Predicting relapse in Crohn's disease: a biopsychosocial model.

BACKGROUND: Crohn's disease (CD) is a chronic relapsing inflammatory bowel disorder. Both biological and psychosocial factors may modulate the illness experience. AIM: The aim of this study was to identify clinical, biological and psychosocial parameters as predictors of clinical relapse in quiescent CD. METHODS: Patients in medically induced remission were followed prospectively for 1 year, or less if they relapsed. Disease characteristics were determined at baseline. Serum cytokines, anti-Saccharomyces cerevisiae antibodies, C-reactive protein (CRP), erythrocyte sedimentation rate and intestinal permeability were measured every 3 months. Psychological distress, perceived stress, minor life stressors and coping strategies were measured monthly. A time-dependent multivariate Cox regression model determined predictors of time to relapse. RESULTS: 101 patients (60 females, 41 males) were recruited. Fourteen withdrew and 37 relapsed. CRP (HR = 1.5 per 10 mg/l, 95% CI 1.1 to 1.9, p = 0.007), fistulising disease (HR = 3.2, 95% CI, 1.1 to 9.4, p = 0.04), colitis (HR = 3.5 95% CI 1.2 to 9.9, p = 0.02) and the interaction between perceived stress and avoidance coping (HR = 7.0 per 5 unit increase for both scales, 95% CI 2.3 to 21.8, p = 0.003) were predictors of earlier relapse. CONCLUSIONS: In quiescent CD, a higher CRP, fistulising disease behaviour and disease confined to the colon were independent predictors of relapse. Moreover, patients under conditions of low stress and who scored low on avoidance coping (ie, did not engage in social diversion or distraction) were least likely to relapse. This study supports a biopsychosocial model of CD exacerbation.

The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study.

BACKGROUND: Lifelong adherence to a strict gluten-free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT-1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae. AIM: To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten. METHODS: An in-patient, double-blind, randomized placebo-controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy. RESULTS: Compared to placebo, no increase in adverse events occurred in patients exposed to AT-1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT-1001 group. Interferon-gamma levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT-1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT-1001 group (P = 0.018). CONCLUSIONS: AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.

Transepithelial leak in Barrett's esophagus.

Using orally administered sucrose as a probe of gastrointestinal permeability, this study focused on determining whether Barrett's metaplasia exhibits a paracellular transepithelial leak to small nonelectrolytes. Subjects in five separate classes (nonendoscoped, asymptomatic controls; endoscoped, asymptomatic controls; gastroesophageal reflux disease without mucosal complications; grossly visible esophagitis; and Barrett's esophagus) consumed a sucrose solution at bedtime and collected all overnight urine. Urine volume was measured and sucrose concentration was determined by high-performance liquid chromatography. Patients with Barrett's were observed to exhibit a transepithelial leak to sucrose whose mean value was threefold greater than that seen in healthy control subjects or patients with reflux but without any mucosal defect. A parallel study of claudin tight junction proteins in endoscopy biopsy samples showed that whereas Barrett's metaplasia contains dramatically more claudin-2 and claudin-3 than is found in normal esophageal mucosa, it is markedly lower in claudins 1 and 5, indicating very different tight junction barriers.

Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia.

Intestinal barrier function was prospectively examined in the course of a clinical trial evaluating the efficacy and safety of lisofylline for reducing cytotoxic therapy-induced intestinal epithelial damage-related infectious morbidity in patients receiving standard remission-induction therapy for acute myeloid leukaemia. The absorption and permeation of oral D-Xylose, lactulose and mannitol were measured weekly from baseline until marrow recovery in adult recipients of idarubicin plus cytarabine for untreated acute myeloid leukaemia. These studies were correlated with non-haematologic chemotherapy-related toxicities reflecting mucosal damage, including nausea, vomiting, stomatitis, diarrhoea, abdominal pain and systemic infection. D-xylose absorption decreased and lactulose:mannitol ratio reflecting intestinal permeability increased from baseline until the second and third week after the beginning of the treatment followed by recovery. These measures correlated with infection rates, nausea, vomiting, diarrhoea and increased blood product utilization. Lisofylline was associated with increased intestinal permeability, nausea, vomiting and infection-related morbidity despite a reduction in the duration of neutropaenia. These surrogates of intestinal barrier function correlated well with clinically important outcomes despite the failure to demonstrate reduced morbidity with lisofylline and represent useful objective outcome measurements for future clinical trials of products for the amelioration of the effects of cytotoxic therapy on the intestinal mucosa.

