Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease

AIM To evaluate how mucosal bacteria impact on the spontaneous and muramyl dipeptide(MDP)-induced inflammation in Crohn's disease(CD) and ulcerative colitis(UC).METHODS Colonic mucosal biopsies were collected from children with active or remissive CD, UC and controls. Two tissue samples were taken from inflamed mucosal segments(in patients with active disease) or from noninflamed mucosa [in patients in remission or in healthy controls(HC)]. Experiments were performed in the presence or absence of antibiotics, to assess whether the disease-associated microbiota can modulate the cytokine response ex vivo. For this purpose, each specimen was half-cut to compare spontaneous and MDP-induced inflammation in the presence of live bacteria(LB) or antibiotics. After 24 h of culture, an array of 17 cytokines was assessed in supernatants. Statistical analyses were performed to find significant differences in single cytokines or in patterns of cytokine response in the different groups. RESULTS We demonstrated that subjects with CD display a spontaneous production of inflammatory cytokines including granulocyte-colony stimulating factor(G-CSF), interleukin(IL) 6, IL8, IL10 and IL12, that was not significantly influenced by the addition of antibiotics. UC specimens also displayed a trend of increased spontaneous secretion of several cytokines, which however was not significant due to broader variability among patients. After the addition of antibiotics, spontaneous IL8 secretion was significantly higher in UC than in controls. In HC, a trend towards the weakening of spontaneous IL8 production was observed in the presence of live mucosal bacteria with respect to the presence of antibiotics. In contrast, in the presence of LB UC showed an increasing trend of spontaneous IL8 production, while MDP stimulation resulted in lower IL8 production in the presence of antibiotics. We also showed that subjects with CD seem to have a lowered production of IL8 in response to MDP in the presence of LB. Only with the addition of antibiotics, likely reducing the contribution of LB, multivariate statistical analysis could identify the combination of measures of G-CSF, tumor necrosis factor alpha, IL4 and IL17 as a good discriminator between CD and UC.CONCLUSION We showed that the presence of LB or antibiotics can significantly influence the inflammatory response ex vivo in inflammatory bowel diseases.     

Preventive health measures in inflammatory bowel disease

We aim to review the literature and provide guidance on preventive health measures in inflammatory bowel disease(IBD). Structured searches were performed in Pub Med,MEDLINE,EMBASE,Web of Science and Cochrane Library from January 1976 to June 2016 using the following keywords:(inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND(health maintenance OR preventive health OR health promotion). Abstracts of the articles selected from each of these multiple searches were reviewed,and those meeting the inclusion criteria(that is,providing data regarding preventive health or health maintenance in IBD patients) were recorded. Reference lists from the selected articles were manually reviewed to identify further relevant studies. Patients with IBD are at increased risk of developing adverse events related to the disease course,therapeutic interventions,or non-adherence to medication. Recent studies have suggested that IBD patients do not receive preventive services with the same thoroughness as patients with other chronic diseases. Preventive health measures can avert morbidity and improve the quality of life of patients with IBD. Gastroenterologists and primary care physicians(PCPs) should have an up to date working knowledge of preventive health measures for IBD patients. A holistic approach and better communication between gastroenterologists and PCPs with explicit clarification of roles will prevent duplication of services and streamline care.     

Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease

Inflammatory bowel disease(IBD) is an immunological disorder that is usually treated with immunosuppressive therapy,potentially leading to increases in vulnerability to infections. Although many infections can be pre-vented by vaccination,vaccination coverage in these patients in clinical practice is insufficient. Therefore,the seroprotection condition should be verified,even for routine vaccines,such as hepatitis B or pneu-mococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B,influenza,and pneumococcal vaccines is impaired in IBD patients,whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand,data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella,varicella,and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response,specifically to vaccines,in patients with immune-mediated diseases(such as IBD),is crucial when developing vaccines that trigger more potent immunologic responses.     

Antibody markers in the diagnosis of inflammatory bowel disease

Inflammatory bowel disease(IBD), including Crohn's disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.     

Infertility in men with inflammatory bowel disease

Inflammatory bowel disease(IBD) predominantly affects young adults. Fertility-related issues are therefore im-portant in the m-anagem-ent of patients with IBD. However, relatively m-odest attention has been paid to reproductive issues faced by m-en with IBD. To investigate the effects of IBD and its treatm-ent on m-ale fertility, we reviewed the current literature using a system-atic search for published studies. A PubM ed search were perform-ed using the m-ain search term-s "IBD AND m-ale infertility", "Crohn's disease AND m-ale infertility", "ulcerative colitis AND m-ale infertility". References in review articles were used if relevant. We noted that active inflammation, poor nutrition, alcohol use, sm-oking, m-edications, and surgery m-ay cause infertility in m-en with IBD. In surgery such as proctocolectom-y with ileal pouch-anal anastom-osis, rectal incision seem-s to be associated with sexual dysfunction. Of the m-edications used for IBD, sulfasalazine reversibly reduces m-ale fertility. No other m-edications appear to affect m-ale fertility significantly, although sm-all studies suggested som-e adverse effects. There are lim-ited data on the effects of drugs for IBD on m-ale fertility and pregnancy outcom-es; however, patients should be inform-ed of the possible effects of paternal drug exposure. This review provides inform-ation on fertility-related issues in m-en with IBD and discusses treatm-ent options.     

