The gut–brain axis in irritable bowel syndrome and inflammatory bowel disease

Research increasingly demonstrates the bidirectional communication between gut microbiota and the brain, enhancing the role of gut microbiota modulation in the treatment of central nervous system (CNS) disorders. The first five years of life are extremely important as it affects the development of gut microbiota, immune system and, consequently, the onset of psychometric alterations, particularly in genetically predisposed individuals.In this review, we focus on the link between specific microbial genera, gastrointestinal (GI) disorders, anxiety and depression and on the effects of different therapeutic strategies for mood disorders on gut microbiota.     

A hypothesis: is diverticulitis a type of inflammatory bowel disease?

It is accepted by epidemiologists that diverticula formation in the colon is related to a deficiency in dietary fiber intake, but the cause of acute diverticulitis remains unknown. A hypothesis is presented that acknowledges from the literature that fiber deficiency is also related to an altered intestinal microecology with a change in the bacterial flora. It is hypothesized that the change in the flora with a decrease in their influence on the immune process permits a low-grade chronic inflammation in the mucosa, which is the first step in developing an acute infection of diverticula or diverticulitis. There is some evidence that the low-grade chronic inflammation is present in subjects with diverticula, which is the forerunner of acute diverticulitis. This hypothesis is strengthened by early reports that anti-inflammatory mucosal agents such as mesalamine and immune process regulators such as probiotics may improve diverticulitis.     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

Genetics of inflammatory bowel disease： The role of the HLA complex

The human leucocyte antigen (HLA) complex on chromosome 6p21.3 is the most extensively studied genetic region in Inflammatory bowel disease (IBD). Consistent evidence of linkage to IBD3 (6p21.1-23), an area which encompasses the HLA complex, has been demonstrated for both Crohn's disease and ulcerative colitis, and a number of replicated associations with disease susceptibility and phenotype have recently emerged. However, despite these efforts the HLA susceptibility gene (s) for IBD remain elusive, a consequence of strong linkage disequilibrium, extensive polymorphism and high gene density across this region. This article reviews current knowledge of the role of HLA complex genes in IBD susceptibility and phenotype, and discusses the factors currently limiting the translation of this knowledge to clinical practice.     

Pharmacogenetics of azathioprine in inflammatory bowel disease: A role for glutathione-S-transferase?

Azathioprine is a purine antimetabolite drug commonly used to treat inflammatory bowel disease(IBD).In vivo it is active after reaction with reduced glutathione(GSH)and conversion to mercaptopurine.Although this reaction may occur spontaneously,the presence of isoforms M and A of the enzyme glutathione-S-transferase(GST)may increase its speed.Indeed,in pediatric patients with IBD,deletion of GST-M1,which determines reduced enzymatic activity,was recently associated with reduced sensitivity to azathioprine and reduced production of azathioprine active metabolites.In addition to increase the activation of azathioprine to mercaptopurine,GSTs may contribute to azathioprine effects even by modulating GSH consumption,oxidative stress and apoptosis.Therefore,genetic polymorphisms in genes for GSTs may be useful to predict response to azathioprine even if more in vitro and clinical validation studies are needed.reserved.     

Intestinal microbiota: The explosive mixture at the origin of inflammatory bowel disease?

Inflammatory bowel diseases(IBDs), namely Crohn's disease and ulcerative colitis, are lifelong chronic disorders arising from interactions among genetic, immunological and environmental factors. Although the origin of IBDs is closely linked to immune response alterations, which governs most medical decision-making, recent findings suggest that gut microbiota may be involved in IBD pathogenesis. Epidemiologic evidence and several studies have shown that a dysregulation of gut microbiota(i.e., dysbiosis) may trigger the onset of intestinal disorders such as IBDs. Animal and human investigations focusing on the microbiota-IBD relationship have suggested an altered balance of the intestinal microbial population in the active phase of IBD. Rigorous microbiota typing could, therefore, soon become part of a complete phenotypic analysis of IBD patients. Moreover, individual susceptibility and environmental triggers such as nutrition, medications, age or smoking could modify bacterial strains in the bowel habitat. Pharmacological manipulation of bowel microbiota is somewhat controversial. The employment of antibiotics, probiotics, prebiotics and synbiotics has been widely addressed in theliterature worldwide, with the aim of obtaining positive results in a number of IBD patient settings, and determining the appropriate timing and modality of this intervention. Recently, novel treatments for IBDs, such as fecal microbiota transplantation, when accepted by patients, have shown promising results. Controlled studies are being designed. In the near future, new therapeutic strategies can be expected, with non-pathogenic or modified food organisms that can be genetically modified to exert anti-inflammatory properties.     

