Retinoic acid attenuates ileitis by restoring the balance between T-helper 17 and T regulatory cells.

BACKGROUND & AIMS: Retinoic acid (RA), produced by intestinal epithelial cells (IECs) and dendritic cells (DCs) promotes the induction of regulatory T cells (Tregs) and decreases the induction of T-helper (Th)17 cells. METHODS: We studied the roles of RA in mice that overproduce tumor necrosis factor (TNF) and develop chronic ileitis (TNF_ARE mice). We assessed the frequency and function of CD103+ DCs, Th17 cells, and Tregs by flow cytometry, and we measured expression of cytokines and retinaldehyde dehydrogenase (RALDH) enzymes in ileum samples, DCs, and IECs by real-time polymerase chain reaction. We quantified RA by electrochemical analysis and examined the effect of RA supplementation on TNF-induced ileitis using histologic, coculture, and suppression assays and flow cytometry. RESULTS: Numbers of CD103+ DCs decreased in the inflamed ilea of mice with chronic disease; RA synthetic machinery (RALDH1,2) was down-regulated. Nevertheless, the proportion of CD4+, CD25+, FoxP3+ Tregs increased, indicating an alternate source for RA. IECs responded to reduced levels of RA by up-regulating RALDH3 in vivo and in vitro. Net tissue levels of RA remained lower in TNF+ARE than wild-type mice, indicating that epithelial up-regulation of RALDH3 could not maintain adequate concentrations of RA, probably because of loss of IEC mass. RA supplementation significantly attenuated disease by increasing the number and function of CD103+ DCs and Tregs and reducing Th17 cells. CONCLUSIONS: Reduced levels of RA appear to induce IECs to up-regulate synthesis of RA. RA supplementation attenuates ileitis through its effects on CD103+ DCs, Tregs, and Th17 cells. RA supplementation might offer therapeutic benefit in Crohn's disease.

Lemon grass (Cymbopogon citratus) ameliorates murine spontaneous ileitis by decreasing lymphocyte recruitment to the inflamed intestine.

OBJECTIVE: Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis. METHODS: Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks. RESULTS: Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells. CONCLUSION: Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

Omega-3 polyunsaturated fatty acids ameliorate the severity of ileitis in the senescence accelerated mice (SAM)P1/Yit mice model.

Clinical studies using omega-3 polyunsaturated fatty acids (omega3-PUFA) to Crohn's disease (CD) are conflicting. Beneficial effects of dietary omega3-PUFA intake in various experimental inflammatory bowel disease (IBD) models have been reported. However, animal models of large intestinal inflammation have been used in all previous studies, and the effect of omega3 fat in an animal model of small intestinal inflammation has not been reported. We hypothesized that the effects of omega3 fat are different between large and small intestine. The aim of this study was to determine whether the direct effect of omega3 fat is beneficial for small intestinal inflammation. Senescence accelerated mice (SAM)P1/Yit mice showed remarkable inflammation of the terminal ileum spontaneously. The numbers of F4/80-positive monocyte-macrophage cells as well as beta7-integrin-positive lymphocytes in the intestinal mucosa were increased significantly compared with those in the control mice (AKR-J mice). The area of mucosal addressin cell adhesion molecule-1 (MAdCAM-1)-positive vessels was also increased. The degree of expression levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6 and interferon (IFN)-gamma mRNA were increased significantly compared with those in the control mice. The feeding of two different kinds of omega3 fat (fish-oil-rich and perilla-oil-rich diets) for 16 weeks to SAMP1/Yit mice ameliorated inflammation of the terminal ileum significantly. In both the omega3-fat-rich diet groups, enhanced infiltration of F4/80-positive monocytes/macrophages in intestinal mucosa of SAMP1/Yit mice cells and the increased levels of MCP-1, IL-6 and IFN-gamma mRNA expression were ameliorated significantly compared with those in the control diet group. The results suggest that omega3 fat is beneficial for small intestinal inflammation by inhibition of monocyte recruitment to inflamed intestinal mucosa.

Colonic Crohn's disease in children does not respond well to treatment with enteral nutrition if the ileum is not involved.

