Why is damage limited to the mucosa in ulcerative colitis but transmural in Crohn’s disease?

It has been a big puzzle as why the inflammation of ulcerative colitis (UC) is limited to the mucosa, while in Crohn’s disease (CD) the inflammation is transmural and can be seen in all layers of the gut. Here, I give a tentative explanation extended from the unified hypothesis I proposed on the etiology of inflammatory bowel disease. This hypothesis suggested that both UC and CD are caused by weakening of the gut barrier due to damage of the protective mucus layer and the underlying tissue by the poorly inactivated digestive proteases resulting from a reduction of gut bacteria by dietary chemicals like saccharin and sucralose. However, the large amounts of bacteria in the colon make the recruitment of neutrophils and formation of crypt abscess the main manifestation of UC, while the infiltration of antigens and dietary particles in the small and large intestine mainly cause the recruitment of macrophages and formation of granulomas as the main manifestations in CD. The fast reacting and short life span of neutrophils make the fight and damage limited to the surface of the mucosa. In contrast, the long life span and constant movement of macrophages may bring the harmful agents deep into the tissue. Therefore, the pathogenesis of UC may be more like bacterial pneumonia, while CD may be more like pneumoconiosis or tuberculosis of the lung.     

Pulmonary manifestations of inflammatory bowel disease

Extraintestinal manifestations of inflammatory bowel disease(IBD) are a systemic illness that may affect up to half of all patients. Among the extraintestinal manifestations of IBD, those involving the lungs are relatively rare and often overlooked. However, there is a wide array of such manifestations, spanning from airway disease to lung parenchymal disease, thromboembolic disease, pleural disease, enteric-pulmonary fistulas, pulmonary function test abnormalities, and adverse drug reactions. The spectrum of IBD manifestations in the chest is broad, and the manifestations may mimic other diseases. Although infrequent, physicians dealing with IBD must be aware of these conditions, which are sometimes life-threatening, to avoid further health impairment of the patients and to alleviate their symptoms by prompt recognition and treatment. Knowledge of these manifestations in conjunction with pertinent clinical data is essential for establishing the correct diagnosis and treatment. The treatment of IBD-related respiratory disorders depends on the specific pattern of involvement, and in most patients, steroids are required in the initial management. Corticosteroids, both systemic and aerosolized, are the mainstay therapeutic approach, while antibiotics must also be administered inthe case of infectious and suppurative processes, whose sequelae sometimes require surgical intervention.     

Inflammatory bowel disease:Pathogenesis

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,is characterized by chronic relapsing intestinal inflammation.It has been a worldwide health-care problem with a continually increasing incidence.It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut,catalyzed by the genetic susceptibility of the individual.Although the etiology of IBD remains largely unknown,it involves a complex interaction between the genetic,environmental or microbial factors and the immune responses.Of the four components of IBD pathogenesis,most rapid progress has been made in the genetic study of gut inflammation.The latest internationally collaborative studies have ascertained 163susceptibility gene loci for IBD.The genes implicated in childhood-onset and adult-onset IBD overlap,suggesting similar genetic predispositions.However,the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD.Meanwhile,the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD,as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation.Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms,including the innate and adaptive immunity,and the interactions between genetic factors and microbial and environmental cues.In this review,we provide an update on the major advances that have occurred in above areas.     

Trefoil factors in inflammatory bowel disease

Inflammatory bowel disease(IBD),which comprises ulcerative colitis and Crohn’s disease,is characterized by inflammation of the gastrointestinal tract.The trefoil factors 1,2,and 3(TFF1-3)are a family of peptides that play important roles in the protection and repair of epithelial surfaces,including the gastrointestinal tract.TFFs may be involved in IBD pathogenesis and are a potential treatment option.In the present review,we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression,possible function and pharmacological role in IBD.     

Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: A pilot study

AIM: To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. METHODS: Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn’s disease). Biopsy samples were taken and CD31 expression was assayed immuno- histochemically; microvascular density was assessed by vessel count. RESULTS: In areas that were endoscopically normal but positive on NBI, ther...     

