Potential roles of neutrophils in regulating intestinal mucosal inflammation of inflammatory bowel disease

Inflammatory bowel diseases (IBD), comprising of ulcerative colitis and Crohn's disease, are inflammatory disorders of the gastrointestinal tract characterized by chronically relapsing mucosal inflammation. Neutrophils, as the effector cells of acute inflammation, have long been reported to play a role in the maintenance of intestinal homeostasis and pathogenesis of IBD. At the early stage of mucosal inflammation in patients with IBD, neutrophils flood into intestinal mucosa, phagocytose pathogenic microbes, and promote mucosal healing and resolution of inflammation. However, large numbers of neutrophils infiltrating in the inflamed mucosa and accumulating in the epithelia cause damage of mucosal architecture, compromised epithelial barrier and production of inflammatory mediators. In this review we discuss the critical roles of neutrophils in modulating innate and adaptive immune responses in intestinal mucosa, and, importantly, clarify the potential roles of neutrophils related to their production of inflammatory mediators, transenthothelial and transepithelial migration into intestinal mucosa, and the underlying mechanisms in regulating mucosal inflammation of IBD. Moreover, we also describe a new subset of neutrophils (i.e., CD177⁺ neutrophils) and illustrate its protective role in modulating intestinal mucosal immune responses in IBD.     

Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases

Background and aimsTreatment goals in inflammatory bowel diseases are evolving beyond the control of symptoms towards the tight control of objectively-measured gastrointestinal inflammation. This review discusses the progress and challenges in adopting a treat-to-target approach in inflammatory bowel diseases.MethodsEvidence from the literature that highlights current thinking in terms of treating-to-target in patients with inflammatory bowel diseases is discussed.ResultsMonitoring for objective evidence of inflammation using endoscopy, cross-sectional imaging or laboratory biomarkers may be a useful approach in inflammatory bowel diseases; however, setting the appropriate treatment goal remains a challenge. Deep remission (a composite of symptom control and mucosal healing) may now be a realistic target in Crohn's disease; however, it remains to be proven that achieving deep remission will modify the long-term disease course. Assessing prognosis at an early stage of the disease course is essential for the development of an appropriate management plan, with the rationale of adapting treatment to disease severity. An algorithm has been proposed for the treatment of early Crohn's disease that involves early treatment with immunosuppressants and tumour necrosis factor antagonists, in the hope of preventing structural bowel damage.ConclusionsTreating beyond symptoms will require a clear management plan influenced by disease severity at presentation, clinical and biological prognostic factors, achievement and maintenance of clinical and biological remission and pharmacoeconomics.     

Medical management of severe inflammatory disease of the rectum and distal colon: Non-nutritional aspects

Rectal bleeding is the cardinal symptom in patients with inflammation of the rectum, and initial management must be directed at establishing an underlying diagnosis. In many patients in the Western World this will be idiopathic inflammatory bowel disease, although in all cases other causes such as infection must be excluded. Idiopathic proctitis is usually due to either ulcerative colitis or Crohn's disease, and in both conditions corticosteroids, either systemic or topical, provide the mainstay of treatment. The 5-aminosalicylic acid drugs are helpful in both acute and maintenance treatment, again given either systemically or topically, while metronidazole is of value in patients with Crohn's disease. In those with refractory proctitis alternative agents such as azathioprine, immunomodulating drugs and barrier agents may be useful.Severe inflammation of the rectum secondary to pelvic irradiation will also usually respond to topical steroid therapy, although sucralfate enemas may be equally successful; in resistant cases other treatments may be needed.Infective proctitis, when diagnosed, may require treatment with specific antimicrobial agents.     

Nutritional therapy of Crohn's disease in childhood

Crohn's disease is a chronic, incurable inflammatory bowel disease commonly diagnosed in childhood and adolescence. Growth failure represents a common, serious complication unique to the pediatric age group. Although the etiology of growth failure is multifactorial, malnutrition due to inadequate nutrient intake is the primary cause. Recent studies have demonstrated that nutritional supplementation through an enteral or parenteral route restores body composition and reverses linear and ponderal growth failure. The development of elemental diets that can be administered nasogastrically at home has afforded a more practical, less expensive, and less hazardous method of providing Crohn's disease patients with nutritional supplementation and bowel rest. Elemental-diet therapy has also been shown to be a safe, effective method of inducing a remission in acute Crohn's disease. Further studies are required to develop optimal nutritional therapy which may sustain long-term remission in this disease.     