Antineuronal antibodies in idiopathic achalasia and gastro-oesophageal reflux disease.

BACKGROUND AND AIMS: The precise aetiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. We screened sera from patients with achalasia or gastro-oesophageal reflux disease (GORD) to test for circulating antimyenteric neuronal antibodies. METHODS: Serum was obtained from 45 individuals with achalasia, 16 with GORD, and 22 normal controls. Serum was used in immunohistochemistry to label whole mount preparations of ileum and oesophagus of the guinea pig and mouse. Also, sections of superior cervical and dorsal root ganglia, and spinal cord were examined. RESULTS: Positive immunostaining of the myenteric plexus was detected in significantly more achalasia and GORD samples than control samples (achalasia, p<0.001; GORD, p<0.01), and immunoreactivity was significantly more intense with achalasia and GORD serum samples than controls (achalasia, p<0.01; GORD, p<0.05). There was no correlation between intensity of immunoreactivity and duration of achalasia symptoms. In most cases, achalasia and GORD sera stained all ileal submucosal and myenteric neurones, and oesophageal neurones. Immunostaining was not species specific; however, immunostaining was largely specific for enteric neurones. Western blot analysis failed to reveal specific myenteric neuronal proteins that were labelled by antibodies in achalasia or GORD serum. CONCLUSIONS: These data suggest that antineuronal antibodies are generated in response to tissue damage or some other secondary phenomenon in achalasia and GORD. We conclude that antineuronal antibodies found in the serum of patients with achalasia represent an epiphenomenon and not a causative factor.

Epidermal growth factor improves nutritional outcome in a rat model of short bowel syndrome.

BACKGROUND/PURPOSE: This study investigates the effect of epidermal growth factor (EGF) on nutrient absorption in a rat model of short bowel syndrome (SBS). METHODS: Male juvenile rats underwent either transection (Sham) or ileocecal resection leaving a 20-cm jejunal remnant. Animals underwent follow-up for 10 days, and resected animals were treated with placebo or recombinant human EGF (1-53). Animals were pair fed; in vivo nutrient absorption, intestinal permeability, morphology, and total intestinal DNA and protein content were measured. RESULTS: Resected EGF-treated animals lost significantly less weight than those in the placebo group (-4.2 +/- 3 v -13.7 +/- 6.9%), absorbed significantly more 3-0 methylglucose (76.8 +/- 6.6 v 64.9 +/- 10.1%), and had reduced permeability (lactulose/mannitol ratio, 0.35 +/- 0.19 v 0.60 +/- 0.20; P <.05 for all comparisons). CONCLUSIONS: These findings show that treatment of short bowel syndrome animals with EGF reduced weight loss and improved carbohydrate absorption and intestinal permeability. These findings suggest that enteral EGF may be a useful therapy for short bowel syndrome; further studies are indicated.

Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease.

OBJECTIVE: Increased small intestinal permeability has been found in patients with Crohn's disease and in a proportion of their healthy relatives. This may reflect a shared environment or shared genes. The finding of abnormal permeability in the healthy spouses of patients would favor an environmental cause for this observation. METHODS: The healthy spouses of patients with Crohn's disease attending three gastroenterology clinics were invited to participate. Eligible subjects consumed a 350-ml solution containing lactulose, mannitol, and sucrose before bedtime. All overnight urine was collected, assayed by high performance liquid chromatography, and the ratio of fractional excretion of lactulose to mannitol was calculated as an index of permeability. The results were compared with those of a previously determined control group. RESULTS: Sixty spouses completed the study. Increased permeability was present in eight (13.3%, 95% CI = 6.0-24.6%). The presence of increased permeability was not related to age, gender, duration of cohabitation, alcohol use, nonsteroidal anti-inflammatory drug use or to disease activity in the patient with Crohn's disease. There was a nonsignificant trend for abnormal permeability to occur in those spouses cohabiting with the patient with Crohn's disease at the time of disease diagnosis (p = 0.128). CONCLUSIONS: Small intestinal permeability is increased in a proportion of healthy spouses of patients with Crohn's disease. The presence of abnormal permeability studies in patients with Crohn's disease and a proportion of their healthy close contacts suggests that this phenomenon is caused by environmental factors.

