Investigating the role of potential genetic markers that can predict risk for steroid refractory inflammatory bowel disease

Contexte - La variation interindividuelle de la réponse aux corticostéroïdes (CS) est un problème important chez les patients atteints de maladies inflammatoires d’intestin. Ce problème est bien plus accentué chez les enfants avec la prévalence de la corticodépendance extrêmement (~40 %) élevée. La maladie réfractaire au CS a des répercussions sur le développement et le bien-être physique et psychologique des patients et impose des coûts médicaux élevés, particulièrement avec la maladie active comparativement à la maladie en rémission, le coût étant 2-3 fois plus élevé en ambulatoire et 20 fois plus élevé en hôpital. Il est ainsi primordial de déterminer les marqueurs prédictifs de la réponse aux CS. Les efforts précédents de découvrir les marqueurs cliniques et démographiques ont été équivoques, ce qui souligne davantage le besoin de marqueurs moléculaires. L'action des CS se base sur des processus complexes déterminés génétiquement. Deux gènes, le ABCB1, appartenant à la famille des transporteurs transmembraneaux, et le NR3C1, encodant le récepteur glucocorticoïde, sont des éléments importants des voies métaboliques. Nous avons postulé que les variations dans ces gènes ont un rôle dans la variabilité observée de la réponse aux CS et pourraient servir en tant que les marqueurs prédictifs. Objectifs - Nous avons visé à: (1) examiner le fardeau de la maladie réfractaire aux CS chez les enfants avec la maladie de Crohn (MC) et le rôle des caractéristiques cliniques et démographiques potentiellement liés à la réponse; (2) étudier l'association entre les variantes d'ADN de gène ABCB1 et la réponse aux CS; (3) étudier les associations entre les variantes d'ADN de gène NR3C1 et la réponse aux CS. Méthodes - Afin d’atteindre ces objectifs, nous avons mené une étude de cohorte des patients recrutés dans deux cliniques pédiatriques tertiaires de gastroentérologie à l’Ottawa (CHEO) et à Montréal (HSJ). Les patients avec la MC ont été diagnostiqués avant l'âge de 18 ans selon les critères standard radiologiques, endoscopiques et histopathologiques. La corticorésistance et la corticodépendance ont été définies en adaptant les critères reconnus. L’ADN, acquise soit du sang ou de la salive, était génotypée pour des variations à travers de gènes ABCB1 et NR3C1 sélectionnées à l’aide de la méthodologie de tag-SNP. La fréquence de la corticorésistance et la corticodépendance a été estimée assumant une distribution binomiale. Les associations entre les variables cliniques/démographiques et la réponse aux CS ont été examinées en utilisant la régression logistique en ajustant pour des variables potentielles de confusion. Les associations entre variantes génétiques de ABCB1 et NR3C1 et la réponse aux CS ont été examinées en utilisant la régression logistique assumant différents modèles de la transmission. Les associations multimarqueurs ont été examinées en utilisant l'analyse de haplotypes. Les variantes nongénotypées ont été imputées en utilisant les données de HAPMAP et les associations avec SNPs imputés ont été examinées en utilisant des méthodes standard. Résultats - Parmi 645 patients avec la MC, 364 (56.2%) ont reçu CS. La majorité de patients étaient des hommes (54.9 %); présentaient la maladie de l’iléocôlon (51.7%) ou la maladie inflammatoire (84.6%) au diagnostic et étaient les Caucasiens (95.6 %). Huit pourcents de patients étaient corticorésistants et 40.9% - corticodépendants. Le plus bas âge au diagnostic (OR=1.34, 95% CI: 1.03-3.01, p=0.040), la maladie cœxistante de la région digestive supérieure (OR=1.35, 95% CI: 95% CI: 1.06-3.07, p=0.031) et l’usage simultané des immunomodulateurs (OR=0.35, 95% CI: 0.16-0.75, p=0.007) ont été associés avec la corticodépendance. Un total de 27 marqueurs génotypés à travers de ABCB1 (n=14) et NR3C1 (n=13) ont été en l'Équilibre de Hardy-Weinberg, à l’exception d’un dans le gène NR3C1 (rs258751, exclu). Dans ABCB1, l'allèle rare de rs2032583 (OR=0.56, 95% CI: 0.34-0.95, p=0.029) et génotype hétérozygote (OR=0.52, 95% CI: 0.28-0.95 p=0.035) ont été négativement associes avec la dépendance de CS. Un haplotype à 3 marqueurs, comprenant le SNP fonctionnel rs1045642 a été associé avec la dépendance de CS (p empirique=0.004). 24 SNPs imputés introniques et six haplotypes ont été significativement associés avec la dépendance de CS. Aucune de ces associations n'a cependant maintenu la signification après des corrections pour des comparaisons multiples. Dans NR3C1, trois SNPs: rs10482682 (OR=1.43, 95% CI: 0.99-2.08, p=0.047), rs6196 (OR=0.55, 95% CI: 0.31-0.95, p=0.024), et rs2963155 (OR=0.64, 95% CI: 0.42-0.98, p=0.039), ont été associés sous un modèle additif, tandis que rs4912911 (OR=0.37, 95% CI: 0.13-1.00, p=0.03) et rs2963156 (OR=0.32, 95% CI: 0.07-1.12, p=0.047) - sous un modèle récessif. Deux haplotypes incluant ces 5 SNPs (AAACA et GGGCG) ont été significativement (p=0.006 et 0.01 empiriques) associés avec la corticodépendance. 19 SNPs imputés ont été associés avec la dépendance de CS. Deux haplotypes multimarqueurs (p=0.001), incluant les SNPs génotypés et imputés, ont été associés avec la dépendance de CS. Conclusion - Nos études suggèrent que le fardeau de la corticodépendance est élevé parmi les enfants avec le CD. Les enfants plus jeunes au diagnostic et ceux avec la maladie coexistante de la région supérieure ainsi que ceux avec des variations dans les gènes ABCB1 et NR3C1 étaient plus susceptibles de devenir corticodépendants.

