis that the alteration of the viral taxa contributes to the pathogenesis of irritable bowel syndrome and related symptoms, and therefore, pave the way for developing a new diagnostic biomarker or anti-viral drugs for the treatment of irritable bowel syndrome.

Quantification of mucosal EEC in jejunum. A comparative study of IBS patients and healthy controls

Background: Enteroendocrine cells (EEC) have been suggested to have a role in the pathogenesis of irritable bowel syndrome (IBS). Although many studies have analysed possible numeric changes of EEC in IBS, the results differ between different studies. One reason might be due to difficulties in standardising the morphometric method.Aim: The aim of this study was to compare two different methods for counting EEC in jejunum biopsies from patients with IBS and healthy controls.Method: Fifty-one patients with IBS and 35 healthy controls were included in the study. Jejunum mucosa was procured using a Watson capsule. Slides were immunostained for serotonin and chromogranin A and then scanned digitally. The morphometry was done by counting cells per high power field (hpf) and per mm2 after defining area of the mucosa. The two methods were compared using Bland Altman analysis.Results: There was no difference in the number of EEC in patients with IBS compared to healthy controls. The number of cells detected by per mm2 area of mucosa were higher than number of cells per hpf. Counting EEC per high power field systematically underestimated the number of cells in the mucosal area.Conclusions: Counting cells per mm2 mucosal area gives a better representation of the number of EEC in small bowel mucosa. The finding of no difference in EEC numbers does not imply an equal function and further studies are needed to evaluate the role, if any of EEC, in IBS.

Ghrelin Gene Polymorphisms in Irritable Bowel Syndrome

Introduction/Objective: Irritable bowel syndrome (IBS) is a bowel disorder characterized by pain accompanying defecation or altered bowel habits, divided into diarrhea-predominant, constipation-predominant, and alternating subtypes, whose pathogenesis is considered to include disordered bowel motility. The hormone ghrelin is a growth hormone secretagogue which furthermore affects gastrointestinal motility. We study the association between its genetic polymorphisms and the risk for IBS. Methods: IBS patients meeting the Rome III criteria and controls similar in age and gender were recruited. Whole blood samples were used for genotyping via polymerase chain reaction and restriction fragment length polymorphism for the polymorphisms rs34911341, rs696217, and rs2075356. Results: Participants included 142 patients and 209 controls. The rs696217 GG genotype frequency was higher in patients (78.87%) compared to controls (55.5%). The rs696217 GT genotype was significantly less frequent among patients than in controls (OR 0.31, 95% CI 0.19–0.52), as was the T allele (OR 0.43, 95% CI 0.28–0.66). No significant differences in genotype distribution were found for the rs34911341 and rs2075356 polymorphisms between patients and controls. The genotype frequencies did not significantly differ between IBS subtype groups for any of the polymorphisms studied. Conclusions: The GG and GT genotypes of the rs696217 polymorphism, as well as the G-allele, demonstrate significant association with IBS susceptibility, while the T allele appears to bear a protective effect. Ghrelin’s polymorphisms are plausibly involved in IBS pathogenesis, but do not correlate with any distinct IBS subtype.

Marshall and Warren Lecture 2019: A paradigm shift in pathophysiological basis of irritable bowel syndrome and its implication on treatment.

Irritable bowel syndrome (IBS), a common functional gastrointestinal disorder (FGID), has often been considered rather inappropriately as psychogenic in the past. Though psychological issues are important comorbidities in a proportion of IBS patients, the evidences are far from enough to label this condition as psychogenic only. In the recent past, evidences are emerging that underscores the concept supporting pure psychogenic theory of IBS and suggest this disorder to be rather microorganic. Accordingly, a move of Rome IV Committee attempting to delete the term "functional" and designating these to be disorders of "gut-brain interaction" rather than that of "brain-gut interaction," it emphasizes the importance of the gut over the brain in the pathogenesis. The introduction of the concept of multidimensional clinical profile in Rome IV requires attention to diagnostic category of FGID, overlap, severity, psychological issues, and physiological dysfunction or biomarkers; this attempts to recognize clinical variability and multidimensionality of pathophysiology and management of these disorders. The recognition of the biological factors in the pathogenesis of IBS is a significant paradigm shift in the recent time. This is somewhat similar to the progress in the pathogenesis of peptic ulcer disease from psychological factor to acid to Helicobacter pylori infection. It is expected that in the near future, therapeutic modalities targeting the different pathogenic mechanisms of different subtypes of IBS may bring revolution in management of the disorder.

