Induction of suppressor cells by Mycobacterium paratuberculosis antigen in inflammatory bowel disease.

We studied the M. paratuberculosis-induced proliferation and suppressor cell generation by peripheral blood lymphocytes from patients with inflammatory bowel disease. Peripheral blood lymphocytes were separated from 33 patients with Crohn's disease, 18 with ulcerative colitis, nine with other intestinal diseases, and five with autoimmune disorders. Proliferation of peripheral blood lymphocytes from normal individuals in response to 10 micrograms/ml of M. paratuberculosis antigen was reduced by depletion of CD4+ T cells. The ability of M. paratuberculosis antigen to suppress concanavalin A-induced proliferation (expressed as a percentage suppression) was reduced by depletion of CD8+ T cells. This suppression was the same whether peripheral blood lymphocytes were from normal individuals, patients with intestinal diseases other than inflammatory bowel disease, or patients with autoimmune disorders (47 +/- 14%, 44 +/- 24%, and 30 +/- 26%, respectively). In contrast, the suppression induced by M. paratuberculosis for patients with Crohn's disease and ulcerative colitis (66 +/- 22% and 67 +/- 22%) was much greater than that for normal individuals (P less than 0.001). In particular, lymphocytes from patients with active Crohn's disease demonstrated little proliferation in response to this antigen but marked suppressor activity (79 +/- 13%). How the immunomodulatory effects of this antigen relate to the pathogenesis of the inflammatory bowel diseases remains to be determined.     

Analysis of the influence of two CD24 genetic variants in Crohn's disease and ulcerative colitis

The aim of this study was to evaluate the possible implication of CD24 gene in the genetic predisposition to inflammatory bowel disease (IBD). Our study population consisted of 1321 female Spanish individuals (369 Crohn's disease [CD] patients, 323 ulcerative colitis [UC] patients, and 629 healthy matched controls). Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646), were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. The "del" allele of the dinucleotide deletion was associated with an increased risk of CD (odds ratio = 1.61, 95% confidence interval = 1.17-2.21, p(FDR) = 6.4E-03) but not with UC. Moreover, this allele was significant associated with the age of CD diagnosis between 17 and 40 years, the ileocolonic location, and the inflammatory behavior of CD. We observed no significant differences between the allelic or genotypic frequencies of the A57V polymorphism in our studied IBD cohort. Our results suggest that the rs3838646 CD24 polymorphism is part of the genetic background of CD.     

Increased expression of NKX2.3 mRNA transcribed from the risk haplotype for ulcerative colitis in the involved colonic mucosa

NKX2.3 is a promising candidate for susceptibility genes to inflammatory bowel disease (IBD). The aim of this study was to perform a candidate gene analysis of NKX2.3 in Japanese IBD and to examine how the risk allele (haplotype) affects susceptibility to IBD using allelic expression ratios of NKX2.3 mRNA in the involved colonic mucosa. A total of 344 patients with Crohn's disease (CD), 253 patients with ulcerative colitis (UC), and 243 healthy controls (HCs) were genotyped for 3 tag-single nucleotide polymorphisms (SNPs; rs10883365, rs888208, and rs11596008) around NKX2.3. The allelic expression ratio of NKX2.3-mRNA was examined by TaqMan assay using rs888208 as an allelic (haplotypic) marker. Two SNPs (rs10883365 and rs888208) were significantly associated with UC (p = 7.79 × 10(-4), odds ratio [OR] = 1.54 [95% confidence interval (95% CI) 1.20-1.99], p = 7.70 × 10(-3), OR = 1.41 [95% CI 1.10-1.81], respectively) and 1 SNP (rs10883365) was associated with CD (p = 0.0366, OR = 1.29 [95% CI 1.02-1.63]). Haplotype B formed by the 3 SNPs demonstrated a significant association with UC (p = 6.11 × 10(-4), OR = 1.56 [95% CI 1.21-2.00]). Subgroup analyses indicated that rs10883365 was significantly associated mainly with colonic CD (p = 1.99 × 10(-3), OR = 1.91 [95% CI 1.27-2.88], vs HCs). The allelic expression ratios of NKX2.3 mRNA transcribed from haplotype B (risk haplotype) to haplotype A (the nonrisk haplotype) in the involved mucosa from 10 IBD patients were significantly higher than the allelic ratio of respective genomic DNA (p = 0.00195). We confirmed the association of SNP rs10883365 located in the 5' flanking region of NKX2-3 with Japanese UC and colonic CD and determined the risk haplotype (haplotype B) for UC. The demonstrated allelic expression imbalance supports the idea that the risk haplotype of NKX2.3 confers susceptibility to UC through increasing expression of NKX2.3 mRNA in the colonic mucosa.     

