Role for protease activity in visceral pain in irritable bowel syndrome

Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.

Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome

BACKGROUND & AIMS: The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. METHODS: IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. RESULTS: Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

Effect of breadmaking process on In Vitro gut microbiota parameters in irritable bowel syndrome

A variety of foods have been implicated in symptoms of patients with Irritable Bowel Syndrome (IBS) but wheat products are most frequently cited by patients as a trigger. Our aim was to investigate the effects of breads, which were fermented for different lengths of time, on the colonic microbiota using in vitro batch culture experiments. A set of in vitro anaerobic culture systems were run over a period of 24 h using faeces from 3 different IBS donors (Rome Criteria–mainly constipated) and 3 healthy donors. Changes in gut microbiota during a time course were identified by fluorescence in situ hybridisation (FISH), whilst the small -molecular weight metabolomic profile was determined by NMR analysis. Gas production was separately investigated in non pH-controlled, 36 h batch culture experiments. Numbers of bifidobacteria were higher in healthy subjects compared to IBS donors. In addition, the healthy donors showed a significant increase in bifidobacteria (P<0.005) after 8 h of fermentation of a bread produced using a sourdough process (type C) compared to breads produced with commercial yeasted dough (type B) and no time fermentation (Chorleywood Breadmaking process) (type A). A significant decrease of δ-Proteobacteria and most Gemmatimonadetes species was observed after 24 h fermentation of type C bread in both IBS and healthy donors. In general, IBS donors showed higher rates of gas production compared to healthy donors. Rates of gas production for type A and conventional long fermentation (type B) breads were almost identical in IBS and healthy donors. Sourdough bread produced significantly lower cumulative gas after 15 h fermentation as compared to type A and B breads in IBS donors but not in the healthy controls. In conclusion, breads fermented by the traditional long fermentation and sourdough are less likely to lead to IBS symptoms compared to bread made using the Chorleywood Breadmaking Process.

Omvårdnadsåtgärder som stärker egenvården hos patienter med Irritable Bowel Syndrome

Syftet med denna systematiska litteraturstudie var att belysa hur sjuksköterskans omvårdnad kan stödja egenvårdsförmågan hos patienter med IBS. Den viktigaste omvårdnadsåtgärden var att tidigt i samband med diagnostiseringen av IBS, ge information och kunskap om sjukdomen, dess prognos samt behandling, vilket visades förbättra upplevd livskvalitet samt ge symtom-lindring. IBS skolor startade av sjuksköterskor förbättrade patienternas hälsobeteende samt minskade symtomen. Genom introduktion av guidebok innehållande råd om kost, motion, stresshantering samt symtomkontroll upplevde patienterna en minskning av symtom, vilket även ledde till en minskning av antalet besök inom sjukvården. När sjuksköterskan använde olika frågeformulär i kontakten med patienter med IBS kunde patienternas problem identifieras och strategier för egenvården planeras samt individuella handlingsplaner skapas. Sjuksköterskans kunskap och förståelse om patientens egen sjukdomsupplevelse samt copingstrategi ledde till att patienten tog en mer aktiv roll i sjukdomshantering. Patienters behandling borde inriktas på livsstilsförändringar, som till exempel psykosocial arbetsmiljö, kost, fysisk aktivitet, samt stresshantering. Genom att patienten förde dagbok över kostintag och sedan gjorde jämförelser med ökade eller minskade symtom kunde faktorer identifieras i matvanor samt kostintag som inverkade på symtomen. Dorotea Orems omvårdnadsmodell har legat till grund för denna studie där tron på människans egna resurser framhålls.

The effects of sildenafil on rectal sensitivity and tone in patients with the irritable bowel syndrome

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases

Background: Paradoxical cases of psoriatic lesions induced or exacerbated by anti-tumor necrosis factor (TNF)-α therapy have been reported more frequently in recent years, but data related to inflammatory bowel disease (IBD) are rare. A systematic literature review was performed to provide information about this adverse effect in patients with IBD who receive anti-TNF therapy. Methods: Published studies were identified by a search of Medline, Embase, Cochrane, SciELO, and LILACS databases. Results: A total of 47 studies (222 patients) fulfilled the inclusion criteria and were selected for analysis. Clinical and therapeutic aspects varied considerably among these reports. Of the 222 patients, 78.38% were diagnosed with Crohn's disease, and 48.20% were female. The mean patient age was 26.50. years, and 70.72% of patients had no history of psoriasis. Patients developed psoriasiform lesions (55.86%) more often than other types of psoriatic lesions, and infliximab was the anti-TNF-α therapy that caused the cutaneous reaction in most patients (69.37%). Complete remission of cutaneous lesions was observed in 63.96% of the cases. Conclusions: We found that psoriatic lesions occurred predominantly in adult patients with Crohn's disease who received infliximab and had no previous history of psoriasis. Most patients can be managed conservatively without discontinuing anti-TNF-α therapy. © 2012 European Crohn's and Colitis Organisation.