Giant cell myocarditis, in a patient with Crohn's disease, treated with etanercept--a tumour necrosis factor-alpha antagonist.

Cardiac disease in association with inflammatory bowel disease (IBD) is uncommon. Reports include pericarditis, pericardial effusion, myocarditis, myocardial infarction, endocarditis and arrythmias. Myocardial inflammation related to IBD may be due to a drug hypersensitivity reaction or micronutrient deficiency, or may be secondary to the underlying IBD as an extraintestinal manifestation. In this setting, myocarditis usually presents as congestive heart failure and/or refractory arrhythmia. Prognosis varies among reported cases, including complete recovery, remission with recurrence and fatal disease. Treatment of myocarditis has included aminosalicylates and immunosuppressive medications. Recently, newer therapies for IBD have been developed, such as tumour necrosis factor-alpha (TNF-a) antagonists. The present report describes a case of a 46-year-old man with clinical and endoscopic evidence of moderately active colonic Crohn's disease who developed congestive heart failure due to giant cell myocarditis. Little clinical improvement occurred with immunosuppressive therapy. Only after the addition of etanercept, a TNF-a p75 receptor antagonist, did complete clinical resolution occur. These authors conclude that the use of TNF-a antagonists may be considered in the treatment of life-threatening extraintestinal manifestations of inflammatory bowel disease.

Oxidative and drug-induced alterations in brush border membrane hemileaflet fluidity, functional consequences for glucose transport.

Oxidation of biological membranes has been suggested as a major pathological process in a variety of disease states including intestinal ischemia and inflammatory bowel disease. Previous studies on the small intestinal brush border membrane have shown that part of the decrease in the activity of the Na(+)-dependent glucose transporter (SGLT1) observed after oxidation could be secondary to the derangement in membrane fluidity that accompanied oxidative damage. The present study examined the relationship between oxidative-induced hemileaflet fluidity alterations and the resultant change in Na(+)-dependent glucose transport activity. To address this issue, in vitro oxidation of guinea pig brush border membrane vesicles was induced by incubation of the vesicles with ferrous sulfate and ascorbate. We found that oxidation decreased the fluidity of both the outer and inner hemileaflets, the decrease being greater in the outer leaflet. Moreover, the preferential alteration in hemileaflet fluidity was accompanied by a decrease in glucose transport. However, when membrane perturbing agents such as hexanol and A(2)C were used to restore membrane fluidity to levels comparable to controls, rates of glucose transport could not be interpreted in terms of variation of bulk membrane fluidity or variation in fluidity of any specific membrane leaflet. On the basis of these experiments, we propose that previous studies that reported coincidental alteration in membrane fluidity and glucose transport cannot be interpreted on the basis of bulk fluidity or hemileaflet fluidity.

Prevalence of IgA-antiendomysial antibody in asymptomatic low bone mineral density.

OBJECTIVE: Celiac disease (CD) is a relatively common gastrointestinal disorder that can be asymptomatic. However, even among asymptomatic patients a long-term reduction in bone mineral density (BMD) is found. Excellent noninvasive screening tests for CD are now available. Studies using older screening techniques have suggested a 10-fold increased prevalence of CD among patients with low BMD, but this has not been confirmed with current testing methodology. We set out to confirm these prevalence estimates using antiendomysial antibody testing. METHODS: A total of 100 consecutive patients referred to our outpatient endocrinology clinic for evaluation of idiopathic low BMD were studied. In addition to the routine evaluation, patients completed a symptom questionnaire and underwent serological testing for the presence of the IgA antiendomysial antibody (EMA). All patients with a positive EMA underwent small bowel biopsy and permeability studies. RESULTS: EMA results were available on 96 patients; 78/96 patients were female and the mean age was 57 yr (range 18-86 yr). Seven of 96 (7.3% [95% CI 2.1-12.5%]) were EMA-positive, but all tests were low titer (< or = 1:20). However, none of the biopsies showed any histopathological features of CD, nor did EMA status correlate with any of the clinical or laboratory features assessed. CONCLUSIONS: Despite a high rate of weakly positive antibody tests, our data do not support an increased prevalence of CD among asymptomatic patients referred for evaluation of low BMD. Without an increase over the background prevalence, the high cost of EMA testing argues against routine use of this test for screening of this population.

