Smoking and nicotine in inflammatory bowel disease: good or bad for cytokines?

Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis and Crohn''s disease respectively. Transdermal application of nicotine had similar effects in ulcerative colitis and therefore was considered to be an effective basic drug which could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid resistant ulcerative colitis. In this communication the short-term use of nicotine in ulcerative colitis is reviewed.     

Adhesive Escherichia coli in inflammatory bowel disease and infective diarrhoea.

The clinical features of ulcerative colitis and Crohn''s disease are similar to those of infections of the bowel, although their cause is uncertain. Many bacteria that cause intestinal diseases adhere to the gut mucosa, and adhesion of pathogenic Escherichia coli is resistant to D-mannose. The adhesive properties of isolates of E coli were assessed by assay of adhesion to buccal epithelial cells with mannose added. The isolates were obtained from patients with inflammatory bowel diseases (50 with a relapse of ulcerative colitis, nine with ulcerative colitis in remission, 13 with Crohn''s disease, and 11 with infectious diarrhoea not due to E coli) and 22 controls. The median index of adhesion to buccal epithelial cells (the proportion of cells with more than 50 adherent bacteria) for E coli from patients with ulcerative colitis in relapse was significantly higher (43%) than that for controls (5%) and patients with infectious diarrhoea (14%). The index was not significantly different among isolates from patients with ulcerative colitis in relapse, Crohn''s disease (53%), and ulcerative colitis in remission (30%). If an index of adhesion of greater than 25% is taken as indicating an adhesive strain 86% of isolates of E coli from patients with inflammatory bowel disease were adhesive compared with 27% from patients with infective diarrhoea and none from controls. The adhesive properties of the isolates from patients with inflammatory bowel disease were similar to those of pathogenic intestinal E coli, raising the possibility that they may have a role in the pathogenesis of the condition; the smaller proportion of adhesive isolates in patients with infective diarrhoea due to other bacteria suggests that the organism may be of primary importance rather than arising secondarily.     

Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis.

OBJECTIVE--To investigate the mode of inheritance of ulcerative colitis and Crohn''s disease by complex segregation analysis. DESIGN--Cross sectional population based survey of familial occurrence of chronic inflammatory bowel disease. SETTING--Population of the Copenhagen county in 1987. SUBJECTS--662 patients in whom inflammatory bowel disease had been diagnosed before 1979, of whom 637 (96%) provided adequate information. Of 504 patients with ulcerative colitis, 54 had 77 relatives with ulcerative colitis and of 133 patients with Crohn''s disease, five had seven relatives with Crohn''s disease. MAIN OUTCOME MEASURES--Patterns of segregation of either disease as assessed by complex segregation analysis performed with the computer program POINTER. RESULTS--The analysis suggested that a major dominant gene with a penetrance of 0.20-0.26 is present in 9-13% of adult patients with ulcerative colitis. The analysis did not allow for other components in the familial aggregation. For Crohn''s disease the best fitting model included a major recessive gene with complete penetrance, for which 7% of the patients are homozygous. However, this model was not significantly different from a multifactorial model. CONCLUSIONS--The segregation pattern indicates that a major dominant gene has a role in ulcerative colitis, and suggests that a major recessive gene has a role in Crohn''s disease.     

Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn''s disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn''s disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn''s disease, clinical improvement as assessed by the Crohn''s disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment.     

In-vitro Inhibition of Leucocyte Migration in Crohn's Disease by a Sarcoid Spleen Suspension

A Kveim suspension has been shown to inhibit the migration of leucocytes in vitro from 12 out of 18 patients with Crohn''s disease but to have no comparable effect on leucocytes from patients with ulcerative colitis or from a group of patients with other diseases. These findings provide further evidence of cross-reactivity or of a possible aetiological link between Crohn''s disease and sarcoidosis and suggest a further immunological distinction between Crohn''s disease and ulcerative colitis.     

