Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

Effects of electroacupuncture at Zusanli (ST 36) on neurons in the colonic myenteric plexus in rats with irritable bowel syndrome with constipation

We studied the effects of electroacupuncture at Zusanli （ST 36） on neurons in the colonic myenteric plexus and on defecation in rats with irritable bowel syndrome with constipation （IBS-C）. We also used intragastric administration of pinaverium bromide as a positive control treatment to reveal the pathway mediating the onset of IBS-C. Both electroacupuncture and pinaverium bromide greatly improved defecation in rats with IBS-C. Immunohistochemical staining of the enteric nervous system neuronal marker protein gene product 9.5 in the colonic myenteric plexus showed that electroacupuncture by itself, or in combination with pinaverium bromide, increased the number of neurons and the staining intensity of protein gene product 9.5 in the colonic myenteric plexus. We conclude that visceral hypersensitivity is likely to be a primary cause of constipation in IBS-C rats.

Colorectal motility patterns and psychiatric traits in functional constipation and constipation-predominant irritable bowel syndrome:A study from China

BACKGROUND Functional constipation(FC)and constipation-predominant irritable bowel syndrome(IBS-C)represent a spectrum of constipation disorders.However,the majority of previous clinical investigations have focused on Western populations,with limited data originating from China.AIM To determine and compare the colorectal motility and psychiatric features of FC and IBS-C in an Eastern Chinese population.METHODS Consecutive chronic constipation patients referred to our motility clinic from December 2019 to February 2023 were enrolled.FC and IBS-C diagnoses were established using ROME IV criteria,and patients underwent high-resolution anorectal manometry(ARM)and a colonic transmit test using the Sitz marker study.Constipation-related symptoms were obtained through questionnaires.Anxiety and depression were assessed by the Hamilton anxiety rating scale and the Hamilton Depression Rating Scale-21.The clinical characteristics and colorectal motility patterns of FC and IBS-C patients were compared.RESULTS No significant differences in sex,age or abdominal discomfort symptoms were observed between IBS-C and FC patients(all P>0.05).The proportion of IBS-C patients with delayed colonic transit was higher than that of patients with FC(36.63%vs 15.91%,P<0.05),while rectosigmoid accumulation of radiopaque markers was more common in the FC group than in the IBS-C group(50%vs 26.73%,P<0.05).Diverse proportions of these dyssynergic patterns were noted within both the FC and IBS-C groups by ARM.IBS-C patients were found to have a higher prevalence of depression than FC patients(66.30%vs 42.42%,P<0.05).The scores for feelings of guilt,suicide,psychomotor agitation,diurnal variation,obsessive/compulsive disorder,hopelessness,self-abasedment and gastrointestinal symptoms were significantly higher in IBS-C patients than that in FC patients(P<0.05).For IBS-C(χ^(2)=5.438,P<0.05)but not FC,patients with normal colon transit time were significantly more likely to have anxiety than those with slow colon transit time.For IBS-C patients but not FC patients,the threshold of first constant sensation,desire to defecate and sustained urgency were all weakly correlated with the degree of anxiety(r=0.414,r=0.404,and r=0.418,respectively,P<0.05).The proportion of patients with a low threshold of desire to defecate among IBS-C patients with depression was lower than that in those without depression(69.6%vs 41.9%,χ2=4.054,P<0.05).CONCLUSION Our findings highlight both overlapping and distinctive patterns of colon transit,dyssynergic patterns,anorectal sensation,psychological distress,and associations of psychiatric and colorectal motility characteristics in FC and IBS-C patients in an Eastern Chinese population,providing valuable insights into the pathophysiological underpinnings of these disorders.

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.

Overlap of functional heartburn and gastroesophageal reflux disease with irritable bowel syndrome

Several studies indicate a significant degree of overlap between irritable bowel syndrome(IBS)and gastroesophageal reflux disease(GERD).Likewise,both functional heartburn(FH)and IBS are functional digestive disorders that may occur in the same patients.However,data establishing a solid link between FH and IBS are lacking,mainly because the clinical definition of FH has undergone substantial changes over the years.The available literature on the overlap between GERD or FH and IBS highlights considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess heartburn and IBS.In particular,several epidemiological studies included patients with concomitant IBS and GERD without any attempt to distinguish FH(as defined by the RomeⅢcriteria)from GERD via pathophysiological investigations.Independent of these critical issues,there is preliminary evidence supporting a significantdegree of FH-IBS overlap.This underscores the need for studies based on updated diagnostic criteria and accurate pathophysiological classifications,particularly to distinguish FH from GERD.This distinction would represent an essential starting point to achieving a better understanding of pathophysiology in the subclasses of patients with GERD and FH and properly assessing the different degrees of overlap between IBS and the subcategories of heartburn.The present review article intends to appraise and critically discuss current evidence supporting a possible concomitance of GERD or FH with IBS in the same patients and to highlight the pathophysiological relationships between these disorders.