The Evolving Role of Gut Microbiota in the Management of Irritable Bowel Syndrome: An Overview of the Current Knowledge.

The intestinal microbiota is one of the most rapidly evolving areas in biology and medicine. Extensive research in the last decade has escalated our understanding of the role of the microbiota in the pathogenesis of several intestinal and extra-intestinal disorders. Marked by high prevalence, substantial morbidity, and enormous costs, irritable bowel syndrome (IBS) is an important chronic gastrointestinal disorder that is widely encountered by gastroenterologists. Despite advances in our understanding of its pathophysiology, curative interventions have yet to be discovered, and therapeutic approaches remain symptom-driven. Recently, accumulating evidence has enlightened the possible impact of an imbalanced gut microbiome in the pathogenesis of IBS. In fact, several studies have documented altered microbiota in patients, while others have shown that IBS severity was associated with a distinct microbiota signature. These findings may pave the way for the use of microbiota manipulation strategies as an attractive option for IBS management, and may have an essential role in efforts to reduce the societal and economic effects of this ever-growing disorder. In this review, we have outlined the results of the latest research on the association between microbiota and IBS and their implications for the clinical management of affected patients.

Increased Ileal Immunoglobulin A Production and Immunoglobulin A-Coated Bacteria in Diarrhea-Predominant Irritable Bowel Syndrome.

OBJECTIVES:Immune activation and intestinal microbial dysbiosis could induce diarrhea-predominant irritable bowel syndrome (IBS-D). We examined the roles of ileal immunoglobulin A (IgA) and IgA-coated bacteria in IBS-D pathogenesis.METHODS:Peripheral blood, fecal samples, and ileal and cecal biopsies were collected from 32 healthy volunteers and 44 patients with IBS-D. Quantitative reverse transcriptase polymerase chain reaction was used to assess differential gene expression. IgA levels in the blood and fecal samples were quantified by an enzyme-linked immunosorbent assay. IgA+ cells were assessed by immunofluorescence imaging. Flow-cytometry-based IgA+ bacterial cell sorting and 16S rRNA gene sequencing (IgA-SEQ) was used to isolate and identify fecal IgA+ bacteria.RESULTS:Fecal IgA, particularly IgA1, was upregulated in patients with IBS-D. IgA class switch and B cell–activating factor-receptor were increased in the terminal ileum of patients. The intestinal microbiota composition was altered in patients compared with that in controls. IgA-SEQ showed that the proportion of fecal IgA-coated bacteria was increased significantly in patients with IBS-D. IgA+ bacteria in patients with IBS-D showed higher abundances of Escherichia–Shigella, Granulicatella, and Haemophilus compared with healthy controls and IgA− bacteria in patients with IBS-D. The Escherichia–Shigella IgA coating index was positively correlated with anxiety and depression. The Escherichia–Shigella relative abundance, luminal IgA activity, and some altered IgA-coated bacteria were positively associated with the clinical manifestations of IBS-D.DISCUSSION:Microbial dysbiosis may promote the terminal ileal mucosa to produce higher levels of IgA, increasing the proportion of IgA-coated bacteria by activating IgA class switching, which might regulate local inflammation and clinical manifestations in IBS-D. IgA may mediate the effects of microbial dysbiosis on the pathogenesis of IBS-D.