Association of IRGM Gene Mutations with Inflammatory Bowel Disease in the Indian Population

Background

Mutations in the IRGM gene have been associated with Crohn''s disease in several populations but have not been explored in Indian patients with this disease. This study examined the association of IRGM mutations with ulcerative colitis and Crohn''s disease in Indian patients with inflammatory bowel disease.

Methods

The IRGM gene was amplified in four segments and Sanger-sequenced in 101 participants (42 Crohn''s disease, 39 ulcerative colitis, and 20 healthy controls). Ten single nucleotide polymorphisms (SNP) were genotyped in 1200 participants (352 Crohn''s disease, 400 ulcerative colitis, and 448 healthy controls) using Sequenom MassARRAY iPLEX. Disease associations were evaluated for each of the ten SNPs.

Results

Thirty one mutations were identified in the IRGM gene, of which two had not hitherto been reported (150226250- ss947429272 & 150227858- ss947429273). Ten SNPs (6 from the above and 4 from the literature) were evaluated. Significant associations with Crohn''s disease were noted with the T allele of rs1000113 (OR 1.46, 95% CI 1.12–1.90), T allele of rs9637876 (OR 1.25, 95% CI 1.005–1.561) and C allele of rs 13361189 (OR 1.33, 95% CI 1.07–1.669). Two SNPs – rs11747270 and rs180802994 – did not exhibit Hardy-Weinberg equilibrium but were associated with both Crohn''s disease and ulcerative colitis in this population. The remaining SNPs did not show significant associations with either Crohn''s disease or ulcerative colitis.

Conclusions

Association of IRGM gene SNPs with Crohn''s disease is reported for the first time in Indian patients. We also report, for the first time, an association of rs 9637876 in the IRGM gene with Crohn''s disease.     

Detection of inflammatory bowel disease in adults and children: evaluation of a new isotopic technique.

The distribution of radioactivity after the oral administration of sucralfate labelled with technetium-99m was studied in 33 patients with Crohn''s disease (13 adults, 20 children), 10 with ulcerative colitis (four adults), and 29 controls (23 with upper intestinal disease, four irritable bowel, one hypolactasia, and one malrotation of the gut). Positive scans were obtained in all patients with ulcerative colitis and 29 of 31 with active Crohn''s disease. The scans of two patients with inactive Crohn''s disease were negative. There were two false negative scans in patients with Crohn''s colitis and one false positive scan. Overall, sensitivity was 95% and specificity 97%. Comparison with radiology in 39 patients showed similar distribution of disease in 24 and more extensive disease in 12. The scan was inexpensive, simple to perform, well tolerated, allowed small and large bowel to be visualised simultaneously, and used a lower dose of radiation than barium studies. It may prove useful as a screening test for inflammatory bowel disease and in the serial assessment of disease activity.     

Finger clubbing in inflammatory bowel disease: its prevalence and pathogenesis.

Finger clubbing, measured objectively by using the hyponychial angle, was present in 75 out of 200 (38%) patients with Crohn''s disease, 15 out of 103 (15%) with ulcerative colitis, and two out of 24 (8%) with proctitis. In Crohn''s disease and ulcerative colitis the hyponychial angle was significantly correlated with both disease activity and the extent of fibrosis in the resected specimens from 47 surgically treated patients. The prevalence of finger clubbing in patients with macroscopic disease within the area of the gut innervated by the vagus nerve was significantly higher than that in patients in whom the disease was confined to the distal colon and rectum. Finger clubbing in patients with Crohn''s disease tended to regress after resection of macroscopic disease. It is concluded that finger clubbing is significantly commoner in Crohn''s disease than ulcerative colitis. The focal stimuli for finger clubbing include mucosal inflammatory change and fibrosis mediated by the vagus and possibly other autonomic pathways acting as the afferent arc of a finger-clubbing reflex.     

Colonic Crohn's disease and use of oral contraception.