Cultures of Human Colonic Epithelial Cells Isolated from Endoscopical Biopsies from Patients with Inflammatory Bowel Disease. Effect of IFNγ, TNFα and IL-1β on Viability,Butyrate Oxidation and IL-8 Secretion

Cytokjne-mediated impairment of viability and metabolic function of epithelial cells has been suggested as a possible early pathogenic event in the development of inflammatory bowel disease (IBD). It is currently unknown whether pro-inflammatory cytokines have a direct effect on human nontransformed colonic epithelial cells. We investigated the effects of TNFα, IFNγ and IL-1β on viability, short chain fatty acid (butyrate) oxidation and IL-8 secretion in human colonic epithelial cell cultures in vitro obtained from macroscopically normal mucosa from IBD patients and controls. Colonic crypts were isolated from endoscopical biopsies by ultra-short (10 min) EDTA/EGTA treatment, and exposed to TNFα, IFNγ and IL-1β for 24 hours. The combination of TNFoc+IFNγ induced a significant decrease in cell viability as judged by methyltetrazoleum (MTT) metabolism which decreased to median 68 % of unexposed cultures (P<0.01). This effect was more pronounced than that observed after addition of TNFα (median 88 %) (P<0.05), but not IFNγ alone (median 78 %), whereas IL-1(3 had no significant effect. Cells from IBD patients were significantly less sensitive to TNFα + IFNγ exposure (median 74 %) compared to cells from controls (median 58 %) (P < 0.05). Butyrate oxidation, as measured by entrapment of CO₂, was not inhibited in cells exposed to TNFα + IFNγ, neither from controls (median 112%) nor from IBD patients (median 108%), suggesting a relative increase of this specific metabolic function in living cells in response to immunoinflammatory stress. IL-8 levels in cell supernatants were increased by TNFα + IFNγ, supporting the role of the epithelium in signalling between luminal factors and mucosal immune cells. In conclusion, we report that TNFα and IFNγ damage and influence human colonic epithelial cell function in vitro and that such mechanisms, if operative in vivo, also may be involved in the pathogenesis of IBD     

The CREM gene is involved in genetic predisposition to inflammatory bowel disease in the Tunisian population

The identification of susceptibility genes for inflammatory bowel disease (IBD) is key to understanding pathogenic mechanisms. Recently, the results of genetic association studies have highlighted many loci that are shared among several autoimmune diseases. We aimed to study the genetic epidemiology of polymorphisms in specific genes previously associated with other autoimmune diseases, namely the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes. Twelve polymorphisms in the CREM, STAT4, STAT5a, Stat5b, and IRF5 genes were genotyped in a cohort of 107 IBD patients (39 Crohn's disease [CD] and 68 ulcerative colitis [UC]) and 162 controls from southern Tunisia. One CREM single nucleotide polymorphism (SNP) displayed evidence for genetic association with IBD (p=8.7×10(-4), odds ratio [OR]=2.84 [1.58; 5.09]). One STAT4 SNP (p=0.026; OR=1.65 [1.06; 2.58]) exhibited a marginal association with UC but not with CD. No significant association was observed with the SNPs in STAT5a, IRF5, and STAT5b. These results suggest that common variants of the CREM gene are involved in the genetic component conferring general susceptibility to IBD, whereas STAT4 appears to be more specifically associated with UC. This work provides motivation for studies aiming to replicate these findings in larger populations.     

Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease

Mouse models of intestinal inflammation resemble aspects of inflammatory bowel disease in humans. These models have provided important insights into mechanisms that control intestinal homeostasis and regulation of intestinal inflammation. This viewpoint discusses themes that have emerged from mouse models of intestinal inflammation including bacterial recognition, autophagy, the IL‐23/Th‐17 axis of inflammation as well as the role of negative regulators. Many of the pathways highlighted by model systems have been identified in recent genome‐wide association studies in human validating the relevance of mouse models to human inflammatory bowel disease. Understanding of the complex biological mechanisms that lead to intestinal inflammation in mouse models may help to define targets for treatment of human diseases.     

Metabolomic profiling in children with inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD) represent inflammatory bowel diseases (IBD) with multifactorial pathogenesis, involving genetic, environmental and microbial factors. Interactions between gut microbiota and immune system result in changes in metabolic pathways. Metabolomics is a comprehensive and quantitative (or semi-quantitative) analysis of metabolites synthetized in human's biological system. It has been shown that metabolic profiling might be used to identify disease biomarkers. Recent findings confirmed alterations in the number of metabolites in patients with IBD. However, most of the studies included adult individuals with ongoing treatment which might have affected the metabolite profiling. Therefore, the aim of our study was to collect the knowledge about metabolomics in paediatric patients with CD or UC based on the currently published literature.     