Data supporting a response to treatment with exclusive enteral nutrition in pediatric colonic Crohn's disease are few. We examined clinical and biochemical responses of ileal, colonic, and ileocolonic Crohn's disease and assessed the endoscopic and histological colonic mucosal response in the colonic and ileocolonic groups. We prospectively enrolled 65 children (age: 8-17 years) with acute intestinal Crohn's disease (Pediatric Crohn's Disease Activity Index [PCDAI] >20). After ileocolonoscopy, gastroscopy, and a barium meal and follow-through, they were distributed into three groups (ileal, n = 12, ileocolonic, n = 39; and colonic, n = 14). All patients received exclusive polymeric feed as treatment, with a repeat endoscopy at completion of treatment. At enrollment the ileal group had significantly less severe disease (P = 0.05) compared to the colonic and ileocolonic groups. However, the colonic disease group showed the least fall in PCDAI scores at completion of treatment with enteral nutrition (P = 0.03), with the lowest remission rate (50%, vs 82.1% in the ileocolonic and 91.7% in the ileal group [chi2 test, P = 0.021]). Endoscopic and histologic colonic mucosal assessment showed a post-treatment improvement in the ileocolonic (P < or = 0.01) but not in the colonic disease group (P = ns). Children with disease in the colon respond better to enteral nutrition if the ileum is also involved. This may be due to different underlying inflammatory mechanisms. Detailed pretreatment assessment in studies of Crohn's disease according to disease distribution with appropriate individualized tailoring of treatment may be important in this regard.

[MRI with oral filling in patients with chronic inflammatory bowel diseases]. / MRT mit oraler Dünndarmdistension bei entzündlichen Darmerkrankungen.

AIM: Evaluation of mannitol-MRI in patients with suspected or established Crohn's disease (CD). METHODS. 75 patients with suspected or established Crohn's disease were included. 1.5 l of mannitol-solution were administered orally within 1 h before imaging. A rectal filling was also employed. Butylscopolamin was applied i.v. Native-sequences were acquired. T1w sequences (axial, coronal) were acquired before and after (fs-T1-w-BH) i.v.Gd-DTPA. Additionally a dynamic CM-study was performed. RESULTS: In 45% of the examinations good image quality was achieved. In 28% opacification of the terminal ileum was insufficient. However, diagnostic assessment was possible. Motion artifacts due to breathing were rare, artifacts due to peristalsis were noted in 16% of the examinations. Alterations indicative to CD were found in 69% of the patients. The SI-increase of the thickened bowel-wall was significantly higher than the increase of not thickened wall (117 vs.75%; p = 0,001 in t-test). We detected stenoses in 56%, fistulas in 23% and an abscess in one patient. CONCLUSION: Mannitol-MRI is a valuable method in the diagnostic work-up of inflammatory bowel disease. Improvement of distal distension should be attempted, because of the good acceptance of the patients and high diagnostical value.

Acetyl-11-keto-beta-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuates experimental ileitis.

The gum resin extract from Boswellia serrata (H15), an herbal product, was recently shown to have positive therapeutic effects in inflammatory bowel disease (IBD). However, the mechanisms and constituents responsible for these effects are poorly understood. This study examined the effect of the Boswellia extract and its single constituent acetyl-11-keto-beta-boswellic acid (AKBA) on leukocyte-endothelial cell interactions in an experimental model of IBD. Ileitis was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) in Sprague-Dawley rats 24 h apart. Rats also received oral treatment with the Boswellia extract (H15) or AKBA at two different doses (low and high) equivalent to recommendations in human disease over 2 days. Controls received only the carriers NaHCO3 (subcutaneously) and tylose (orally). Effects of treatment were assessed by intravital microscopy in ileal submucosal venules for changes in the number of rolling and adherent leukocytes and by macroscopic and histological scoring. Increased leukocyte-endothelial cell adhesive interactions and severe tissue injury accompanied indomethacin-induced ileitis. Treatment with the Boswellia extract or AKBA resulted in a dose-dependent decrease in rolling (up to 90%) and adherent (up to 98%) leukocytes. High-dose Boswellia extract as well as both low- and high-dose AKBA significantly attenuated tissue injury scores. Oral therapy with the Boswellia extract or AKBA significantly reduces macroscopic and microcirculatory inflammatory features normally associated with indomethacin administration, indicating that the anti-inflammatory actions of the Boswellia extract in IBD may be due in part to boswellic acids such as AKBA.

Crohn's disease of aphthous type: serial changes in intestinal lesions.