On the in vitro vasoactivity of bile acids.

We compared the vasorelaxant action of nine different bile acids and correlated their vasorelaxant activity with their individual indices for hydrophobicity or lipophilicity. Vasorelaxant activity correlated with the relative lipid solubility of bile acids with lipophilic bile acids exhibiting the greatest vasorelaxant activity with modest to no vasorelaxant activity exhibited by hydrophilic bile acids. We also investigated whether bile acid-induced vasorelaxation is mediated by antagonism of a prototypal contractile receptor, the alpha(1)-adrenoceptor, by stimulation of a bile acid surface membrane receptor, by the release of endothelium-derived relaxant factors, by promoting the generation of reactive oxygen species and increasing the extent of lipid peroxidation, or by modifying membrane fluidity. Lipophilic bile acids induce vasorelaxation possibly by antagonizing alpha(1)-adrenoceptors, a phenomenon that manifests itself as a lowering of the affinity of vascular alpha(1)-adrenoceptors. Bile acid-induced vasorelaxation was not dependent upon stimulation of a bile acid surface membrane receptor or the release of endothelium-derived relaxant factors. Lipophilic bile acids can also increase the extent of lipid peroxidation with a subtle reduction in the fluidity of rat vascular smooth muscle membranes not associated with loss of membrane cholesterol or phospholipid. We have concluded that lipophilic bile acids are non-selective vasorelaxants whose mechanism of action is a multifaceted process involving antagonism of contractile surface membrane receptors possibly effected by an increased extent of lipid peroxidation and/or membrane fluidity but occurs independent of the release of endothelial-derived relaxant factors or stimulation of a surface membrane bile acid binding site.

Environmental stress-induced gastrointestinal permeability is mediated by endogenous glucocorticoids in the rat.

BACKGROUND & AIMS: Abnormal presentation of luminal constituents to the mucosal immune system, caused by dysfunction of the intestinal epithelial barrier, is a candidate theory for the cause of Crohn's disease. Increased epithelial permeability is found in subgroups of patients at high risk for the development of Crohn's disease and has been found to precede disease recurrence. Clinical observations have suggested that disease recurrence can follow times of increased psychological stress, although the underlying mechanism remains obscure. We hypothesized that environmental stress increases gastrointestinal permeability. METHODS: We evaluated site-specific gastrointestinal permeability after application of graded levels of stress in rats. RESULTS: Increased epithelial permeability after stress was shown in all regions of the gastrointestinal tract and seemed to be mediated by adrenal corticosteroids. Stress-induced increases in epithelial permeability disappeared after adrenalectomy or pharmacologic blockade of glucocorticoid receptors. Dexamethasone treatment of control animals increased gastrointestinal permeability and mimicked the effects of stress. CONCLUSIONS: Psychological stress may increase gastrointestinal permeability, allowing luminal constituents access to the mucosal immune system. This provides a potential mechanism for the observation of stress-induced disease recurrence in Crohn's disease.

Defining the role of fiberoptic sigmoidoscopy in the investigation of patients presenting with bright red rectal bleeding.