Case-control study of factors that trigger inflammatory bowel disease flares

AIM:To explore the association between inflammatory bowel diseases(IBD)flares and potential triggers.METHODS:Patients evaluated for an acute flare of IBD by a gastroenterologist at the Dallas VA Medical Center were invited to participate,as were a control group of patients with IBD in remission.Patients were systematically queried about nonsteroidal anti-inflammatory drug use,antibiotic use,stressful life events,cigarette smoking,medication adherence,infections,and travel in the preceding 3 mo.Disease activity scores were calculated for each patient at the time of enrollment and each patient’s chart was reviewed.Multivariate regression analysis was performed.RESULTS:A total of 134 patients with IBD(63 with Crohn’s disease,70 with ulcerative colitis,and 1 with indeterminate colitis)were enrolled;66 patients had flares of their IBD and 68 were controls with IBD in remission(for Crohn’s patients,average Crohn’s disease activity index was 350 for flares vs 69 in the controls;for UC patients,Mayo score was 7.6 for flares vs 1 for controls in those with full Mayo available and 5.4p for flares vs 0.1p for controls in those with partial Mayo score).Only medication non-adherence was significantly more frequent in the flare group than in the control group(48.5%vs 29.4%,P=0.03)and remained significant on multivariate analysis(OR=2.86,95%CI:1.33-6.18).On multivariate regression analysis,immunomodulator use was found to be associated with significantly lower rates of flare(OR=0.40,95%CI:0.19-0.86).CONCLUSION:In a study of potential triggers for IBD flares,medication non-adherence was significantly associated with flares.These findings are incentive to improve medication adherence.     

Recent trends in the epidemiology of inflammatory bowel diseases： Up or down？

INTRODUCTION The pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD) is only partly understood. Inflammatory bowel disease (IBD) is a multifactorial disease with probable genetic heterogeneity. In addition, several environmental risk factors…     

Loss of fragile histidine triad protein expression in inflammatory bowel disease

INTRODUCTION Inflammatory bowel disease (IBD) is a collection of chronic idiopathic in? ammatory disorders of the intestine and/or colon, including two independent diseases: ulcerative colitis (UC) and Crohn’s disease (CD)[1]. Up to now, the complex etio…     

Helicobacter pylori infection and inflammatory bowel disease: Is there a link?

Helicobacter pylori(H.pylori)infection is one of the most widely spread infectious diseases in humans.It can cause chronic gastritis,peptic ulcer disease and gastric malignancies and has been associated with extra-gastric disorders.H.pylori elicit a chronic systemic inflammatory response which,under certain conditions,may trigger autoimmune reactions and may be implicated in the pathogenesis of autoimmune diseases.Although the pathogenesis of inflammatory bowel disease(IBD)is unknown,it is thought to result from complex interactions between environmental factors and microbiota in the gut of individuals who are genetically susceptible.Several bacterial and viral agents have been implicated in the aetiology of IBD.In theory,H.pylori infection could be involved in the pathogenesis of IBD by inducing alterations in gastric and/or intestinal permeability or by causing immunological derangements resulting in absorption of antigenic material and autoimmunity via various immunological pathways.Similar mechanisms may also be responsible for the co-existence of IBD with other autoimmune diseases and/or extra-intestinal manifestations.However,the epidemiological data fail to support this association.Infact,various studies indicate that the prevalence of H.pylori infection is low in patients with IBD,suggesting a protective role for this infection in the development of IBD.In this report,we aim to shed light on proposed mechanisms and confounding factors underlying the potential link between H.pylori infection and IBD.     

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease(IBD),including immunosuppressants and biologics.Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients,as induction and maintainance treatment.Infliximab,as well as cyclosporine,is considered a second line therapy in the case of severe ulcerative colitis,or non-responders to intravenous corticosteroids.An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy.Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines.Evidence for the use of methotrexate in ulcerative colitis is insufficient.The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease,these treatments could be considered in case of failure of all other therapeutic options.In patients with moderately active ulcerative colitis,refractory to thiopurines,the use of tacrolimus is considered an alternative to biologics.An increase of the dose or a decrease in the interval of administration of biologic treatment could be useful in the presence of an incomplete clinical response.In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered.Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients.The final outcome of the treatment should be considered the clinical remission,with mucosa healing,and not the clinical response.The evaluation of serum concentration of thiopurine methyl transferase activity,thiopurine metabolites,biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice.The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.     