In Crohn's disease (CD), aphthous lesions are regarded as possible precursors of typical intestinal involvement. To determine the natural course of intestinal lesions in CD of aphthous type, the clinical course of 10 patients was retrospectively investigated during a period ranging from 6 to 16 years after diagnosis. The criterion for inclusion was confirmed aphthous lesions within the gastrointestinal tract with histologically verified epithelioid granuloma. The degrees of aphthous lesions in the small intestine and the colon were graded by small bowel radiography, barium enema examination and colonoscopy. Five patients developed typical CD during a period ranging from 0.8-3.3 years. The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient. Typical small intestinal CD occurred in four of seven patients with marked aphthous lesions of the small intestine, whereas colonic CD occurred in two of eight patients with such aphthous lesions of the colon. These findings suggest that CD of aphthous type is not necessarily a precursor of clinically overt disease. This may especially be the case for colonic aphthous lesions.

Regional variation in the histological appearance of the small and large intestine of the rat following acute and chronic administration of Melo's Conquer Mixture.

The effect of acute and chronic administration of various doses of Melo's Conquer Mixture (MCM) on the histological appearance of the small and large intestine was investigated in albino Wistar rats. Obtained results show that at recommended therapeutic dose, MCM is able to evoke an acute inflammatory response, with infiltration of the mucosa and submucosa by neutrophils, lymphocytes and eosinophils. In addition, there was submucosal lymphoid follicle hyperplasia and increased mucus secreting cells. The severity of these changes were dependent more on prolonged administration than dose. These findings suggest strongly that MCM is a potential toxic agent. We therefore recommend further chemical analysis to identify the possible toxic agent(s) in this mixture.

Hyperthermia prevents functional, histological and biochemical abnormalities induced during ileitis.

Inflammatory bowel disease is associated with altered intestinal motility and epithelial damage. Hyperthermia induces heat shock protein expression, components of a basic cellular defence mechanism, and consequently prevents ischaemic damage. Here we investigate whether hyperthermia may prevent altered smooth muscle function as well as underlying inflammation in a model of inflammatory bowel disease. Ileal heat shock protein expression was induced in rats by hyperthermic shock (41.5 degrees C; 5 min). Two hours after heating or sham treatment, ileitis was evoked by TNBS. Ileal samples were taken 4 h later to determine the contractile response of circular muscle strips, and to measure heat shock protein expression, LTB4 generation and damage/inflammation. Ileitis was associated with an increase in the contractile response of circular muscle to substance P but not neurokinin A or nerve stimulation. Hyperthermia induced heat shock protein expression and also prevented this functional change as well as TNBS-induced LTB4 production, subsequent infiltration of neutrophils and epithelial damage. Thus, intestinal inflammation is associated with alterations in tachykinergic control of smooth muscle as well as inflammatory changes. Hyperthermia prevents these changes and induces heat shock protein expression. Pharmacological induction of these proteins may offer a novel clinical strategy in treating both of these aspects of disease.

Computed tomography of bowel wall in patients with Crohn's disease: relationship of inflammatory activity to biological indices.

Bowel wall thickening in Crohn's disease can be demonstrated by Computed Tomography. The aim of this investigation was to correlate different patterns of bowel wall thickening, detected with Computed Tomography, with serological parameters of activity of Crohn's disease. Thirty-eight patients (24 males, 14 females, aged 21 to 62 years) were studied. Patients were divided into 3 groups according to Computed Tomography appearance of bowel wall: 1) homogeneous symmetrical thickening of wall; 2) bowel showing a layer of submucosal low attenuation; 3) scarred narrowing of wall producing stenosis. A patient was considered to have biochemically active disease if at least 2 of the following parameters were abnormal: ESR, C-reactive protein, seromucoids, serum albumin, serum alpha-2 globulin. The first group comprised 20 patients (16 active disease, 4 inactive) and the second group 13 (all inactive); the 2 groups showed a significant difference (Fisher exact test: p < 0.0005) in biological activity. Since only 5 patients belonged to the third group (3 active, 2 inactive disease), no definite conclusion can be drawn on the possible correlation between this Computed Tomography pattern and activity of disease. Results shows a correlation between Computed Tomography patterns of bowel wall disease and biochemical activity of Crohn's disease.

Anal canal inflammation after ileal pouch-anal anastomosis. The need for treatment.

