Herbert J. Van Kruiningen

Possible role of mycobacteria in inflammatory bowel disease

A previously unrecognizedMycobacterium species was isolated from two patients with Crohns disease. The organism is an acid-fast, mycobactin-dependentMycobacterium that has characteristics which do not conform to any of the presently recognized species. It belongs to the Runyon group III mycobacteria and is most closely related toMycobacterium paratuberculosis. Animal inoculation revealed pathogenicity for mice when injected intravenously or intraperitoneally, but not for rats, guinea pigs, rabbits, or chickens. The mice developed hepatic and splenic granulomas which contained numerous acid-fast mycobacteria. A 7-day-old goat which was inoculated orally with 50 mg of the organism developed both humoral and cell-mediated immunologic responses in two to three weeks and granulomatous disease of the distal small intestine, with noncaseating tuberculoid granulomas in five months. Acid-fast bacilli were not demonstrable in sections of the intestine, but a single organism was seen in each of two microgranulomas of the mesenteric lymph node. TheMycobacterium species was reisolated from the lymph node but not from intestine. Our findings raise the possibility that aMycobacterium plays an etiologic role in at least some cases of Crohns disease.

Immunocytochemical evidence of Listeria, Escherichia coil, and Streptococcus antigens in Crohn's disease

Abstract Background/Aims Infectious agents have long been suspected of playing a role in the initiation of Crohns disease. The objective of this study was to search for likely microbial agents in diseased tissues using immunocytochemical techniques. Methods Intestines and mesenteric lymph node specimens of 21 patients from two French families with a high frequency of Crohns disease and from Connecticut were studied. The microbial agents searched for included Bacteroides vulgatus, Borrelia burgdorferi, Escherichia coil, Listeria monocytogenes, Streptococcus spp., bovine viral diarrhea virus, influenza A virus, measles virus, parainfluenza virus, and respiratory syncytial virus. Results Seventy-five percent of the patients with Crohns disease (12 of 16) were positively labeled with the antibody to Listeria. Macrophages and giant cells immunolabeled for this antigen were distributed underneath ulcers, along fissures, around abscesses, within the lamina propria, in granulomas, and in the germinal centers of mesenteric lymph nodes. In addition, 57% (12 of 21) of the cases contained the E. coli antigen, and 44% (7 of 16) contained the streptococcal antigen. The immunolabeling for the latter two agents also occurred within macrophages and giant cells, distributed in a pattern similar to that of Listeria antigen. Conclusions The results suggest that Listeria spp., E. coli, and streptococci, but not measles virus, play a role in the pathogenesis of Crohns disease.

Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn’s disease

OBJECTIVE:Bacterial agents have been implicated in the early recurrence of Crohns disease after ileocolectomy. The aim of our study was to identify and quantify bacteria associated with the ileal mucosa in patients and controls and to correlate specific bacteria with recurrence.METHODS:The predominant bacterial microflora of the ileum were enumerated and identified, aerobically and anaerobically, in biopsies obtained at the time of surgery or by endoscopy from 61 patients with Crohns disease and 10 ileocolectomy controls. The 61 specimens were comprised of 13 ileal biopsies taken from resection specimens, seven taken after ileostomy, and 41 taken after ileocolectomy.RESULTS:Ileocolectomy induced a significant increase in bacterial counts and variety in the neoterminal ileum in both patients and controls that was not observed in ileostomy biopsies. Comparison between patients and controls revealed greater numbers of Escherichia coli and enterococci in Crohns disease and of bifidobacteria and ruminococci in controls. Early recurrence was associated with high counts of E. coli and bacteroides and the frequent isolation of fusobacteria.CONCLUSION:After ileocolectomy, colonization of the neoterminal ileum is increased. Our data suggest that increases in the populations of specific bacteria such as E. coli, enterococci, bacteroides, and fusobacteria may be important in postoperative recurrence of Crohns disease.

Antibiotics Associated With Increased Risk of New-Onset Crohn's Disease But Not Ulcerative Colitis: A Meta-Analysis

OBJECTIVES:The objective of this study was to perform a meta-analysis investigating antibiotic exposure as a risk factor for developing inflammatory bowel disease (IBD).METHODS:A literature search using Medline, Embase, and Cochrane databases was performed to identify studies providing data on the association between antibiotic use and newly diagnosed IBD. Included studies reported Crohn’s disease (CD), ulcerative colitis (UC), or a composite of both (IBD) as the primary outcome and evaluated antibiotic exposure before being diagnosed with IBD. A random-effects meta-analysis was conducted to determine overall pooled estimates and 95% confidence intervals (CIs).RESULTS:A total of 11 observational studies (8 case–control and 3 cohort) including 7,208 patients diagnosed with IBD were analyzed. The pooled odds ratio (OR) for IBD among patients exposed to any antibiotic was 1.57 (95% CI 1.27–1.94). Antibiotic exposure was significantly associated with CD (OR 1.74, 95% CI 1.35–2.23) but was not significant for UC (OR 1.08, 95% CI 0.91–1.27). Exposure to antibiotics most markedly increased the risk of CD in children (OR 2.75, 95% CI 1.72–4.38). All antibiotics were associated with IBD, with the exception of penicillin. Exposure to metronidazole (OR 5.01, 95% CI 1.65–15.25) or fluoroquinolones (OR 1.79, 95% CI 1.03–3.12) was most strongly associated with new-onset IBD.CONCLUSIONS:Exposure to antibiotics appears to increase the odds of being newly diagnosed with CD but not UC. This risk is most marked in children diagnosed with CD.