Role of antibiotics for treatment of inflammatory bowel disease

Inflammatory bowel disease is thought to be caused by an aberrant immune response to gut bacteria in a genetically susceptible host. The gut microbiota plays an important role in the pathogenesis and complications of the two main inflammatory bowel diseases: Crohn's disease(CD) and ulcerative colitis. Alterations in gut microbiota, and specifically reduced intestinal microbial diversity, have been found to be associated with chronic gut inflammation in these disorders. Specific bacterial pathogens, such as virulent Escherichia coli strains, Bacteroides spp, and Mycobacterium avium subspecies paratuberculosis, have been linked to the pathogenesis of inflammatory bowel disease. Antibiotics may influence the course of these diseases by decreasing concentrations of bacteria in the gut lumen and altering the composition of intestinal microbiota. Different antibiotics, including ciprofloxacin, metronidazole, the combination of both, rifaximin, and anti-tuberculous regimens have been evaluated in clinical trials for the treatment of inflammatory bowel disease. For the treatment of active luminal CD, antibiotics may have a modest effect in decreasing disease activity and achieving remission, and are more effective in patients with disease involving the colon. Rifamixin, a non absorbable rifamycin has shown promising results. Treatment of suppurative complications of CD such as abscesses and fistulas, includes drainage and antibiotic therapy, most often ciprofloxacin, metronidazole, or a combination of both. Antibiotics might also play a role in maintenance of remission and prevention of post operative recurrence of CD. Data is more sparse for ulcerative colitis, and mostly consists of small trials evaluating ciprofloxacin, metronidazole and rifaximin. Most trials did not show a benefit for the treatment of active ulcerative colitis with antibiotics, though 2 meta-analyses concluded that antibiotic therapy is associated with a modest improvement in clinical symptoms. Antibiotics show a clinical benefit when used for the treatment of pouchitis. The downsides of antibiotic treatment, especially with recurrent or prolonged courses such as used in inflammatory bowel disease, are significant side effects that often cause intolerance to treatment, Clostridium dificile infection, and increasing antibiotic resistance. More studies are needed to define the exact role of antibiotics in inflammatory bowel diseases.     

Elderly patients and inflammatory bowel disease

The incidence and prevalence of inflammatory bowel disease(IBD) is increasing globally. Coupled with an ageing population, the number of older patients with IBD is set to increase. The clinical features and therapeutic options in young and elderly patients are comparable but there are some significant differences. The wide differential diagnosis of IBD in elderly patients may result in a delay in diagnosis. The relative dearth of data specific to elderly IBD patients often resulting from their exclusion from pivotal clinical trials and the lack of consensus guidelines have made clinical decisions somewhat challenging. In addition, age specific concerns such as co-morbidity; locomotor and cognitive function, poly-pharmacy and its consequences need to be taken into account. In applying modern treatment paradigms to the elderly, the clinician must consider the potential for more pronounced adverse effects in this vulnerable group and set appropriate boundaries maximising benefit and minimising harm. Meanwhile, clinicians need to make personalised decisions but as evidence based as possible in the holistic, considered and optimal management of IBD in elderly patients. In this review we will cover the clinical features and therapeutic options of IBD in the elderly; as well as addressing common questions and challenges posed by its management.     

Pancreatic disorders in inflammatory bowel disease

An increased incidence of pancreatic disorders either acute pancreatitis or chronic pancreatitis has been rec-orded in patients with inflammatory bowel disease(IBD) compared to the general population.Although most of the pancreatitis in patients with IBD seem to be related to biliary lithiasis or drug induced,in some cases pancreatitis were defined as idiopathic,suggesting a direct pancreatic damage in IBD.Pancreatitis and IBD may have similar presentation therefore a pancreatic disease could not be recognized in patients with Crohn's disease and ulcerative colitis.This review will discuss the most common pancreatic diseases seen in patients with IBD.     