Risk factors of work disability in patients with inflammatory bowel disease — A Dutch nationwide web-based survey: Work disability in inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) is associated with high costs to society. Few data on the impact of IBD on work disability and potential predictive factors are available.AimTo assess the prevalence of and predictive factors for work disability in Crohn's disease (CD) and ulcerative colitis (UC).MethodsA web-based questionnaire was sent out in seven university hospitals and seven general hospitals in the Netherlands. Initially, 3050 adult IBD patients were included in this prospective, nationwide cohort study, whereof 2629 patients were within the working-age (18–64 years). We used the baseline questionnaire to assess the prevalence rates of work disability in CD and UC patients within working-age. Prevalence rates were compared with the Dutch background population using age- and sex-matched data obtained from Statistics Netherlands. Multivariable logistic regression analyses were performed to identify independent demographic- and disease-specific risk factors for work disability.ResultsIn CD, 18.3% of patients was fully disabled and 8.8% partially disabled, compared to 9.5% and 5.4% in UC patients (p < 0.01), respectively. Compared to Dutch controls, the prevalence was significantly higher, especially in CD patients. Higher age, low education, depression, chronic back pain, joint manifestations and typical disease-related risk factors such as penetrating disease course and surgery in the past were all found to be associated with work disability.ConclusionWe report high work disability rates in a large sample of IBD patients in the Netherlands. CD patients suffer more frequently from work disability than UC patients. A combination of demographic and disease-related factors is predictive of work disability.     

Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity?

BACKGROUND/AIMS: Neutrophil elastase is a proteinase which exists in granulocytes and plays an important role in the pathogenesis of inflammatory disorders. In inflammatory bowel disease there is a leukocyte infiltration of the bowel mucosa. The purpose of this study was to examine whether plasma elastase represents a reliable laboratory marker for establishing the activity of chronic inflammatory bowel disease. METHODOLOGY: We measured plasma elastase concentrations in 61 patients suffering from either Crohn's disease or ulcerative colitis and compared these data with other clinical and laboratory findings and with elastase concentrations in 40 healthy controls. The sensitivity and specificity of the elastase values in chronic IBD were calculated with the use of concomitant measurements of CRP and ESR. RESULTS: Plasma levels were found to be significantly higher in patients (49 micrograms/l) compared with healthy controls (23 micrograms/l). Patients with active disease had higher plasma levels than patients in remission. In general, the sensitivity of elastase to detect active inflammatory bowel disease was about 60%; the specificity was 65%. For patients in remission, the sensitivity was higher than 80%. However, there was a wide range of overlapping values between chronic inactive patients and those with moderately active disease. CONCLUSIONS: We conclude that plasma elastase is a useful independent marker of disease activity in inflammatory bowel disease. Especially for identifying patients in remission, the measurements of elastase seem to be more suitable than other parameters of inflammation, like CRP or ESR.     

The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation �C a single-centre experience

OBJECTIVE:

To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes.

METHODS:

Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used.

RESULTS:

Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pre-transplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC post-transplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years post-transplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival.

CONCLUSION:

Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.     

Granulocyte and monocyte apheresis in inflammatory bowel disease: The patients’ point of view

Background

Granulocyte and monocyte apheresis is the main non-pharmacological treatment for inflammatory bowel disease (IBD), but we do not know how well accepted it is by patients in our setting.