Inhibitory effects of patchouli alcohol on stress-induced diarrhea-predominant irritable bowel syndrome

AIM To elucidate the mechanism of patchouli alcohol(PA) in treatment of rat models of diarrhea-predominant irritable bowel syndrome(IBS-D).METHODS We studied the effects of PA on colonic spontaneous motility using its cumulative log concentration(3 × 10^(-7) mol/L to 1 × 10^(-4)mol/L). We then determined the responses of the proximal and distal colon segments of rats to the folowing stimuli:(1) carbachol(1 × 10^(-9) mol/L to 1 × 10^(-5) mol/L);(2) neurotransmitter antagonists including N~ω-nitro-l-arginine methyl ester hydrochloride(10μmol/L) and(1 R~*, 2 S~*)-4-[2-Iodo-6-(methylamino)-9 Hpurin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt(1 μmol/L);(3) agonist α,β-methyleneadenosine 5′-triphosphate trisodium salt(100 μmol/L); and(4) single KCl doses(120 mmol/L). The effects of blockers against antagonist responses were also assessed by pretreatment with PA(100 μmol/L) for 1 min. Electrical-field stimulation(40 V, 2-30 Hz, 0.5 ms pulse duration, and 10 s) was performed to observe nonadrenergic, noncholinergic neurotransmitter release in IBS-D rat colon. The ATP level of Kreb's solution was also determined.RESULTS PA exerted a concentration-dependent inhibitory effect on the spontaneous contraction of the colonic longitudinal smooth muscle, and the half maximal effective concentration(EC_(50)) was 41.9 μmol/L. In comparison with the KCl-treated IBS-D group, the contractile response(mg contractions) in the PA + KCl-treated IBS-D group(11.87 ± 3.34) was significantly decreased in the peak tension(P < 0.01). Compared with CCh-treated IBS-D rat colon, the cholinergic contractile response of IBS-D rat colonic smooth muscle(EC_(50) = 0.94 μmol/L) was significantly decreased by PA(EC_(50) = 37.43 μmol/L)(P < 0.05). Lack of nitrergic neurotransmitter release in stress-induced IBS-D rats showed contraction effects on colonic smooth muscle. Pretreatment with PA resulted in inhibitory effect on l-NAME-induced(10 μmol/L) contraction(P < 0.05). ATP might not be the main neurotransmitter involved in inhibitory effects of PA in the colonic relaxation of stressinduced IBS-D rats.CONCLUSION PA application may serve as a new therapeutic approach for IBS-D.

Post-infectious irritable bowel syndrome

Post-infectious irritable bowel syndrome (PI-IBS) is a common disorder wherein symptoms of IBS begin after an episode of acute gastroenteritis. Published studies have reported incidence of PI-IBS to range between 5% and 32%. The mechanisms underlying the development of PI-IBS are not fully understood, but are believed to include persistent sub-clinical inflammation, changes in intestinal permeability and alteration of gut flora. Individual studies have suggested that risk factors for PI-IBS include patients' demographics, psychological disorders and the severity of enteric illness. However, PI-IBS remains a diagnosis of exclusion with no specific disease markers and, to date, no definitive therapy exists. The prognosis of PIIBS appears favorable with spontaneous and gradual resolution of symptoms in most patients.

Ehealth:Low FODMAP diet vs Lactobacillus rhamnosus GG in irritable bowel syndrome

AIM: To investigate the effects of a low fermentable, oligosaccharides, disaccharides, monosaccharides and polyols diet (LFD) and the probiotic Lactobacillus rhamnosus GG (LGG) in irritable bowel syndrome (IBS).