Leptin antagonist ameliorates chronic colitis in IL-10 mice

Background

Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-β1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression.

Aim

We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis.

Results

Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39⁺ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-β1, -β2 and -β3 expressing CD4⁺ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-β1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis.

Conclusion

This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD.     

Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review

Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of inflammatory bowel disease (IBD). We conducted a comprehensive review of meta-analyses to summarize the reported effectiveness of different drugs for IBD. We performed a literature search and a total of 110 meta-analyses from 66 articles were summarized and re-analyzed (62 in UC and 48 in CD). In summary, 5-ASA was more effective than placebo in both induction and maintenance treatment of UC, but there were conflicting results on the effect of 5-ASA on the induction treatment or relapse of CD. The use of immunomodulatory agents in the induction or maintenance phase of UC and CD using immunomodulators appeared to be more effective than placebo, but the results were impacted by small number of patients, discordant results with the largest study and risk of biases. Anti-TNF-α and anti-integrin therapeutic antibodies in both, induction and maintenance, showed a better efficacy than placebo in a large proportion of patients analyzed. Other agents, such as probiotics, antibiotics, omega-3, were shown to be more effective than placebo, but the same issues arose as stated above with the use of immunomodulatory agents. In conclusion, we performed a comprehensive review of meta-analysis on comparative efficacy of pharmacotherapy used in the management of IBD. Our review will augment our understanding of the treatment of UC and CD by providing a guideline for interpreting the statistically significant findings and discusses the optimal choice for IBD treatment.     

Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis

Genes encoding for receptors of the innate immune system are potential candidates for susceptibility to inflammatory bowel disease, e.g., mutations in the cytosolic receptor NOD2/CARD15 were associated with Crohn's disease. Herein, two mutations of the Toll-like receptor (TLR)-4 gene (Asp299Gly and Thr399Ile) resulting in impaired lipopolysaccharide signaling, the -159C/T promotor polymorphism of the CD14 gene, polymorphisms of the lipopolysaccharide binding protein gene and the bactericidal permeability increasing protein gene were evaluated in 102 patients with Crohn's disease, 98 patients with ulcerative colitis and 145 healthy controls. The allele and carrier frequencies for the Thr399Ile mutation in TLR4 gene were significantly increased in ulcerative colitis when compared to the controls (P = 0.014 and P = 0.018, respectively). None of the other five polymorphisms was associated with inflammatory bowel disease. In conclusion, a novel association between a functional polymorphism in TLR4 and ulcerative colitis is reported. This observation underscores the importance of impaired innate immunity in inflammatory bowel disease.     

Association among genetic predisposition,gut microbiota,and host immune response in the etiopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn''s disease (CD) and ulcerativecolitis (UC), is a chronic disorder that affects thousands of people around theworld. These diseases are characterized by exacerbated uncontrolled intestinalinflammation that leads to poor quality of life in affected patients. Although theexact cause of IBD still remains unknown, compelling evidence suggests that theinterplay among immune deregulation, environmental factors, and genetic polymorphismscontributes to the multifactorial nature of the disease. Therefore, in this review wepresent classical and novel findings regarding IBD etiopathogenesis. Considering thegenetic causes of the diseases, alterations in about 100 genes or allelic variants,most of them in components of the immune system, have been related to IBDsusceptibility. Dysbiosis of the intestinal microbiota also plays a role in theinitiation or perpetuation of gut inflammation, which develops under altered orimpaired immune responses. In this context, unbalanced innate and especially adaptiveimmunity has been considered one of the major contributing factors to IBDdevelopment, with the involvement of the Th1, Th2, and Th17 effector population inaddition to impaired regulatory responses in CD or UC. Finally, an understanding ofthe interplay among pathogenic triggers of IBD will improve knowledge about theimmunological mechanisms of gut inflammation, thus providing novel tools for IBDcontrol.     

Classical and recent advances in the treatment of inflammatory bowel diseases

Crohn''s disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.     

Inflammatory bowel disease and the risk of osteoporosis and fracture

Inflammatory bowel disease (IBD) is commonly believed to increase the risk of bone mineral loss, leading to osteoporosis and an increased risk of disabling fractures. In this narrative review, we will presenting a summary of the published medical literature in regards to the relationship between IBD and the development of osteoporosis, bone mineral loss, and fractures. We will explore the epidemiology of metabolic bone disease in IBD, focusing on the prevalence and both the general and IBD-specific risk factors for the development of osteoporosis and of fracture in persons with IBD. We will also examine the role of the inflammatory process in IBD promoting excessive bone mineral loss, as well as the role that low body mass, corticosteroid use, diet, and nutrient malabsorption play in contributing to bone disease. Last, we will discuss our recommendation for: screening for osteoporosis in IBD patients, the use of preventative strategies, and therapeutic interventions for treating osteoporosis in persons with IBD.     