UNLABELLED: One technique used during restorative proctocolectomy to prevent loss of continence involves preservation of the anal canal. This technique retains a small amount of colonic mucosa and transitional mucosa that may become inflamed or develop dysplastic or neoplastic changes. PURPOSE: This study was designed to determine the presence and severity of anal canal inflammation and the need for treatment. METHOD: Records of 217 patients with mucosal ulcerative colitis who underwent restorative proctocolectomy with a stapled ileal pouch-anal anastomosis without anal mucosectomy from 1987 through 1990 were retrospectively reviewed. RESULTS: Anal canal inflammation was evident on both endoscopy and biopsy in 48 patients (22.11 percent); 18 patients (8.29 percent) had a normal ileal pouch (9 had symptoms; 5 required topical treatment), and 30 patients (13.82 percent) had associated ileal pouch inflammation (23 with symptoms requiring systemic treatment because of pouchitis; 10 patients had concomitant topical treatment). CONCLUSION: Symptomatic inflammation of the retained mucosa occurred in 32 (14.7 percent) patients. Nine (4.1 percent) patients had inflammation of the anal canal alone, and 23 (10.6 percent) had pouchitis in addition. The need for treatment occurred in 28 (12.9 percent) of the total ((2.3 percent) patients with anal canal inflammation and 23 (10.6 percent) with anal canal inflammation plus pouchitis).

[A case of esophageal carcinoma complicated by Crohn's disease].

A case of an esophageal cancer complicated by Crohn's disease is reported. A 76-year-old female was admitted to the Nara National Hospital with symptoms of melena and dysphagia. An esophageal X-ray study revealed a circular, stenotic lesion at the lower intra-thoracic esophagus. Histological examination of a specimen confirmed a moderately differentiated squamous cell carcinoma. A barium enema was then given which showed an irregular stenotic lesion, 28 cm in length, at the terminus of the ileum. Thus, an esophageal blind resection and a resection of the terminal portion of the ileum was jointly performed. A histological examination of the resected ileum confirmed Crohn's disease.

[Radiological assessment of Crohn disease]. / Bilancio radiologico della malattia di Crohn.

Fifty-eight consecutive cases of patients affected by Crohn's disease, with ileum (23/58), colon (10/58) and ileo-colic (25/58) involvement were studied. A good overall sensitivity was reached by the radiological procedures employed (barium meal, barium enema, enteroclysis). Enteroclysis is proposed as a second-step method for the study of ileum involvement, because it provides a quite precise assessment of disease stage and extent. Some criteria for a rational use of current radiological procedures in the follow-up of both surgically and medically treated patients are proposed. Moreover it is suggested that better coordination of anatomo-radiological and clinical aspects could improve the therapeutic approach and prognostic judgement in such cases.

Crohn's disease--a diagnostic rarity in Singapore.

Nine cases of Crohn's disease from the Department of Medicine, Singapore General Hospital were collected over a duration of 9 years (1978-1986). Male (5): Female (4) ratio was nearly equal. Predominantly young people (mean age 30.5 year, range 12-59 year) from all races in Singapore were affected. Presentation could be acute (1), subacute (2), or chronic (6). The commonest symptoms were abdominal pain (8) diarrhoea (6) and weight loss (6). Three patients had a palpable right iliac fossa mass, 3 had definite malabsorption from ileal disease and 1 had perianal involvement leading to an anal stricture. The only extraintestinal manifestations of disease were clubbing and sacroiliatis. Haematological (haemoglobin, total white count, erythrocyte sedimentation rate) and biochemical (albumin) parameters generally reflected the degree of activity and chronicity of disease prior to presentation. The diagnosis and assessment of disease sites were based on a combination of radiological, endoscopic, operative and histological criteria. Ileal disease (4) per se was commonest followed by ileocolic disease (3) and colonic disease (2). Medical treatment consisted of sulphasalazine +/- steroids in all patients. Azathioprine and metronidazole were used for steroid sparing and perianal disease respectively. Laparotomy was performed in 2 patients. Six patients were well with infrequent (less than or equal to 2 times/year) or no relapses during follow up. Of the remaining three, 2 had either chronically active disease or frequent relapses (greater than 2 times/year) and one severe recurrent disease despite repeated gut resection.

[The extent of Crohn's disease. Radiological measurements. Correlation with surgical findings]. / La estensione dell'enterite di Crohn. Misurazione radiologica. Correlazione con i reperti chirurgici.

Twenty-three patients with small intestinal Crohn's disease were studied by barium-methylcellulose infusion. All patients underwent surgery within 1-24 months (average 7 months). The extent of the lesions and the small bowel length were radiologically evaluated by means of a map measurer. The same measurements were performed at surgery. Radiological and surgical data concerning the extent of enteritis were statistically correlated (r = 0.7). The correlation between radiological and surgical measurements of total small bowel length was not significant.