What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease(NAFLD)and irritable bowel syndrome(IBS)are two very common diseases in the general population.To date,there are no studies that highlight a direct link between NAFLD and IBS,but some recent reports have found an interesting correlation between obesity and IBS.A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD,leading to an increased cardiovascular risk,and IBS,leading to microbial dysbiosis,impaired intestinal barrier and altered intestinal motility.It is not known when considering local and systemic inflammation/immune system activation,which one has greater importance in NAFLD and IBS pathogenesis.Also,the nervous system is implicated.In fact,inflammation participates in the development of mood disorders,such as anxiety and depression,characteristics of obesity and consequently of NAFLD and,on the other hand,in intestinal hypersensitivity and dysmotility.

Overlapping gastroesophageal reflux disease and irritable bowel syndrome:Increased dysfunctional symptoms

AIM:To investigate the association of gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS) in Iranian patients and examine the prevalence of functional symptoms of the gastrointestinal tract in patients presenting with either IBS, GERD or both.METHODS: Six thousand four hundred and seventy six patients presented to the Gastro-intestinal (GI) clinic with symptoms of functional dysfunction of GI tract, 1419 patients (62.0% women, 38.0% men; mean age: 37.4±11.5 years) met Rome or Rome criteria(depending on the year of diagnosis)for IBS.2658 patients were diagnosed with GERD based on clinical presentation and endoscopic findings.We assessed other functional symptoms(epigastric pain,nausea,vomiting,belching,constipation and diarrhea)in patients suffering from GERD,IBS or both.RESULTS: Among IBS subjects, 63.6% (69.0% women, 31.0% men; mean age: 36.4±10.3 years) also hadGERD, whereas 34.7% of the non-IBS patients had GERD [odds ratio (OR) =3.2, 95% confidence interval (CI): 2.9-3.7, P<0.0001]. Among patients with GERD, 33.9% of subjects met Rome criteria compared to 13.5% of non-GERD patients (OR=3.6, 95% CI: 3.1-4.3, P<0.0001). Prevalence of all functional symptoms was higher in overlapping GERD and IBS subjects, when compared with their prevalence in the IBS subjects without GERD or GERD only subjects (P<0.05).CONCLUSION: This finding shows that in overlapping GERD and IBS, other functional abnormalities of the GI tract are also highly prevalent, suggesting a common underlying dysfunction.

Is irritable bowel syndrome an infectious disease?

Irritable bowel syndrome(IBS) is the most common of all gastroenterological diseases. While many mechanisms have been postulated to explain its etiology, no single mechanism entirely explains the heterogeneity of symptoms seen with the various phenotypes of the disease. Recent data from both basic and clinical sciences suggest that underlying infectious disease may provide a unifying hypothesis that better explains the overall symptomatology. The presence of small intestinal bowel overgrowth(SIBO) has been documented in patients with IBS and reductions in SIBO as determined by breath testing correlate with IBS symptom improvement in clinical trials. The incidence of new onset IBS symptoms following acute infectious gastroenteritis also suggests an infectious cause. Alterations in microbiota-host interactions may compromise epithelial barrier integrity, immune function, and the development and function of both central and enteric nervous systems explaining alterations in the brain-gut axis. Clinical evidence from treatment trials with both probiotics and antibiotics also support this etiology. Probiotics appear to restore the imbalance in the microflora and improve IBS-specific quality of life. Antibiotic trials with both neomycin and rifaximin show improvement in global IBS symptoms that correlates with breath test normalization in diarrhea-predominant patients. The treatment response to two weeks of rifaximin is sustained for up to ten weeks and comparable results are seen in symptom reduction with retreatment in patients who develop recurrent symptoms.

Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects

AIM: To assess the long-term effects of physical activity on irritable bowel syndrome(IBS) symptoms and on quality of life, fatigue, depression and anxiety.METHODS: Seventy-six patients from a previous randomized controlled interventional study on increased physical activity in IBS were asked to participate in this long-term follow-up study. The included patients attended one visit in which they filled out questionnaires and they underwent a submaximal cycle ergometer test. The primary end point was the change in the IBS Severity Scoring System(IBS-SSS) at baseline, i.e., before the intervention and at follow-up. The secondary endpoints were changes in quality of life, fatigue, depression and anxiety.RESULTS: A total of 39 [32 women, median age 45(28-61) years] patients were included in this followup. Median follow-up time was 5.2(range: 3.8-6.2) years. The IBS symptoms were improved compared with baseline [IBS-SSS: 276(169-360) vs 218(82-328), P = 0.001]. This was also true for the majority of the dimensions of psychological symptoms such as disease specific quality of life, fatigue, depression and anxiety. The reported time of physical activity during the week before the visit had increased from 3.2(0.0-10.0) h at baseline to 5.2(0.0-15.0) h at follow-up, P = 0.019. The most common activities reported were walking, aerobics and cycling. There was no significant difference in the oxygen uptake 31.8(19.7-45.8) m L per min per kg at baseline vs 34.6(19.0-54.6) m L/min per kg at follow-up.CONCLUSION: An intervention to increase physical activity has positive long-term effects on IBS symptoms and psychological symptoms.