The prevalence of use of oral contraception before the onset of disease was established in 100 consecutive women attending follow up clinics for inflammatory bowel disease. A significant excess of women with Crohn''s disease confined to the colon had taken oral contraceptives in the year before developing symptoms (10/16 (63%] compared with women with small-intestinal Crohn''s disease (12/49 (24%); p less than 0.02) and women with ulcerative colitis (3/35 (9%); p less than 0.0005). When the patient groups were matched for age and year of onset of disease usage of oral contraception before the onset of disease was still more common among women with isolated colonic Crohn''s disease (9/12, 75%) than among those with ulcerative colitis (2/12 (17%); p less than 0.02) and was also more common than would be expected from reported figures for oral contraception in England and Wales (31.4% of women aged under 41; p less than 0.005). A survey of current patient records showed that isolated colonic disease was at least twice as common among women with Crohn''s disease (63/218, 29%) compared with men (25/181, 14%; p less than 0.001). These data support the suggestion made previously that oral contraceptives may predispose to a colitis that resembles colonic Crohn''s disease.     

The use of oral topically acting glucocorticosteroids in the treatment of inflammatory bowel disease.

Glucocorticosteroids are the mainstay of treatment of active Crohn''s disease and ulcerative colitis. These drugs however carry important cosmetic short-term side effects and when used long-term they induce severe irreversible complications. Topically acting glucocorticosteroids, especially budesonide, have been designed to achieve local effect at the site of inflammation without systemic effects of the drug. The first results of clinical trials are promising and budesonide has been shown to have an improved safety with almost comparable efficacy in comparison with prednisolone. The optimal enema dose seems to be 2 mg/100 ml at night whereas 9 mg o.m. is the optimal dose to treat ileal or right ileocolonic Crohn''s disease. Topically acting GCS, like standard GCS are not effective for maintenance of remission of Crohn''s disease or recurrence prevention after resection of the involved Crohn''s segment.     

Juvenile onset inflammatory bowel disease: height and body mass index in adult life.

OBJECTIVE--To establish the frequency of permanent growth failure in juvenile onset inflammatory bowel disease. DESIGN--Measurement of height and weight in a geographically based cohort at a mean of 14 (range 5.2-29.5) years after diagnosis. Comparison with data from surveys of British adults in 1980 and 1987. SETTING--NHS hospitals throughout Scotland. SUBJECTS--105 Children admitted to hospital during 1968-83 who fulfilled diagnostic criteria for Crohn''s disease or ulcerative colitis and lived in specified regions. 87 were aged over 18 and living in Britain at follow up. MAIN OUTCOME MEASURES--Height, weight, body mass index, and sexual maturity. RESULTS--All patients were sexually mature. 67 of the 70 patients examined were of normal height, and three women with Crohn''s disease were abnormally short. Weight and body mass index were normal in all patients with ulcerative colitis. Patients with Crohn''s disease had significantly lower weight than those with ulcerative colitis (men 66.8 (9.5) kg v 78.4 (13.8) kg, P = 0.04; women 51.5 (8.2) kg v 63.0 (12.1) kg, P < 0.02) irrespective of disease activity. Body mass index was also significantly lower than the normal distribution (P < 0.01). Growth retardation was not mentioned as a problem for any of the 17 patients interviewed only by telephone. CONCLUSIONS--Despite growth retardation in the teenage years most young people with inflammatory bowel disease will eventually achieve normal height. Reasons for lower weight in patients with Crohn''s disease remain to be established.     