Hospitalisation,surgical and medical recurrence rates in inflammatory bowel disease 2003–2011—A Danish population-based cohort study

ObjectiveThe aim of this study is to evaluate the cumulative probability of recurrence and admission rates in an inflammatory bowel disease (IBD) inception cohort diagnosed in 2003–2004.MethodsData on medications, phenotypes and surgery for 513 individuals with ulcerative colitis (UC, n = 300) and Crohn's disease (CD, n = 213) were obtained from medical records and linked to population-based health administrative database information. The admission rates and cumulative probability of recurrences were estimated, and the association with the baseline factors and medication was tested.ResultsThe cumulative risk of first recurrence after 1, 5 and 7 years was 40%, 63%, and 66% in CD patients and 51%, 75%, and 79% in UC patients, respectively. The cumulative risk of first surgical relapse was 6%, 18%, and 23% at 1, 5 and 7 years in CD respectively. One hundred and CD patients (66%) and 142 UC patients (47%) had at least one IBD-related hospitalisation. The hospitalisation rate decreased from 7.0 days/person-year in year one to 0.9 day at year 5 in CD, and from 4.7 days to 0.4 days for UC patients. Age above 40, current smoking, stricturing behaviour, and disease localisation (colonic, ileocolonic, and upper-GI) at diagnosis were predictors of recurrence in CD. In UC, age above 40 and former smoker status were predictors of recurrence and left-sided and extensive colitis were predictors of first-time hospitalisation.ConclusionIn an era of improved treatment options, the recurrence rates, but not the surgery or hospitalisation rates, have decreased for CD but not for UC. The phenotypic characteristics at diagnosis predict the risk of recurrence and hospitalisation.     

Genetics of inflammatory bowel disease: The beginning of the end or the end of the beginning?

Recent identification of the first susceptibility gene for Crohn's disease has led to increasing enthusiasm for the investigation and dissection of inflammatory bowel disease. In the future, identification of additional genes and careful correlation of the genetic background with clinical features of the disease will help to elucidate the causes and cure of inflammatory bowel disease. However, caution is still needed in the short term since our present knowledge has limited influence on clinical management. This review focuses on the genetic background of inflammatory bowel disease, the process of discovering the mutations of the NOD2/CARD15 gene in Crohn's disease patients, and the functional clues of the genetic variants of this gene in relation to clinical features.     

COPD: an inflammatory disease of the airways?

COPD is characterized by a not fully reversible airflow limitation which is progressive and associated with an abnormal inflammatory reaction of the lungs. Airflow limitation is most often assessed by FEV (1.0). However, FEV (1.0) does not always reflect the course of the disease and does not appropriately describe the functional effect of a pharmacological or non-pharmacological intervention. Measurement of inspiratory parameters, e.g. IC or FIV (1.0), as well as assessment of exercise capacity should therefore be part of functional tests. The abnormal inflammatory reaction of the lungs can be assessed by a variety of methods. However, the characteristic increase of the number of neutrophils does not indicate a new therapeutic target. The term abnormal inflammation of the airways in bronchial asthma as well as in COPD presumably prompted a number of studies investigating the effects of inhalative corticosteroids in COPD. ICS do not alter the course of the disease, however they may reduce the number and severity of exacerbations. Combination of long-acting beta -agonists and ICS exert a better effect than either compound alone. This beneficial effect is difficult to explain by an anti-inflammatory action, as the long acting anticholinergic tiotropium has a comparable symptomatic and functional effect and reduces exacerbations without any known anti-inflammatory component. Future pharmacological therapies should therefore be based on a better understanding of the functional consequences of the disease and its pathogenesis.     

Characterisation of enterocolitis in the piroxicam-accelerated interleukin-10 knock out mouse — A model mimicking inflammatory bowel disease

BackgroundIn inflammatory bowel disease a defective mucosal barrier, a dysregulated immune response and an excessive reactivity against the gut microbiota are assumed to cause a breakdown of the intestinal homeostasis and lead to chronic inflammation. Piroxicam treatment is a method for induction of colitis in IL-10 k.o. mice, which integrates a dysfunction of both the intestinal barrier and the immune system. However, the translational value of this model has not been thoroughly clarified.AimTo characterise the piroxicam-accelerated colitis (PAC) IL-10 k.o. model with respect to clinical features, pathogenic mechanisms and its ability to respond to existing therapies.MethodsThe PAC IL-10 k.o. model was established on a C57BL/6 J background and the clinical manifestations, immunological mechanisms and efficacy of ampicillin and anti-IL-12/23p40 treatment were assessed.ResultsThe PAC IL-10 k.o. mice developed weight loss and diarrhoea, and colonoscopy revealed a thickened granulomatous mucosa. Histological evaluation of ileum and colon showed Crohn's disease-like changes with pronounced hyperplasia and focal transmural inflammation. Ileitis was also observed in piroxicam treated wild type mice. The total number of neutrophils, monocytes and natural killer cells was elevated in the blood compared to IL-10 k.o. and wild type mice, indicating a role of the innate immune system in the pathogenesis. These findings were supported by analyses of the intestinal cytokine profile. Ampicillin and anti-IL-12/23p40 treatment significantly suppressed disease in the model.ConclusionThe PAC IL-10 k.o. model resembles several features of Crohn's disease and could be a useful in vivo model in preclinical research.     