Molecular characterisation of the gut microflora of healthy and inflammatory bowel disease cats using fluorescence in situ hybridisation with special reference to Desulfovibrio spp

Inflammatory bowel disease (IBD) is a common cause of chronic large bowel diarrhoea in cats. Although the aetiology of IBD is unknown, an immune-mediated response to a luminal antigen is thought to be involved. As knowledge concerning the colonic microflora of cats is limited and requires further investigation, the purpose of this study was to determine the presence of specific bacterial groups in normal and IBD cats, and the potential role they play in the health of the host. Total bacterial populations, Bacteroides spp., Bifidobacterium spp., Clostridium histolyticum subgp., Lactobacillus-Enterococcus subgp. and Desulfovibrio spp. were enumerated in 34 healthy cats and 11 IBD cats using fluorescence in situ hybridisation. The study is one of the first to show the presence of Desulfovibrio in cats. Total bacteria, Bifidobacterium spp. and Bacteroides spp. counts were all significantly higher in healthy cats when compared with IBD cats, whereas Desulfovibrio spp. (producers of toxic sulphides) numbers were found to be significantly higher in colitic cats. The information obtained from this study suggests that modulation of bacterial flora by increasing bifidobacteria and decreasing Desulfovibrio spp. may be beneficial to cats with IBD. Dietary intervention may be an important aspect of their treatment.

Effects of a novel galactooligosaccharide on the faecal microbiota of healthy and inflammatory bowel disease cats during a randomized, double-blind, cross-over feeding study

Inflammatory bowel disease (IBD) is a common gastrointestinal disorder of cats with no known aetiological agent. Previous work has suggested that the faecal microbiota of IBD cats is significantly different from that of healthy cats, including significantly lower bifidobacteria, bacteroides and total counts in IBD cats and significantly lower levels of sulfate-reducing bacteria in healthy cats. Prebiotics, including galactooligosaccharides (GOS), have been shown to elicit a bifidogenic effect in humans and other animals. The purpose of the current study was to examine the impact of a novel GOS supplementation on the faecal microbiota of healthy and IBD cats during a randomized, double-blind, cross-over feeding study. Eight oligonucleotide probes targeting specific bacterial populations and DAPI stain (total bacteria) were used to monitor the feline faecal microbiota. Overall, inter-animal variation was high; while a trend of increased bifidobacterial levels was seen with GOS supplementation it was not statistically significant in either healthy or IBD cats. No significant differences were observed in the faecal microbiota of IBD cats and healthy cats fed the same diet. Members of the family Coriobacteriaceae (Atopobium cluster) were found to be the most abundant bacteria in the feline microbiota.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Prevalence of mental health disorders in inflammatory bowel disease: an Australian outpatient cohort