Abnormalities of uterine cervix in women with inflammatory bowel disease

INTRODUCTION Cervical cancer is responsible for almost 4000 deaths annually in the United States[1]. Due in large part to mass screening protocols with papanicolaou (Pap) smears, mortality from cervical cancer has declined by over 70% in the past 50 years…     

Colorectal cancer surveillance in patients with inflammatory bowel disease: What is new?

Several studies assessing the incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients have found an increased risk globally estimated to be 2 to 5 times higher than for the general population of the same age group. The real magnitude of this risk, however, is still open to debate. Research is currently being carried out on several risk and protective factors for CRC that have recently been identified in IBD patients. A deeper understanding of these factors could help stratify patient risk and aid specialists in choosing which surveillance program is most efficient. There are several guidelines for choosing the correct surveillance program for IBD patients; many present common characteristics with various distinctions. Current recommendations are far from perfect and have important limitations such as the fact that their efficiency has not been demonstrated through randomized controlled trials, the limited number of biopsies performed in daily endoscopic practice, and the difficulty in establishing the correct time to begin a given surveillance program and maintain a schedule of surveillance. That being said, new endoscopic technologies should help by replacing random biopsy protocols with targeted biopsies in IBD patients, thereby improving the efficiency of surveillance programs.However, further studies are needed to evaluate the cost-effectiveness of introducing these techniques into daily endoscopic practice.     

Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility

Inflammatory bowel disease(IBD),which includes Crohn’s disease(CD)and ulcerative colitis(UC),represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals.Genetic markers are associated with disease phenotype and long-term evolution,but their value in everyday clinical practice is limited at the moment.IBD has a clear immunological background and interleukins play key role in the process.Almost130 original papers were revised including meta-analysis.It is clear these data are very important for understanding the base of the disease,especially in terms of clinical utility and validity,but text often do not available for the doctors use these in the clinical practice nowadays.We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD,performing an electronic search of PubMed Database from publications of the last 10 years,and used the following medical subject heading terms and/or text words:IBD,CD,UC,interleukins and polymorphisms.     

Immunosuppressive therapies for inflammatory bowel disease

Inflammatory bowel disease(IBD)is comprised of Crohn’s disease and ulcerative colitis,both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course.For many years,the drug therapy was limited to sulfasalazine and related aminosalicylates,corticosteroids and antibiotics.Studies suggesting that the pathophysiology of these disorders relates to a disregulated,overactive immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD.This review details the mechanisms of action,clinical efficacy,and adverse effects of these agents.     

Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil

AIM: To evaluate the demographic characteristics and clinical phenotypes of inflammatory bowel disease(IBD) in a geographic area in Northeastern Brazil.METHODS: This retrospective study was conducted at the Hospital of the Federal University of Piauí in Northeastern Brazil. Demographic characteristics and clinical phenotypes of IBD were analyzed in relation to the time of diagnostic confirmation, which was defined as the date of disease onset. Data were collected between January 2011 and December 2012 and included all census patients 18 years of age or older during that period for whom there was diagnostic confirmation of Crohn's disease(CD), ulcerative colitis(UC), or unclassified colitis according to the Montreal criteria. We also analyzed the period of time between the onset of clinical manifestations and the diagnosis of IBD(delay in the diagnosis). Statistical analyses included means and standard deviations for numeric variables and the Pearson χ2 adherence test for nominal variables. The annual index occurrence and overall prevalence of IBD at our institution were also calculated, with P values 0.05 indicating statistical significance. This study was approved by the Institutional Ethics and Research Committee.RESULTS: A total of 252 patients with IBD were included, including 152(60.3%) UC patients and 100(39.7%) CD patients. The clinical and demographic characteristics of all patients with IBD showed a female to male ratio of 1.3:1.0 and a mean age of35.2(SD = 14.5) years. In addition, the majority of patients were miscegenated(171, 67.9%), had received higher education(157, 62.4%), lived in urban areas(217, 86.1%), and were under the age of 40 years(97, 62.5%). For patients with CD, according to the Montreal classification, the predominant features present from the onset of disease were an age between 17 and 40 years(A2); colonic disease location(L2); and nonstricturing, nonfistulizing disease behavior(B1). However, approximately one-quarter of all CD patients demonstrated perineal involvement. We also observed considerable delay in the diagnosis of IBD throughout the entire study period(mean = 35.5 mo). In addition, the annual index occurrence rose from 0.08 to 1.53 cases/105 inhabitants/year during the study period, and the prevalence rate was 12.8 cases/105 inhabitants in 2012. Over the last two decades, there was a noted increase in the frequency of IBD in the study area.CONCLUSION: In this study, there was a predominance of patients with UC, young people under 40 years of age, individuals with racial miscegenation, and low annual incomes.     