The Prospective Antifungal Therapy Alliance? registry: A two-centre Canadian experience

BACKGROUND:

The Prospective Antifungal Therapy Alliance^® registry is a prospective surveillance study that collected data on the diagnosis, management and outcomes of invasive fungal infections (IFIs) from 25 centres in North America from 2004 to 2008.

OBJECTIVE:

To evaluate surveillance data on IFIs obtained from study centres located in Canada.

METHODS:

Patients with proven or probable IFIs at two Canadian medical centres were enrolled in the registry. Information regarding patient demographics, fungal species, infection sites, diagnosis techniques, therapy and survival were analyzed.

RESULTS:

A total of 347 patients from Canada with documented IFIs were enrolled in the Prospective Antifungal Therapy Alliance registry. Infections occurred most commonly in general medicine (71.8%), nontransplant surgery (32.6%) and patients with hematological malignancies (21.0%). There were 287 proven IFIs, including 248 Candida infections. Forty-six patients had invasive aspergillosis (IA); all of these were probable infections. Most cases of invasive candidiasis were confirmed using blood culture (90.5%), while IA was most frequently diagnosed using computed tomography scan (82.6%) and serological methods (82.6%). Fluconazole was the most common therapy used for Candida infections, followed by the echinocandins. Voriconazole therapy was most commonly prescribed for IA.

CONCLUSIONS:

The present study demonstrated that general medicine, surgery and hematological malignancy patients in Canada are susceptible to developing IFIs. In contrast to the United States, Candida albicans remains responsible for most IFIs in these Canadian centres. Surrogate serum markers are commonly being used for the diagnosis of IA, while therapy for both IFIs has shifted to broader-spectrum azoles and echinocandins.     

Oral Campylobacter species: Initiators of a subgroup of inflammatory bowel disease?

In recent years, a number of studies detected a significantly higher prevalence of Campylobacter species such as Campylobacter concisus (C. concisus) in intestinal biopsies and fecal samples collected from patients with inflammatory bowel disease (IBD) compared to controls. Most of these Campylobacter species are not of zoonotic origin but are human oral Campylobacter species. Bacterial species usually cause diseases in the location where they colonize. However, C. concisus and other oral Campylobacter species are associated with IBD occurring at the lower parts of the gastrointestinal tract, suggesting that these Campylobacter species may have unique virulence factors that are expressed in the lower parts of the gastrointestinal tract.     

Hygiene hypothesis in inflammatory bowel disease： A critical review of the literature

The hygiene hypothesis is thought to be a significant contributor to the growing incidence of inflammatory bowel disease （IBD） around the world, although the evidence for specific factors that underlie the hygiene hypothesis in IBD is unclear. We aimed to systematically review the literature to determine which hygiene-related factors are associated with the development of IBD. Publications identified from a broad based MEDLINE and Current Contents search between 1966 and 2007 on key terms relevant to the ＇hygiene hypothesis＇ and IBD including H pylori exposure, helminths, cold chain hypothesis, measles infection and vaccination, antibiotic use, breastfeeding, family size, sibship, urban upbringing, day care attendance and domestic hygiene were reviewed. The literature suggests that the hygiene hypothesis and its association with decreased microbial exposure in childhood probably plays an important role in the development of IBD, although the strength of the supporting data for each of the factors varies considerably. The most promising factors that may potentially be associated with development of IBD include H pylori exposure, helminths, breastfeeding and sibship. However, the vast majority of studies in this area are plagued by serious methodological shortcomings, particularly the reliance on retrospective recall of information making it difficult to truly ascertain the importance of a ＇hygiene hypothesis＇ in IBD. The ＇hygiene hypothesis＇ in IBD is an important area of research that may give clues to the aetiology of this disease. Directions for future research are recommended.