Ehealth monitoring in irritable bowel syndrome patients treated with low fermentable oligo-, di-, mono-saccharides and polyols diet

In the present study we report on changes in irritable bowel syndrome-severity scoring system (IBS-SSS) and irritable bowel syndrome-quality of life (IBS-QoL) in 19 IBS patients, aged 18 to 74 years (F/M: 14/5), during 12 wk registering their symptoms on the web-application (www.ibs.constant-care.dk). During a control period of the first 6-wk patients were asked to register their IBS-SSS and IBS-QoL on the web-application weekly without receiving any intervention. Thereafter, low fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet (LFD) was introduced for the next 6 wk while continuing the registration. Though a small sample size a significant improvement in disease activity (IBS-SSS) was observed during both the control period, median: 278 (range: 122-377), P = 0.02, and subsequently during the LFD period, median: 151 (range: 29-334), P &#x0003c; 0.01. The IBS-QoL solely changed significantly during the LFD period, median: 67 (37-120), P &#x0003c; 0.01. The significant reduction in disease activity during the control period shows a positive effect of the web-application on IBS symptoms when presented as a &#x0201c;traffic light&#x0201d;. However adding the diet reduced IBS-SSS to &#x0003c; 150, inactive to mild symptoms. In the future results from larger scale trials are awaited.

Elevated pro-inflammatory and lipotoxic mucosal lipids characterise irritable bowel syndrome

AIM： To investigate the pathophysiology of irritable bowel syndrome （IBS） by comparing the global mucosal metabolic profiles of IBS patients with those of healthy controls. METHODS： Fifteen IBS patients fulfilling the Rome II criteria, and nine healthy volunteers were included in the study. A combined lipidomics （UPLC/MS） and metabolomics （GC × GC-TOF） approach was used to achieve global metabolic profiles of mucosal biopsies from the ascending colon. RESULTS： Overall, lipid levels were elevated in patients with IBS. The most significant upregulation was seen for pro-inflammatory lysophosphatidylcholines. Other lipid groups that were significantly upregulated in IBS patients were lipotoxic ceramides, glycosphingolipids, and di-and triacylglycerols. Among the meo tabolites, the cyclic ester 2（3H）-furanone was almost 14-fold upregulated in IBS patients compared to healthy subjects （P = 0.03）. CONCLUSION： IBS mucosa is characterised by a distinct pro-inflammatory and lipotoxic metabolic profile. Especially, there was an increase in several lipid species such as lysophospholipids and ceramides.

Changing face of irritable bowel syndrome

Recent years have witnessed tremendous progress in our understanding of irritable bowel syndrome （IBS）. It is evident that this is a truly global disease associated with significant symptoms and impairments in personal and social functioning for afflicted individuals. Advances in our understanding of gut flora-mucosal interactions, the enteric nervous system and the brain-gut axis have led to substantial progress in the pathogenesis of symptoms in IBS and have provided some hints towards the basic etiology of this disorder, in some subpopulations, at the very least. We look forward to a time when therapy will be addressed to pathophysiology and perhaps, even to primary etiology. In the meantime, a model based on a primary role for intestinal inflammation serves to integrate the various strands, which contribute to the presentation of IBS

Influence of irritable bowel syndrome on treatment outcome in gastroesophageal reflux disease