Update on nutritional status,body composition and growth in paediatric inflammatory bowel disease

Growth and nutritional status are important issues in paediatric inflammatory bowel disease(IBD).While linear growth is easy to assess,nutritional status is more complicated,with reports often compromised by the use of simple measures,such as weight and the body mass index,to assess nutritional status rather than more appropriate and sophisticated techniques to measure body composition.This review is an update on what is currently known about nutritional status as determined by body composition in paediatric IBD.Further,this review will focus on the impact of biologics on growth in paediatric IBD.Significant lean mass deficits have been reported in children with IBD compared with controls,and there is evidence these deficits persist over time.Furthermore,data imply that gender differences exist in body composition,both at diagnosis and in response to treatment.With respect to growth improvements following treatment with biologics,there are conflicting data.While some studies report enhancement of growth,others do not.The relationship between disease severity,impaired growth and the requirement for biologics needs to be considered when interpreting these data.However,key features associated with improvements in growth appear to be successful clinical response to treatment,patients in early stages of puberty,and the presence of growth failure at the onset of treatment.     

Serum adipokines in inflammatory bowel disease

AIM:To investigate serum adipokine levels in inflammatory bowel disease(IBD)patients before treatment and after achieving clinical remission.METHODS:Serum concentrations of six adipokines(tissue growth factor-β1,adiponectin,leptin,chemerin,resistin,and visfatin)were studied in 40 subjects with active IBD[24 subjects with Crohn’s disease(CD)and in 16 subjects with ulcerative colitis(UC)]before and after three months of therapy with corticosteroids and/or azathioprine.Clinical diagnoses were based on ileocolonoscopy,computed tomography or magnetic resonance enterography and histological examination of mucosal biopsies sampled during endoscopy.Serum levels of adipokines were assessed by an indirect enzyme-linked immunosorbent assay.The control group was comprised of 16 age-and sex-matched healthyvolunteers.RESULTS:Baseline leptin concentrations were significantly decreased in both types of IBD compared to controls(8.0±9.1 in CD and 8.6±6.3 in UC vs 16.5±10.1 ng/mL in controls;P<0.05),and significantly increased after treatment only in subjects with CD(14.9±15.1 ng/mL;P<0.05).Baseline serum resistin concentrations were significantly higher in CD(19.3±12.5ng/mL;P<0.05)and UC subjects(23.2±11.0 ng/mL;P<0.05)than in healthy controls(10.7±1.1 ng/mL).Treatment induced a decrease in the serum resistin concentration only in UC subjects(14.5±4.0 ng/mL;P<0.05).Baseline serum concentrations of visfatin were significantly higher in subjects with CD(23.2±3.2ng/mL;P<0.05)and UC(18.8±5.3 ng/mL;P<0.05)than in healthy controls(14.1±5.3 ng/mL).Treatment induced a decrease in the serum visfatin concentrations only in CD subjects(20.4±4.8 ng/mL;P<0.05).Serum levels of adiponectin,chemerin and tissue growth factor-β1 did not differ between CD and UC subjects compared to healthy controls and also were not altered by anti-inflammatory therapy.Clinical indices of IBD activity did not correlate with adipokine levels.CONCLUSION:IBD modulates serum adipokine levels by increasing resistin and visfatin release and suppressing leptin production.     