OBJECTIVE: This study was done to determine whether sigmoidoscopy could theoretically constitute sufficient investigation for some patients with bright red rectal bleeding. METHODS: One hundred and forty-three patients undergoing investigative colonoscopy for bright red rectal bleeding and whose source of bleeding was identified were studied. The investigation took place in a large urban hospital over an 11-month period. Data obtained included changes in stool pattern, characteristics of the bleeding, lesions identified, and the distance of the lesion from the anus. RESULTS: In patients younger than 55 yr, all serious lesions except for one malignancy in a patient with massive bleeding lay within 60 cm of the anus and theoretically within reach of the fiberoptic sigmoidoscope. The mixing of red blood with stool was commonly due to distal lesions, especially hemorrhoids. CONCLUSIONS: In young persons with bright red rectal bleeding, fiberoptic sigmoidoscopy may prove to constitute appropriate initial investigation.

Upper gastrointestinal toxicity of alendronate.

OBJECTIVE: Alendronate is rapidly gaining widespread use in the treatment of osteoporosis. However, recent postmarketing surveys and endoscopic studies suggest that its use may be associated with significant predictable esophageal and gastric mucosal toxicity, similar to that of aspirin and nonsteroidal anti-inflammatory drugs. Because treatment of osteoporosis may be needed in as many as 30% of all postmenopausal women, and considering that alendronate could be used in all postmenopausal women as prevention, definition of potential mucosal toxicity is crucial. Our aim was to study the upper gastrointestinal toxicity of alendronate in an age-appropriate female population using a clinically applicable dose (10 mg/day) to determine whether it causes predictable damage in the proximal gastrointestinal mucosa in a fashion similar to that seen with aspirin and nonsteroidal anti-inflammatory drugs. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in 32 healthy female volunteers between the ages of 40 and 65 yr recruited by newspaper advertisement. Endoscopic mucosal abnormalities in the esophagus, stomach, and duodenum both before and after 1 month of treatment were scored and compared using validated endoscopic grading systems. Symptom scores before and after treatment were determined. Noninvasive measurements of gastrointestinal permeability were obtained before, during, and after treatment using sucrose and mannitol/lactulose urinary excretions. RESULTS: Endoscopic scores before and after treatment with alendronate were not significantly different. Similarly, mean symptom scores in the alendronate group did not change significantly after treatment. There were no significant mucosal permeability changes in the stomach or small intestine after treatment. CONCLUSION: Alendronate does not cause predictable esophageal, gastric, or duodenal mucosal damage when used as directed.

Gastric tolerance of high-dose pulse oral prednisone in multiple sclerosis.

BACKGROUND: Prednisone and methylprednisolone are well absorbed orally and have lower treatment costs than IV methylprednisolone, but concern that low-dose corticosteroid may cause increased disease activity and that high oral doses may cause gastric ulceration inhibits use of oral therapy for MS attacks. METHODS: Gastric mucosal injury, detected by measurement of gastric permeability, was examined after five alternate day doses of IV methylprednisolone (1 g) or oral prednisone (1,250 mg) in 21 patients with MS. A triple sugar test solution was consumed at bedtime, and urine was collected overnight. Urine sugar concentrations were determined by high-pressure liquid chromatography. Gastric permeability was expressed as total mg of sucrose excreted. RESULTS: Seventeen patients completed the protocol (12 oral, 5 IV). Baseline sucrose excretion was normal in all. Both groups demonstrated an increase in gastric permeability after steroid treatment, but there was no difference between the two groups (95% CI 95 to 91 mg, p = 0.96). After treatment, three (25%) patients in the oral group, and two (40%) patients the IV group, had modestly abnormal gastric permeability (95% CI 34 to 64%, P = 0.6). CONCLUSIONS: Short-term high-dose oral prednisone is not associated with greater gastric damage, as measured with permeability tests, than IV methylprednisolone. High-dose oral prednisone should be considered a first-line treatment option for MS attacks.

Modulation of host cell membrane fluidity: a novel mechanism for preventing bacterial adhesion.