Video capsule endoscopy in inflammatory bowel disease

Video capsule endoscopy(VCE) has evolved to become an important tool for the non-invasive examination of the small bowel, which hitherto had been relatively inaccessible to direct visualisation. VCE has beenshown to play a role in monitoring the activity of small bowel Crohn's disease and can be used to assess the response to anti-inflammatory treatment in Crohn's disease. For those patients with Crohn's disease who have undergone an intestinal resection, VCE has been assessed as a tool to detect post-operative recurrence. VCE may also aid in the reclassification of patients with a diagnosis of Inflammatory Bowel Disease Unclassified to Crohn's disease. The evolution of colon capsule endoscopy(CCE) has expanded the application of this technology further. The use of CCE to assess the activity of ulcerative colitis has been described. This advance in capsule technology has also fuelled interest in its potential role as a minimally invasive tool to assess the whole of GI tract opening the possibility of its use for the panenteric assessment of Crohn's disease. VCE is a safe procedure. However, the risk of a retained capsule is higher in patients with suspected or confirmed Crohn's disease compared with patients having VCE examination for other indications. A retained video capsule is rare after successful passage of a patency capsule which may be utilised to pre-screen patients undergoing VCE. This paper describes the use of VCE in the assessment of inflammatory bowel disease.     

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.     

Influence of environmental factors on the onset and course of inflammatory bowel disease

Numerous environmental factors have been linked with inflammatory bowel disease. These include smoking, diet, hygiene, drugs, geographical and psychosocial factors. These factors may either increase the risk of or protect against developing this condition and can also affect the course of illness in a positive or negative manner. A number of studies have examined the influence of environmental factors on inflammatory bowel diseases as a whole as well as on ulcerative colitis and Crohn's disease separately. As there are differences in the pathogenesis of ulcerative colitis and Crohn's disease, the effect of environmental factors on their onset and course is not always similar. Some factors have shown a consistent association, while reports on others have been conflicting. In this article we discuss the current evidence on the roles of these factors on inflammatory bowel disease, both as causative/protective agents and as modifiers of disease course.     

How to predict clinical relapse in inflammatory bowel disease patients

Inflammatory bowel diseases have a natural course characterized by alternating periods of remission and relapse. Disease flares occur in a random way and are currently unpredictable for the most part. Predictors of benign or unfavourable clinical course are required to facilitate treatment decisions and to avoid overtreatment. The present article provides a literature review of the current evidence on the main clinical, genetic, endoscopic, histologic, serologic and fecal markers to predict aggressiveness of inflammatory bowel disease and discuss their prognostic role, both in Crohn's disease and ulcerative colitis. No single marker seems to be reliable alone as a flare predictor, even in light of promising evidence regarding the role of fecal markers, in particular fecal calprotectin, which has reported good results recently. In order to improve our daily clinical practice, validated prognostic scores should be elaborated, integrating clinical and biological markers of prognosis. Finally, we propose an algorithm considering clinical history and biological markers to intercept patients with high risk of clinical relapse.     

Inter- and intraobserver agreement in computed tomography enterography in inflammatory bowel disease

AIM To evaluate intra- and interobserver agreement in imaging features in inflammatory bowel disease and comparison with fecal calprotectin(FC) levels.METHODS Our institutional computed tomography enterography(CTE) database was retrospectively queried to identify patients who underwent CTE from January 2014 to June 2015. Patient inclusion criteria were confirmed inflammatory bowel disease(IBD) and FC collected 4 mo after CTE without any change in clinical treatment or surgical treatment during this interval. The exclusion criterion was poor image quality. Two blinded abdominal radiologists, with 12 and 3 years of experience analyzed the CTE regarding localization(small bowel, colonic, both, or no disease detected);type of IBD(inflammatory, stenosing, fistulizing, 1 pattern, or normal); and signs of active disease(present or absent). In 42 of 44 patients evaluated, routine CTE reports were made by one of the readers who reevaluated the CTEs ≥ 6 mo later, to determine the intraobserver agreement. FC was considered a sign of disease activity when it was higher than 250 μg/g.RESULTS Forty-four patients with IBD(38 with Crohn's disease and 6 with ulcerative colitis) were included. There was a moderate interobserver agreement regarding localization of IBD(k = 0.540), type of disease(k = 0.410) and the presence of active signs in CTE(k = 0.419). There was almost perfect intraobserver agreement regarding localization, type and signs of active disease in IBD. The k values were 0.902, 0.937 and 0.830, respectively. After a consensus between both radiologists regarding inflammatory activity in CTE, we found that 24(85.7%) of 28 patients who were classified with active disease had elevated FC, and six(37.5%) of 16 patients without inflammatory activity in CTE had elevated FC(P = 0.003). The correlation between elevated FC and the presence of active disease in CTE was significant(k = 0.495, P = 0.001).CONCLUSION We found almost perfect intraobserver and moderate interobserver agreement in the signs of active disease in CTE with concurrence of high FC levels.     