Vaccines and recommendations for their use in inflammatory bowel disease

The patient with inflammatory bowel disease will be predisposed to numerous infections due their immune status. It is therefore important to understand the immune and serologic status at diagnosis and to put the patient into an adapted vaccination program. This program would be applied differently according to two patient groups: the immunocompromised and the non-immunocom-promised. In general, the first group would avoid the use of live-virus vaccines, and in all cases, inflammatory bowel disease treatment would take precedence over vaccine risk. It is important to individualize vaccination schedules according to the type of patient, the treatment used and the disease pattern.In addition, patient with inflammatory bowel disease should be considered for the following vaccines: varicella vaccine, human papilloma virus, influenza, pneumococcal polysaccharide vaccine and hepatitis B vaccine.     

Negative impact of bone-marrow-derived mesenchymal stem cells on dextran sulfate sodium-induced colitis

AIM:To investigate the effects of mesenchymal stem cells(MSCs)on dextran sulfate sodium-induced inflammatory bowel disease(IBD).METHODS:C57BL/6 mice were fed 3.5%(g/L)dextran sulfate sodium.On day seven,the mice received intraperitoneal injections of 1×106 MSCs.The survival rate,disease activity index values,and body weight,were monitored daily.On day ten,colon lengths and histopathologic changes were assessed.In addition,immunoregulatory changes following MSC administration were evaluated by determining the levels of effector T cell responses in the spleen and mesenteric lymph nodes,and the expression levels of inflammatory cytokines in homogenized colons.RESULTS:Intraperitoneal administration of MSCs did not prevent development of colitis and did not reduce the clinicopathologic severity of IBD.No significant difference was evident in either survival rate or disease activity index score between the control and MSCtreated group.Day ten-sacrificed mice exhibited no significant difference in either colon length or histopathologic findings.Indeed,the MSC-treated group exhibited elevated levels of interleukin(IL)-6 and transforming growth factor-β,and a reduced level of IL-10,in spleens,mesenteric lymph nodes,and homogenized colons.The IL-17 level was lower in the mesenteric lymph nodes of the MSC-treated group(P=0.0126).In homogenized colons,the IL-17 and tumor necrosis factor-α(P=0.0092)expression levels were also lower in the treated group.CONCLUSION:MSC infusion provided no significanthistopathologic or clinical improvement,thus representing a limited therapeutic approach for IBD.Functional enhancement of MSCs is needed in further study.     

Laboratory markers in ulcerative colitis: Current insights and future advances

Ulcerative colitis(UC)and Crohn’s disease(CD)are the major forms of inflammatory bowel diseases(IBD)in man.Despite some common features,these forms can be distinguished by different genetic predisposition,risk factors and clinical,endoscopic and histological characteristics.The aetiology of both CD and UC remains unknown,but several evidences suggest that CD and perhaps UC are due to an excessive immuneresponse directed against normal constituents of the intestinal bacterial flora.Tests sometimes invasive are routine for the diagnosis and care of patients with IBD.Diagnosis of UC is based on clinical symptoms combined with radiological and endoscopic investigations.The employment of non-invasive biomarkers is needed.These biomarkers have the potential to avoid invasive diagnostic tests that may result in discomfort and potential complications.The ability to determine the type,severity,prognosis and response to therapy of UC,using biomarkers has long been a goal of clinical researchers.We describe the biomarkers assessed in UC,with special reference to acute-phase proteins and serologic markers and thereafter,we describe the new biological markers and the biological markers could be developed in the future:(1)serum markers of acute phase response:The laboratory tests most used to measure the acute-phase proteins in clinical practice are the serum concentration of C-reactive protein and the erythrocyte sedimentation rate.Other biomarkers of inflammation in UC include platelet count,leukocyte count,and serum albumin and serum orosomucoid concentrations;(2)serologic markers/antibodies:In the last decades serological and immunologic biomarkers have been studied extensively in immunology and have been used in clinical practice to detect specific pathologies.In UC,the presence of these antibodies can aid as surrogate markers for the aberrant host immune response;and(3)future biomarkers:The development of biomarkers in UC will be very important in the future.The progress of molecular biology tools(microarrays,proteomics and nanotechnology)have revolutionised the field of the biomarker discovery.The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve,characterize and analyse large amounts of data generated by the technological advances.The techniques available for biomarkers development are genomics(single nucleotide polymorphism genotyping,pharmacogenetics and gene expression analyses)and proteomics.In the future,the additionof new serological markers will add significant benefit.Correlating serologic markers with genotypes and clinical phenotypes should enhance our understanding of pathophysiology of UC.