Adhesion of bacterial enteropathogens to host mucosal surfaces is a critical primary step in the pathogenesis of diarrheal disease. We investigated the effects of altering the physical properties of eukaryotic cells on bacterial adhesion with the use of a series of three structurally dissimilar membrane fluidizers and several Escherichia coli as test strains. Lipid fluidity of the cell plasma membrane was measured by steady-state fluorescence anisotropy employing the probe 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3, 5-hexatriene. There was a dose-dependent and reversible inhibition of bacterial adhesion with increasing membrane fluidity. Time course experiments indicated that increasing membrane fluidity during the early stages of bacterial adhesion was essential for inhibition of attachment. None of the fluidizers affected the viability of either eukaryotic or prokaryotic cells. These findings demonstrate, for the first time, that changes in plasma membrane physical properties of epithelial cells can prevent microbial adhesion. This also suggests that altering the membrane properties of host cells could form a basis for novel strategies to prevent bacterial adhesion during infection in vivo.

Complementary and alternative medicine use by patients with inflammatory bowel disease: An Internet survey.

OBJECTIVES: To determine the degree and determinants of the use of complementary and alternative medicine (CAM) by patients with inflammatory bowel disease (IBD) with the use of the Internet and to compare the results with those found by using a similar survey in patients attending gastroenterology clinics in Calgary, Alberta. SUBJECTS AND METHODS: A cross-sectional survey of 263 patients with IBD with the use of a World Wide Web-based, structured questionnaire was conducted. RESULTS: Complementary therapies had been used by 46% of patients in the previous two years. Current use was reported by 34%. Vitamins, herbal products and natural health practices were the most commonly reported therapies. Side effects and lack of effectiveness of standard therapies were the most commonly cited reasons for seeking complementary medicine. However, despite this, respondents who had previously received surgery, or intravenous or oral steroids were less likely to be current CAM users. Important differences between the determinants of and reasons for CAM use in the present study and those of a similar study of IBD patients in a local tertiary care setting were noted. CONCLUSIONS: Complementary medicine use is common in patients with IBD. Differences in the determinants of and reasons for CAM use noted between the present Internet sample and a gastroenterology clinic sample suggest that conclusions from the present study and from previous studies based only on clinic samples provide a limited view of CAM use by people with IBD. More comprehensive assessments are needed.

Intestinal permeability and postheparin plasma diamine oxidase activity in the prediction of Crohn's disease relapse.

A method of detecting presymptomatic relapse of Crohn's disease could allow for the selective use of maintenance or intensified medical therapy in those with an increased risk of relapse. The aim of this study was to evaluate three potential laboratory markers of relapse: intestinal and gastroduodenal permeability and plasma diamine oxidase activity. Intestinal permeability (lactulose/mannitol test), gastroduodenal permeability (urinary sucrose excretion), and postheparin plasma diamine oxidase activity were serially measured in 61 adults with Crohn's disease in remission (CDAI <150) for at least 30 days. Subjects were followed periodically for clinical relapse (CDAI >150 and increased by at least 100 points or the need for steroids or surgery). Fourteen patients (23%) relapsed. A cut-off of 0.030 for the lactulose/mannitol ratio was defined. Those with ratios above the cutoff had a 7.0 times greater risk of relapse (p<0.001). Three subjects who went from a normal ratio to an abnormal ratio relapsed, whereas none of 32 subjects with a repeatedly normal ratio relapsed. Sucrose excretion and plasma diamine oxidase activity did not predict relapse. Serial testing of intestinal permeability, but not of gastroduodenal permeability or plasma diamine oxidase activity, was useful in predicting relapse in asymptomatic patients.

Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat.

The BB rat spontaneously develops autoimmune diabetes. Feeding these animals a hydrolyzed casein diet significantly reduces the incidence of this disease, suggesting that a dietary antigen is involved in the pathogenesis of this disease. In other syndromes associated with luminal antigens, including celiac and Crohn's disease, increased intestinal permeability has been suggested to play an etiological role. Therefore, the objective of this study was to evaluate whether increased permeability was also present in BB rats before disease development. By measuring gastrointestinal permeability, in animals on a regular or hydrolyzed casein diet, we were able to demonstrate that increased gastric and small intestinal permeability appeared before the development of both insulitis and clinical diabetes. Although hydrolysis of dietary protein significantly reduced the incidence of diabetes, it did not alter the small intestinal permeability abnormality, suggesting that this is an early event. Increased permeability appears to have an early role in the genesis of several immunological diseases and may represent a common event in these diseases.