Influence of environmental factors in the development of inflammatory bowel diseases

Idiopathic inflammatory bowel diseases(IBD), Crohn's disease(CD) and ulcerative colitis(UC), are multifactorial diseases that are manifested after disruption of a genetic predisposed individual and its intestinal microflora through an environmental stimulus. Urbanization and industrialization are associated with IBD. Epidemiological data, clinical observations and family/immigrants studies indicate the significance of environmental influence in the development of IBD. Some environmental factors have a different effect on the subtypes of IBD. Smoking and appendectomy is negatively associated with UC, but they are aggravating factors for CD. A westernized high fat diet, full of refined carbohydrates is strongly associated with the development of IBD, contrary to a high in fruit, vegetables and polyunsaturated fatty acid-3 diet that is protective against these diseases. High intake of nonsteroidal antiinflammatory drug and oral contraceptive pills as well as the inadequacy of vitamin D leads to an increased risk for IBD and a more malignant course of disease. Moreover, other factors such as air pollution, psychological factors, sleep disturbances and exercise influence the development and the course of IBD. Epigenetic mechanism like DNA methylation, histone modification and altered expression of miR NAS could explain the connection between genes and environmental factors in triggering the development of IBD.     

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.     

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.     

Oral pathology in inflammatory bowel disease

The incidence of inflammatory bowel diseases(IBD)-Crohn's disease(CD) and ulcerative colitis(UC)- has been increasing on a global scale, and progressively, more gastroenterologists will be included in the diagnosis and treatment of IBD. Although IBD primarily affects the intestinal tract, extraintestinal manifestations of the disease are often apparent, including in the oral cavity, especially in CD. Specific oral manifestations in patients with CD are as follows: indurate mucosal tags, cobblestoning and mucogingivitis, deep linear ulcerations and lip swelling with vertical fissures. The most common non-specific manifestations, such as aphthous stomatitis and angular cheilitis, occur in both diseases, while pyostomatitis vegetans is more pronounced in patients with UC. Non-specific lesions in the oral cavity can also be the result of malnutrition and drugs. Malnutrition, followed by anemia and mineral and vitamin deficiency, affects the oral cavity and teeth. Furthermore, all of the drug classes that are applied to the treatment of inflammatory bowel diseases can lead to alterations in the oral cavity due to the direct toxic effects of the drugs on oral tissues, as well as indirect immunosuppressive effects with a risk of developing opportunistic infections or bone marrow suppression. There is a higher occurrence of malignant diseases in patients with IBD, which is related to the disease itself and to the IBD-related therapy with a possible oral pathology. Treatment of oral lesions includes treatment of the alterations in the oral cavity according to the etiology together with treatment of the primary intestinal disease, which requires adequate knowledge and a strong cooperation between gastroenterologists and specialists in oral medicine.     

Minimally invasive surgery for inflammatory bowel disease: Current perspectives

The surgical management of complicated and recurrent inflammatory bowel disease(IBD),has remained a challenge.Minimally invasive surgery(MIS),in the form of laparoscopic resections,single port approach and robotic-assisted dissections in the management of IBD,have been examined in several prospective studies.All of them have shown advantages over open surgeryin terms of reduction of physical trauma of surgery,recovery time,better cosmetic outcomes and shorter hospitalization.However,it is important to appreciate that not all patients with IBD are suitable for MIS,so a combination of both open and MIS should be adopted to achieve optimum outcomes.A review on this subject performed by Neumann et al in this issue of World Journal of Gastrointestinal Pharmacology and Therapeutics have provided evidence in support of the contemporary practice of MIS in the management of IBD and the accompanying commentary further critically evaluates their application in clinical practice.     

Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: a review article

Emerging data have highlighted the co-existence of nonalcoholic fatty liver disease(NAFLD) and inflammatory bowel disease; both of which are increasingly prevalent disorders with significant complications and impact on future health burden. Cross-section observational studies have shown widely variable prevalence rates of co-existing disease,largely due to differences in disease definition and diagnostic tools utilised in the studies. Age,obesity,insulin resistance and other metabolic conditions are common risks factors in observational studies. However,other studies have also suggested a more dominant role of inflammatory bowel disease related factors such as disease activity,duration,steroid use and prior surgical intervention,in the development of NAFLD. This suggests a potentially more complex pathogenesis and relationship between the two diseases which may be contributed by factors including altered intestinal permeability,gut dysbiosis and chronic inflammatory response. Commonly used immunomodulation agents pose potential hepatic toxicity,however no definitive evidence exist linking them to the development of hepatic steatosis,nor are there any data on the impact of therapy and prognosis in patient with co-existent diseases. Further studies are required to assess the impact and establish appropriate screening and management strategies in order to allow early identification,intervention and improve patient outcomes.