BACKGROUND: This study aimed to characterize prevalence of anxiety and depressive conditions and uptake of mental health services in an Australian inflammatory bowel disease (IBD) outpatient setting.

METHODS: Eighty-one IBD patients (39 males, mean age 35 years) attending a tertiary hospital IBD outpatient clinic participated in this study. Disease severity was evaluated according to the Manitoba Index. Diagnosis of an anxiety or depressive condition was based upon the Mini-International Neuropsychiatric Interview and the Hospital Anxiety and Depression Scale.

RESULTS: Based on Hospital Anxiety and Depression Scale subscale scores >8 and meeting Mini-International Neuropsychiatric Interview criteria, 16 (19.8%) participants had at least one anxiety condition, while nine (11.1%) had a depressive disorder present. Active IBD status was associated with higher prevalence rates across all anxiety and depressive conditions. Generalized anxiety was the most common (12 participants, 14.8%) anxiety condition, and major depressive disorder (recurrent) was the most common depressive condition reported (five participants, 6.2%). Seventeen participants (21%) reported currently seeking help for mental health issues while 12.4% were identified has having at least one psychological condition but not seeking treatment.

CONCLUSION: We conclude that rates of anxiety and depression are high in this cohort, and that IBD-focused psychological services should be a key component of any holistic IBD service, especially for those identified as having active IBD.

Experimental models of autoimmune inflammatory ocular diseases

A inflamação ocular é uma das principais causas de perda visual e cegueira. As uveítes constituem um grupo complexo e heterogêneo de doenças caracterizadas por inflamação dos tecidos intraoculares. O olho pode ser o único órgão envolvido ou a uveíte pode ser parte de uma doença sistêmica. A etiologia é desconhecida em um número significativo de casos, que são considerados idiopáticos. Modelos animais têm sido desenvolvidos para estudar a fisiopatogênese da uveíte autoimune devido às dificuldades na obtenção de tecidos de olhos humanos inflamados para experimentos. Na maioria desses modelos, que simulam as uveítes autoimunes em humanos, a uveíte é induzida com proteínas específicas de fotorreceptores (antígeno-S, proteína ligadora de retinoide do interfotoreceptor, rodopsina, recoverina e fosducina). Antígenos não retinianos, como proteínas associadas à melanina e proteína básica de mielina, são também bons indutores de uveíte em animais. Entender os mecanismos básicos e a patogênese dessas doenças oculares é essencial para o desenvolvimento de novas formas de tratamento das uveítes autoimunes e de novos agentes terapêuticos. Nesta revisão serão abordados os principais modelos experimentais utilizados para o estudo de doenças inflamatórias oculares autoimunes.

Dietary Polydextrose Prevents Inflammatory Bowel Disease in Trinitrobenzenesulfonic Acid Model of Rat Colitis

Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder that involves interactions among the immune system, genetic susceptibility, and environmental factors, especially the bacterial flora. Polydextrose, a polysaccharide constituted by 90% nondigestible and nonabsorbable soluble fibers, has several physiological effects consistent with those of dietary fibers, including proliferation of colon microflora. Because sulfasalazine presents serious side effects through long-term use at high doses, the aim of the present study was to evaluate the preventative effect of polydextrose on trinitrobenzenesulfonic acid-induced intestinal inflammation and its effects on the intestinal anti-inflammatory activity of sulfasalazine. Results indicated that polydextrose and its association with sulfasalazine present an anti-inflammatory effect that reduces myeloperoxidase activity, counteracts glutathione content, and promotes reductions in lesion extension and colonic weight/length ratio.

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.

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.