AIM: To investigate the influence of irritable bowel syndrome (IBS)-like symptoms on treatment outcomes with pantoprazole in gastroesophageal reflux disease (GERD) in a real life setting. METHODS: For this prospective, open-label, multinational, multicentre study, 1888 patients assessed by the investigators as suffering from GERD were recruited. The patients were additionally classified as with or without IBS-like symptoms at baseline. They were treated with pantoprazole 40 mg once daily and completed the Reflux Questionnaire (ReQuest) short version daily. Response rates and symptom scores were compared after 4 and 8 wk of treatment for subgroups defined by the subclasses of GERD [erosive(ERD) and non-erosive reflux disease (NERD)] and the presence of IBS-like symptoms. RESULTS: IBS-like symptoms were more prevalent in NERD than in ERD (18.3% vs 12.7%, P = 0.0015). Response rates after 4 and/or 8 wk of treatment were lower in patients with IBS-like symptoms than in patients without IBS-like symptoms in both ERD (Week 4: P < 0.0001, Week 8: P < 0.0339) and NERD (Week 8: P = 0.0088). At baseline, ReQuest "lower abdominal com- plaints" symptom scores were highest in NERD patients with IBS-like symptoms. Additionally, these patients had the strongest symptom improvement after treatment compared with all other subgroups. CONCLUSION: IBS-like symptoms influence treatment outcome and symptom burden in GERD and should be considered in management. Proton pump inhibitors can improve IBS-like symptoms, particularly in NERD.

State-of-the-art of irritable bowel syndrome and inflammatory bowel disease research in 2008

Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are two of the leading causes of chronic intestinal conditions in the world. This issue of World Journal of Gastroenterology (WJG ) presents a series of papers from world experts who discuss the current knowledge and opinions on these important conditions. Although great strides have been made in the diagnosis, treatment and pathology of IBS and IBD; much has yet to be explained. The etiologies and risk factors of these multifactorial conditions remain elusive. Specific diagnostic biomarkers need to be developed and safer treatments developed. The burden of IBS and IBD on the healthcare system is felt with repeated medical care visits and high costs. IBS and IBD patients can account for 30%-50% of office visits at gastroenterology services/clinics. Over one million people have IBD in the United States, with 30 000 new cases being diagnosed every year. One-quarter million people in the UK are afflicted with IBD. The cost of medical care in the United States for IBD is estimated to be $1.8 billion/year.

Nodular lymphoid hyperplasia: A marker of low-grade inflammation in irritable bowel syndrome?

AIM To evaluate the prevalence of nodular lymphoid hyperplasia(NLH) in adult patients undergoing colonoscopy and its association with known diseases. METHODS We selected all cases showing NLH at colonoscopy in a three-year timeframe, and stratified them into symptomatic patients with irritable bowel syndrome(IBS)-type symptoms or suspected inflammatory bowel disease(IBD), and asymptomatic individuals undergoing endoscopy for colorectal cancer screening.Data collection included medical history and final diagnosis. As controls, we considered all colonoscopies performed for the aforementioned indications during the same period.RESULTS One thousand and one hundred fifty colonoscopies were selected. NLH was rare in asymptomatic individuals(only 3%), while it was significantly more prevalent in symptomatic cases(32%). Among organic conditions associated with NLH, the most frequent was IBD, followed by infections and diverticular disease. Interestingly, 31% of IBS patients presented diffuse colonic NLH. NLH cases shared some distinctive clinical features among IBS patients: they were younger, more often female, and had a higher frequency of abdominal pain, bloating, diarrhoea, unspecific inflammation, self-reported lactose intolerance and metal contact dermatitis. CONCLUSION About 1/3 of patients with IBS-type symptoms or suspected IBD presented diffuse colonic NLH, which could be a marker of low-grade inflammation in a conspicuous subset of IBS patients.

Celiac disease in patients with presumed irritable bowel syndrome:A case-finding study

AIM:To estimate the prevalence of celiac disease(CD) in adult patients with presumed irritable bowel syndrome(IBS) .METHODS:Between March 2005 and December 2008,742 consecutive patients(293 male,median age 43 years,range 18-69 years) fulfilling the Rome Ⅱ criteria for IBS were prospectively enrolled in the study.IBS was diagnosed via self-completed Rome Ⅱ modular questionnaires.Anti-tissue transglutaminase(anti-tTG) serology was checked to initially recognize possible CD cases.Patients with a positive test were offered endoscopic duodenal biopsy to confirm the diagnosis of CD.RESULTS:Thirty two patients(15 male,median age 41 years,range 19-59 years) were found to have organic diseases other than CD.Twenty four patients tested positive for anti-tTG antibodies,and duodenal biopsies confirmed the diagnosis in all of them.Thus,in this patient population with presumed IBS,3.23% actually had CD.CONCLUSION:CD is common in patients with presumed IBS.Routine screening for CD in patients with symptoms of IBS is recommended.

Perceived risk as a barrier to appropriate diagnosis of irritable bowel syndrome

AIM: To evaluate perceived risk, diagnostic testing, and acceptance of a diagnosis of irritable bowel syndrome (IBS) among the Korean laypersons.