Raised titres of anti-klebsiella IgA in ankylosing spondylitis,rheumatoid arthritis,and inflammatory bowel disease

Serum titres of IgA are raised in ankylosing spondylitis and increased titres of antibodies to klebsiella have also been reported. The humoral response was investigated in ankylosing spondylitis and other inflammatory disorders. IgA antibodies to klebsiella pneumoniae K43 were measured in patients with ankylosing spondylitis, Crohn''s disease, ulcerative colitis, and rheumatoid arthritis and in controls. Significantly raised median titres of anti-klebsiella IgA, measured as optical density at 405 nm with an enzyme linked immunosorbent assay (ELISA), were seen among the patients with ankylosing spondylitis (0·7), Crohn''s disease (0·8), rheumatoid arthritis (0·6), and ulcerative colitis (0·8) compared with controls (0·4). Activity of disease in ankylosing spondylitis and titres of anti-klebsiella IgA were not correlated. In contrast, titres of anti-klebsiella IgM were significantly lower in patients with ankylosing spondylitis and ulcerative colitis.The increase in the titres of anti-klebsiella IgA may be due to increased permeability of the gut to bacterial antigens, leading to an increased IgA response in the gut mucosa and permitting the release of IgA into the circulation. As the increased antibody titres were seen in Crohn''s disease and rheumatoid arthritis as well as in ankylosing spondylitis the response may be non-specific, occurring because of possible underlying inflammatory bowel disease in these conditions.     

Medical treatment of inflammatory bowel disease: new therapies,new drugs.

Ulcerative colitis, ulcerative proctitis and Crohn''s disease are chronic inflammatory conditions that affect the gastrointestinal tract. Conventional treatment has stressed the role of anti-inflammatory agents to suppress the inflammatory response. New compounds that can deliver 5-aminosalicylic acid to the colon have recently been released in Canada. Metronidazole and azathioprine may also be of benefit in Crohn''s disease. Therapy with cyclosporine and clonidine should be based on the results of further clinical trials. The use of nutritional support as primary therapy in Crohn''s disease appears promising. At present, both pharmacologic and nutritional therapies should be considered in the treatment of inflammatory bowel disease.     

An antibiotic-responsive mouse model of fulminant ulcerative colitis

Background

The constellation of human inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn''s disease, which both display a wide spectrum in the severity of pathology. One theory is that multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. However, experimental proof of this concept is still lacking. Several genetic mouse models that each recapitulate some aspects of human IBD have utilized a single gene defect to induce colitis. However, none have produced pathology clearly distinguishable as either ulcerative colitis or Crohn''s disease, in part because none of them reproduce the most severe forms of disease that are observed in human patients. This lack of severe IBD models has posed a challenge for research into pathogenic mechanisms and development of new treatments. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn''s disease.

Methods and Findings

We generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of proinflammatory cytokines resulting in large part from T cell activation. The disease process could be significantly ameliorated by administration of antibodies against IFNγ and TNFα and was completely inhibited by a combination of broad-spectrum antibiotics.

Conclusions

Here, we develop to our knowledge the first mouse model of fulminant ulcerative colitis by combining multiple genetic hits in immune regulation and demonstrate that the resulting disease is sensitive to both anticytokine therapy and broad-spectrum antibiotics. These findings indicated the IL-10 and TGFβ pathways synergize to inhibit microbially induced production of proinflammatory cytokines, including IFNγ and TNFα, which are known to play a role in the pathogenesis of human ulcerative colitis. Our findings also provide evidence that broad-spectrum antibiotics may have an application in the treatment of patients with ulcerative colitis. This model system will be useful in the future to explore the microbial factors that induce immune activation and characterize how these interactions produce disease.     

Indium-111 autologous leucocyte scanning: comparison with radiology for imaging the colon in inflammatory bowel disease.

Indium-111 autologous leucocyte scanning was compared with barium enema for assessing the extent of colonic disease in Crohn''s colitis and ulcerative colitis. Scanning was shown to be as accurate as conventional radiology in colitis, reliably distinguishing active from inactive disease. The results suggest that 111In-leucocyte scanning is an accurate, non-invasive, alternative technique for imaging the extent of disease in colitis.     

Smoking and Crohn's disease.

In a case-control study 82 patients with Crohn''s disease and matched controls drawn from general practice lists were questioned about their smoking habits. Patients with Crohn''s disease were significantly more likely to be smokers than the controls, and the association was stronger for smoking habit before the onset of the disease than for current smoking habit, the relative risks for smokers compared with non-smokers being 4.8 and 3.5 respectively. Taken in conjunction with earlier data showing an association between non-smoking and ulcerative colitis, these results suggest that smoking habit may be an important determinant of the type of inflammatory bowel disease that develops in predisposed subjects.     