Presymptomatic Crohn's Disease in a Young Patient Diagnosed Just After the Onset of Idiopathic Acute Pancreatitis

Acute pancreatitis is an extraintestinal manifestation of inflammatory bowel disease. There have been few reports describing acute pancreatitis preceding a diagnosis of inflammatory bowel disease. We herein report a rare case of a 16-year-old boy with presymptomatic Crohn''s disease that was newly diagnosed just after the onset of idiopathic acute pancreatitis. Crohn''s disease of any stage, much less in the presymptomatic stage, is rarely diagnosed just after the development of acute pancreatitis. The present case suggests that acute pancreatitis without an apparent cause in young or pediatric population can precede a diagnosis of presymptomatic Crohn''s disease.     

Increased Serum Levels of Vascular Endothelial Growth Factor in Patients with Inflammatory Bowel Disease

Background: Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing, and calcium-dependent enzyme-modulating cytokine with overexpression in various pathologic disorders, including granulomatous inflammation, tissue repair, delayed hypersensitivity reactions, rheumatoid arthritis, and tissue ischemia. The present study investigates the role of VEGF in chronic inflammatory bowel disease. Methods: Thirty-one patients with Crohn's disease, 15 patients with ulcerative colitis, and 9 healthy volunteers were studied. VEGF serum levels were measured with a solid-phase enzyme-linked immunosorbent assay. Results: Significantly increased VEGF serum levels were observed in both active Crohn's disease and active ulcerative colitis when compared with healthy controls. Patients with active Crohn's disease and active ulcerative colitis showed significantly higher VEGF serum levels than patients with quiescent disease. No difference was observed between inactive disease and healthy controls. In addition, strongly increased VEGF serum levels were found in patients with Crohn's disease with fistulas in the absence of clinical, endoscopic, histologic, and laboratory findings of disease activity. Conclusions: Significantly increased VEGF serum levels were observed in patients with active Crohn's disease and ulcerative colitis, which suggests that VEGF has an important role in chronic inflammatory bowel disease. Its possible association with fistulas has yet to be determined.     

The role of capsule endoscopy in small bowel Crohn's disease

Video capsule endoscopy is an invaluable tool for examining the small bowel. It is non-invasive and generally well tolerated, however its role in the assessment of the severity and extent of small bowel Crohn's disease has not, to date, been adequately evaluated.MethodsAll capsule endoscopies performed over a two year period in a tertiary referral centre in subjects with known or suspected Crohn's disease were reviewed.ResultsTwenty-six capsule endoscopy studies in total were included. These were performed in 15 cases of known Crohn's disease, 5 cases of suspected Crohn's disease, 3 cases of endoscopically diagnosed non-specific terminal ileal inflammation and finally 3 post colectomy cases of indeterminant being considered for IPAA formation. Ten patients known to have small bowel Crohn's disease were prospectively recruited; of 3 with normal small bowel follow through or CT exams, one had an abnormal capsule endoscopy. The other 7 patients had small bowel follow through or abdominal CT scans consistent with small bowel Crohn's disease; additional mucosal abnormalities were detected by capsule endoscopy in 6 cases with capsule retention in the stomach in one. Of 5 with colonic Crohn's disease normal small bowel imaging corresponded with normal capsule endoscopy in all but one. A diagnosis of Crohn's disease was made in 2 out of 5 cases of suspected Crohn's disease on the basis of the capsule endoscopy findings. Three patients with non-specific acute terminal ileal inflammation at ileocolonoscopy were confirmed to have ongoing inflammation. The capsule was retained in four subjects beyond 24 h.ConclusionCapsule endoscopy more accurately determines the severity and extent of the Crohn's disease in the small bowel than traditional imaging modalities.     

Comparison of leukocyte excretion and blood loss in inflammatory disease of the bowel.

Clinical relapse of inflammatory bowel disease is characterised by increased neutrophil migration into the intestine. The site of the neutrophil chemoattractant(s), whether luminal or mucosal, may be important since, on contact with a chemoattractant, neutrophils cause indiscriminate damage to their immediate surroundings by generating reactive oxygen species and by lysosomal enzyme release. If this happens within the mucosa, inflammation should correlate significantly with tissue damage as assessed by bleeding, but if it occurs within the intestinal lumen, the inflammation would be disproportionately greater than the bleeding such as is seen in classical exudation. Intestinal inflammation and bleeding were quantitated with the simultaneous use of indium-111 labelled neutrophils (four day faecal excretion of indium-111) and chromium-51 labelled red cells in patients with ulcerative colitis (n = 12), Crohn''s disease (n = 15), and NSAID induced enteropathy (n = 34). Intestinal inflammation and blood loss correlated significantly (Spearman) in patients with ulcerative colitis (20.3% v 6.5 ml/d (median) r: 0.85, p < 0.001) and NSAiD enteropathy (1.6% v 1.9 ml/d, r: 0.60, p < 0.01) but not in Crohn''s disease (17.0% v 2.1 ml/d, r: 0.38, p > 0.1). For a given indium-111 excretion, patients with ulcerative colitis had significantly greater (p < 0.01) blood loss than patients with Crohn''s disease. These results suggest that the predominant site of neutrophil chemoattractants may be within the mucosa in ulcerative colitis and NSAID enteropathy and within the lumen in Crohn''s disease.     