Clinical Course of COVID-19 in Patients with Inflammatory Bowel Disease in Korea: a KASID Multicenter Study

In 2020, the novel coronavirus disease 2019 (COVID-19) began to spread worldwide and remains an ongoing medical challenge. This case series reports on the clinical features and characteristics of patients with inflammatory bowel disease (IBD) and confirmed COVID-19 infection. From February 2020 to March 2021, nine patients with IBD had confirmed COVID-19 across four hospitals in Korea. The median age at COVID-19 diagnosis was 42 years. Six patients were male, and seven patients had ulcerative colitis (UC). No patients required oxygen therapy, intensive care unit hospitalizations, or died. The most common symptom was fever, and gastrointestinal (GI) symptoms developed as diarrhea in five patients with UC. Oral steroids were used to combat UC aggravation in two patients. In this case series of nine IBD patients diagnosed with COVID-19 in Korea, the clinical presentation was predominately a mild respiratory tract infection. Most patients with UC developed new GI symptoms including diarrhea.     

Inflammatory bowel disease and the risk of osteoporosis and fracture

Inflammatory bowel disease (IBD) is commonly believed to increase the risk of bone mineral loss, leading to osteoporosis and an increased risk of disabling fractures. In this narrative review, we will presenting a summary of the published medical literature in regards to the relationship between IBD and the development of osteoporosis, bone mineral loss, and fractures. We will explore the epidemiology of metabolic bone disease in IBD, focusing on the prevalence and both the general and IBD-specific risk factors for the development of osteoporosis and of fracture in persons with IBD. We will also examine the role of the inflammatory process in IBD promoting excessive bone mineral loss, as well as the role that low body mass, corticosteroid use, diet, and nutrient malabsorption play in contributing to bone disease. Last, we will discuss our recommendation for: screening for osteoporosis in IBD patients, the use of preventative strategies, and therapeutic interventions for treating osteoporosis in persons with IBD.     

Differential expression of the TRAIL/TRAIL-receptor system in patients with inflammatory bowel disease

TNF-related apoptosis inducing-ligand (TRAIL) is a potent inducer of apoptosis and plays an important role in immune regulation. To explore the role of TRAIL in inflammatory bowel disease (IBD), we examined the expression of the TRAIL/TRAIL-receptor system in colonic resections from patients with ulcerative colitis and Crohn's disease in comparison to normal colon and appendicitis.     

Immunopathological characterization of selected mouse models of inflammatory bowel disease: Comparison to human disease

Inflammatory bowel diseases (IBD) are chronic, relapsing conditions of multifactorial etiology. The two primary diseases of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both entities are hypothesized to occur in genetically susceptible individuals due to microbial alterations and environmental contributions. The exact etiopathogenesis, however, is not known for either disease. A variety of mouse models of CD and UC have been developed to investigate the pathogenesis of these diseases and evaluate treatment modalities. Broadly speaking, the mouse models can be divided into 4 categories: genetically engineered, immune manipulated, spontaneous and erosive/chemically induced. No one mouse model completely recapitulates the immunopathology of CD or UC, however each model possesses particular similarities to human IBD and offers advantageous for specific details of IBD pathogenesis. Here we discuss the more commonly used models in each category and critically evaluate how the immunopathology induced compares to CD or UC, as well as the advantages and disadvantages associated with each model.     

The importance of vitamin D in the pathology of bone metabolism in inflammatory bowel diseases

Etiological factors of bone metabolism disorders in inflammatory bowel diseases have been the subject of interest of many researchers. One of the questions often raised is vitamin D deficiency. Calcitriol acts on cells, tissues and organs through a vitamin D receptor. The result of this action is the multi-directional effect of vitamin D. The reasons for vitamin D deficiency are: decreased exposure to sunlight, inadequate diet, inflammatory lesions of the intestinal mucosa and post-gastrointestinal resection states. This leads not only to osteomalacia but also to osteoporosis. Of significance may be the effect of vitamin D on the course of the disease itself, through modulation of the inflammatory mechanisms. It is also necessary to pay attention to the role of vitamin D in skeletal pathology in patients with inflammatory bowel diseases and thus take measures aimed at preventing and treating these disorders through the supplementation of vitamin D.     

Expression of selected cytochrome P450 isoforms and of cooperating enzymes in colorectal tissues in selected pathological conditions

The current interest in CYP expression in the colon results from its uniqueness as a target organ for cancer.