Mechanism and effect of esculetin in an experimental animal model of inflammatory bowel disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Cell therapy in experimental model of inflammatory bowel disease

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Products for the treatment of inflammatory bowel disease: a patent review (2013-2014)

Introduction: Inflammatory bowel disease (IBD) consists of Crohn's disease, ulcerative colitis and an unspecific IBD. The unclear etiology of IBD is a limiting factor that complicates the development of new pharmacological treatments and explains the high frequency of refractory patients to current drugs, including both conventional and biological therapies. In view of this, recent progress on the development of novel patented products to treat IBD was reviewed.Areas covered: Evaluation of the patent literature during the period 2013 - 2014 focused on chemical compounds, functional foods and biological therapy useful for the treatment of IBD.Expert opinion: Majority of the patents are not conclusive because they were based on data from unspecific methods not related to intestinal inflammation and, when related to IBD models, few biochemical and molecular evaluations that could be corroborating their use in human IBD were presented. On the other hand, methods and strategies using new formulations of conventional drugs, guanylyl cyclase C peptide agonists, compounds that influence anti-adhesion molecules, mAbs anti-type I interferons and anti-integrin, oligonucleotide antisense Smad7, growth factor neuregulin 4 and functional foods, particularly fermented wheat germ with Saccharomyces cerevisiae, are promising products for use in the very near future.

Inflammatory bowel disease: an overview of immune mechanisms and biological treatments

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Probiotics: the scientific evidence in the context of inflammatory bowel disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Tolerance and nutritional therapy of dietary fibre from konjac glucomannan hydrolysates for patients with inflammatory bowel disease (IBD)

Carbohydrates may provide an alternative therapeutic approach for a number of digestive health disorders such as inflammatory bowel disease (IBD). The aim of this work was to characterise the tolerance and efficacy of low and high molecular weight konjac glucomannan hydrolysates within healthy volunteers and patients suffering from IBD and associated gut conditions. These conditions included constipation, Crohn's disease and ulcerative colitis. For general tolerance, fourteen patients participated whilst for the digestive disorder trial, there were twenty. Scores of taste/texture of the product, bowel movement, stool consistency, diarrhoea, existence/absence of blood in the faeces, abdominal pains, flatulence, vomiting, fever, improvement of life style after use, willingness to use in the future and clinician's statements about each patient's conditions before and after use were recorded. The results showed that the hydrolysates were tolerated well for patients with diarrhoea and had a significant improvement on bowel movement, stool consistency, abdominal pain and flatulence after ten days. With respect to effects on IBD, there was a significant health benefit after fourteen days of consumption for bowel movement, stool consistency, diarrhoea, existence/absence of blood in the faeces, abdominal pain, flatulence and vomiting. Most patients declared an improvement of their life style after consuming the hydrolysates. The use of konjac glucomannan hydrolysates as a therapeutic agent or adjunct to standard treatments could prove a successful tool for the treatment of a range of disorders; although large scale studies are required to characterise further the role of the carbohydrates.

Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy

BACKGROUND & AIMS: Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS: We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS: Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS: We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.

Pyostomatitis vegetans and its relation to inflammatory bowel disease, pyoderma gangrenosum, pyodermatitis vegetans, and pemphigus

J Oral Pathol Med (2012) 41: 584588 Pyostomatitis vegetans (PSV) is an intraoral pustular eruption considered by most authors to represent the mucous analogous of cutaneous pyoderma gangrenosum and its vegetating presentations (pyodermatitis vegetans). A strong correlation of PSV with inflammatory bowel disease (IBD) is well documented. The histopathology of PSV lesions usually reveals acanthosis, and neutrophils and/or eosinophils infiltration with intraepithelial or subepithelial abscesses; acantholysis is present in some cases. We studied four patients with IBD that presented oral lesions suggestive of PSV. Two male and two female patients were included. The histopathology of oral lesions of two patients revealed findings typical for PSV. The other two patients showed findings typical for pemphigus vulgaris (PV), although the course of their symptoms paralleled that of the bowel disease. Our findings may suggest that pustular lesions in patients with IBD can be a presentation of both PSV and PV; adequate diagnosis is required because clinical presentation is very similar.