Histopathological characterization of cholecystectomy specimens in patients with inflammatory bowel disease

Background and aimsInflammatory bowel disease is associated with increased risk of cholelithiasis. However, the histologic patterns in gallbladders have not been extensively studied. This study is designed to characterize the histopathologic features of cholecystectomy specimens in inflammatory bowel disease patients, compared to a control group.MethodsCholecystectomy specimens in 78 Crohn's disease patients and 50 ulcerative colitis patients were reviewed. These were compared with 93 cholecystomies from noninflammatory bowel disease patients of approximate age and sex. The pattern and extent of inflammation was noted.ResultsMarked chronic cholecystitis was present in 12% of ulcerative colitis patients (P < 0.05) and 10.3% of Crohn's disease patients (P > 0.05), compared to 4.3% of the noninflammatory bowel disease control group. Eight percent of ulcerative colitis patients (P < 0.05) and 2.6% of Crohn's disease patients (P > 0.05) had acute serositis, compared to 0% of the noninflammatory bowel disease control. The third inflammatory pattern, nodular lymphoid aggregates, was significantly increased in Crohn's disease patients after adjusting for the effect of cholelithiasis. Nodular lymphoid aggregates were found in 21.2% of Crohn's disease patients and 9.7% of ulcerative colitis patients without cholelithiasis, compared to 5% of noninflammatory bowel disease controls without cholelithiasis, a statistically significant difference between the Crohn's disease and control groups (P < 0.05).ConclusionsInflammatory bowel disease patients show similar inflammatory patterns in cholecystectomy specimens compared to the general population. However, two inflammatory patterns that occur more often in ulcerative colitis patients are marked chronic cholecystitis and acute serositis, while nodular lymphoid aggregates are more common in Crohn's disease patients.     

Bactericidal Permeability Increasing Protein Gene Polymorphism is Associated with Inflammatory Bowel Diseases in the Turkish Population

Background/Aims:

Inflammatory bowel disease, a chronic inflammatory disease with unknown etiology, affects the small and large bowel at different levels. It is increasingly considered that innate immune system may have a central position in the pathogenesis of the disease. As a part of the innate immune system, bactericidal permeability increasing protein has an important role in the recognition and neutralization of gram-negative bacteria. The aim of our study was to investigate the involvement of bactericidal permeability increasing protein gene polymorphism (bactericidal permeability increasing protein Lys216Glu) in inflammatory bowel disease in a large group of Turkish patients.

Patients and Methods:

The present study included 528 inflammatory bowel disease patients, 224 with Crohn''s disease and 304 with ulcerative colitis, and 339 healthy controls.

Results:

Bactericidal permeability increasing protein Lys216Glu polymorphism was found to be associated with both Crohn''s disease and ulcerative colitis (P = 0.0001). The frequency of the Glu/Glu genotype was significantly lower in patients using steroids and in those with steroid dependence (P = 0.012, OR, 0.80; 95% confidence interval [CI]: 0.68-0.94; P = 0.0286, OR, 0.75; 95% CI: 0.66-0.86, respectively). There was no other association between bactericidal permeability increasing protein gene polymorphism and phenotypes of inflammatory bowel disease.

Conclusions:

Bactericidal permeability increasing protein Lys216Glu polymorphism is associated with both Crohn''s disease and ulcerative colitis. This is the first study reporting the association of bactericidal permeability increasing protein gene polymorphism with steroid use and dependence in Crohn''s disease.     

Enfermedad de Crohn en paciente con artritis idiopática juvenil de inicio sistémico: ¿asociación o complicación asociada al tratamiento?

The progression of systemic-onset juvenile idiopathic arthritis (JIAs) to the different forms of presentation of inflammatory bowel disease is extremely rare. We present the first report of a patient with SJIA that progressed to Crohn's disease in which mutations have been detected in genes responsible for the adequate regulation of the innate immune system.     

The significance of toll-like receptors in human diseases

Toll-like receptors (TLRs) are a family of transmembrane receptors that have been preserved throughout evolution and which selectively recognize a broad spectrum of microbial components and endogenous molecules released by injured tissue. Identification of these ligands by TLRs triggers signalling pathways which lead to the expression of numerous genes involved in a defensive response. In mammals, the products of these genes initiate inflammation, coordinate the effector functions of innate immunity, instruct and modulate adaptive immunity and initiate tissue repair and regeneration. Different mutations and experimental models which alter TLR function have revealed the significance of these receptors in susceptibility to infection and their involvement in the pathogenesis of a large number of non-infective inflammatory disorders such as cancer, allergy, autoimmunity, inflammatory bowel disease, or atherosclerosis. TLRs are currently viewed as important targets for the development of new vaccines and innovative therapies to prevent and treat human diseases.     

Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease

Faecal calprotectin has been proposed as a non-invasive surrogate marker of intestinal inflammation in inflammatory bowel disease. Close correlation between faecal calprotectin concentration and faecal leukocyte excretion quantified with ¹¹¹indium has been described. This faecal marker can be detected using simple and cheap techniques. Faecal calprotectin has a good diagnostic precision for separating organic and functional intestinal diseases. However, the specificity for the diagnosis of inflammatory bowel disease is lower than desirable, as several diseases other than inflammatory bowel disease – specially colorectal neoplasia and gastrointestinal infection – can also increase faecal calprotectin. High concentration of calprotectin in faeces is a strong argument to carry out a colonoscopy in order to rule out the presence of inflammatory bowel disease or other organic pathologies. Parallelism between faecal calprotectin levels and inflammatory bowel disease activity has been confirmed, although this faecal marker appears to better reflect the disease activity in ulcerative colitis than in Crohn's disease. Faecal calprotectin's capacity to predict inflammatory bowel diseases relapse is promising. It has been suggested that, in inflammatory bowel disease patients receiving treatment, a normalization or decrease in faecal calprotectin concentrations is an accurate indicator of endoscopic healing. Greater faecal calprotectin concentration has been shown in asymptomatic first-degree relatives of patients with inflammatory bowel disease, suggesting that there is a high prevalence of subclinical intestinal inflammation in them.     

Detection of Pro- and Anti-Inflammatory Cytokines in Stools of Patients with Inflammatory Bowel Disease

Background: Cytokines play a predominant role in immune and inflammatory reactions in inflammatory bowel disease. Any cytokine that is produced locally as a result of gut inflammation may leak into the bowel lumen and appear in the stools. We examined the usefulness of determining cytokine profiles in the stools of patients with ulcerative colitis or Crohn's disease. Methods: Cytokine concentrations in stool extracts were measured in 36 patients with ulcerative colitis, 32 patients with Crohn's disease, 9 controls with inflammatory disease, and 18 normal controls by means of enzyme-linked immunosorbent assays. Results     

High Frequency of Silent Inflammatory Bowel Disease in Spondylarthropathy

Objective. To search for an association between gut infection, gut inflammation, and spondylarthropathies. Methods. Ileocolonoscopy was performed in 118 patients with various inflammatory and noninflammatory joint diseases and in 24 patients with uncomplicated acute bacterial gastroenteritis. Results. Endoscopic lesions were more frequent in patients with spondylarthropathy (44%) compared with those with other inflammatory arthritides (6%; P = 0.001). Ileal changes were observed only in patients with spondylarthropathy (20% versus 0%; P = 0.01). Inflammatory bowel disease was the endoscopic diagnosis in 19% of the arthritis patients. Possible or definite Crohn's disease was diagnosed in 26% of patients with chronic spondylarthropathy, and ulcerative colitis in 1 patient with rheumatoid arthritis and in 1 with chronic uroarthritis. Histologic evidence of inflammation differed less distinctly than endoscopy findings between patient groups. There was no association of gut lesions with the use of nonsteroidal antiinflammatory drugs or with the presence of HLA-B27. Conclusion. Gut inflammation is frequent in patients with spondylarthropathy, and one-fourth of the patients who have chronic disease have early features of Crohn's disease.     

Refractory IBD: medical management

Refractory inflammatory bowel disease (IBD) can be defined as persistent acute symptomatic disease despite anti-inflammatory therapy or as chronically active disease requiring continuous treatment for relief of symptoms. Treatment options include azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX), cyclosporine (CYA), and experimental therapies that are cytokines or cytokine antagonists. AZA and 6-MP have identical actions in IBD. 6-MP is effective in about 75% of patients with inflammatory Crohn's disease. The mean time until the onset of action is 3.1 months. AZA is effective in ulcerative colitis as a steroid-sparing agent. Side-effects occur in 10–15% of patients on AZA or 6-MP for IBD. MTX induces symptomatic remission in about 40% of patients with Crohn's disease. The potential for hepatic fibrosis from MTX is a concern. CYA appears effective in the acute management of severe ulcerative colitis. CYA has not proven useful in the long-term management of Crohn's disease. Potentially serious side-effects include hypertension and renal insufficiency. The cytokine antagonist, anti-tumor-necrosis-factor-alpha antibody, and the anti-inflammatory cytokine, interleukin 10, appear promising for the treatment of Crohn's disease.