Inflammatory bowel disease in the West Indies.

Inflammatory bowel disease is generally assumed to be rare among negroes and Indians. Over 10 years 34 cases of ulcerative colitis and 14 cases of Crohn''s disease were seen in one medical and one surgical unit in Port-of-Spain, Trinidad. Twenty-six patients were Negroes, 18 were Indians, three were of mixed race, and one was Caucasian. In many of these patients the disease was extensive and several of those with Crohn''s disease suffered severe complications. The assumption that inflammatory bowel disease is rare among West Indians of African and Indian origin therefore seems to be wrong.     

Drug therapy: dose-response relationship of oral mesalazine in inflammatory bowel disease.

Mesalazine is widely used in the treatment of inflammatory bowel disease. Little is known about the dose-response relationship and about possible dose related side effects. In ulcerative colitis higher dosages of mesalazine (3 g) are more effective in maintaining a remission than lower dosages (1.5 g). In mild to moderately active ulcerative colitis, studies also indicate that higher dosages might be more effective in inducing remission. Dose-comparing studies in Crohn''s disease are even more sparse, but the available results indicate higher efficacy at higher dose levels. None of the known side effects of mesalazine are clearly dose-related. A pH-dependent release system, however, can cause a sudden release of high doses of mesalazine. Consequent peak levels in serum have been implicated in mesalazine induced nephrotoxicity. In conclusion, despite the current practice of using increasing dosages of mesalazine in inflammatory bowel disease, both efficacy and safety have been established tentatively.     

Crohn's Disease and Pregnancy

This paper reports the outcome of 60 pregnancies in 40 women, all of whom had concomitant Crohn''s disease. Detailed analysis of pregnancy rates in Crohn''s disease supports in outline the hypothesis that some patients with bowel symptoms may be rendered temporarily subfertile by the activity of their bowel complaints. In contrast there is little or no evidence of any adverse effect during pregnancy on mother or child. Most pregnancies went normally to term and, if anything, Crohn''s disease tended to improve during the period of confinement.After delivery, however, over 40% of patients suffered a relapse of Crohn''s disease. Such a situation might well constitute a logical indication for the administration of corticosteroid therapy.     

Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease

Background

We previously showed that activation of the bile salt nuclear receptor Farnesoid X Receptor (FXR) protects against intestinal inflammation in mice. Reciprocally, these inflammatory mediators may decrease FXR activation. We investigated whether FXR activation is repressed in the ileum and colon of inflammatory bowel disease (IBD) patients in remission. Additionally, we evaluated whether genetic variation in FXR is associated with IBD.

Methods

mRNA expression of FXR and FXR target gene SHP was determined in ileal and colonic biopsies of patients with Crohn''s colitis (n = 15) and ulcerative colitis (UC; n = 12), all in clinical remission, and healthy controls (n = 17). Seven common tagging SNPs and two functional SNPs in FXR were genotyped in 2355 Dutch IBD patients (1162 Crohn''s disease (CD) and 1193 UC) and in 853 healthy controls.

Results

mRNA expression of SHP in the ileum is reduced in patients with Crohn''s colitis but not in patients with UC compared to controls. mRNA expression of villus marker Villin was correlated with FXR and SHP in healthy controls, a correlation that was weaker in UC patients and absent in CD patients. None of the SNPs was associated with IBD, UC or CD, nor with clinical subgroups of CD.

Conclusions

FXR activation in the ileum is decreased in patients with Crohn''s colitis. This may be secondary to altered enterohepatic circulation of bile salts or transrepression by inflammatory signals but does not seem to be caused by the studied SNPs in FXR. Increasing FXR activity by synthetic FXR agonists may have benefit in CD patients.