Candida albicans colonization and ASCA in familial Crohn's disease

OBJECTIVES:Anti-Saccharomyces cerevisiae antibodies (ASCAs) are present in 50–60% of patients with Crohns disease (CD) and in 20–25% of their healthy relatives (HRs). The yeast, Candida albicans, has been shown to generate ASCAs, but the presence of C. albicans in the digestive tract of CD patients and their HRs has never been investigated. Therefore, we studied C. albicans carriage in familial CD and its correlation with ASCAs.METHODS:Study groups consisted of 41 CD families composed of 129 patients and 113 HRs, and 14 control families composed of 76 individuals. Mouth swabs and stool specimens were collected for isolation, identification, and quantification of yeasts. Serum samples were collected for detection of ASCAs and anti-C. albicans mannan antibodies (ACMAs).RESULTS:C. albicans was isolated significantly more frequently from stool samples from CD patients (44%) and their HRs (38%) than from controls (22%) (P<0.05). The prevalence of ACMAs was similar between CD patients, their HRs, and controls (22, 19, and 21%, respectively, P=0.845), whereas the prevalence of ASCAs was significantly increased in CD families (72 and 34% in CD and HRs, respectively, in contrast to 4% in controls, P<0.0001). AMCA levels correlated with C. albicans colonization in all populations. ASCA levels correlated with C. albicans colonization in HRs but not in CD patients.CONCLUSIONS:CD patients and their first-degree HRs are more frequently and more heavily colonized by C. albicans than are controls. ASCAs correlate with C. albicans colonization in HRs but not in CD. In HRs, ASCAs could result from an altered immune response to C. albicans. In CD, a subsequent alteration in sensing C. albicans colonization could occur with disease onset.

Distribution of Peyer's patches in the distal ileum

Background and AimsPeyers patches play a major role in intestinal immunity, are portals of entry for significant pathogens, and may be important in Crohns disease. Whereas their microscopic anatomy and immune function are well described, surprisingly little is known of their macroscopic anatomy and distribution. Our aim was to assess their number, area, and distribution in the normal distal ileum, with particular reference to patient age. MethodsDistal ilea (200 cm) obtained at autopsy from 55 adults without intestinal disease were opened along the mesenteric border, fixed in acetic acid, and transilluminated. Peyers patches were counted, and the length, breadth, and distance from the ileocecal valve were recorded. ResultsPatches were most numerous in the terminal 10–15 cm where they formed a lymphoid ring. More proximal patches were oval, antimesenteric, and irregularly spaced. By area, 46% of patch tissue occurred in the terminal 25 cm. The mean number of patches ranged from 29.4 ± 5.4 in the youngest group studied, to 19.0 ± 3.0 in the oldest. Total patch area was greatest in the group aged 21–30 (47.4 ± 1.0 cm2). ConclusionPeyers patches are concentrated in the distal 25 cm of ileum but extend proximally for 200 cm. The variation in their size, shape, and distribution in different individuals is greater than often appreciated and may influence the presentation of diseases centered on these structures.

Environmental factors in familial Crohn's disease in Belgium

Background: Environmental factors are believed to trigger the onset of Crohns disease (CD) in genetically susceptible individuals. The aim of this study was to assess environmental and familial factors that might be etiologically related to CD. Methods: Twenty‐one families with 3 or more affected first‐degree relatives were studied, together with 10 matched control families. There were 74 patients with CD, 84 unaffected family members, and 59 controls. Family members were interviewed together at the parental home. A 176‐item questionnaire delved into first symptoms, childhood vaccinations and diseases, food items, potable water supplies, social activities, travel, pets, and home and surrounding environment. Questions were directed specifically for 2 time‐frames, childhood until age 20 and a 10‐year epoch before the onset of first symptoms within a family. The possible factors linked to disease were evaluated using univariate and multivariate logistic regression. Results: There were significantly more smokers in the patients and their relatives than in controls. Patients had more appendicitis during adolescence, ate less oats, rye, and bran than controls, and consumed more unpasteurized cheese. Patients drank significantly less tap water and more well water than controls. Clustering of cases in time occurred in 13 of the 21 affected families. Conclusions: The less frequent consumption of oats, rye, and bran and the more frequent eating of unpasteurized cheeses imitate potential dietary influences on gastrointestinal flora. More importantly, our data suggest that the drinking of well water represents an important risk factor for CD.

The West Nile virus:its recent emergence in North America

West Nile fever emerged in New York in the summer of 1999 when seven people, several horses and thousands of wild birds died. It was soon established that the human disease and the mortality of birds were related. Continued surveillance detected West Nile virus in mosquitoes, birds, horses, small mammals, bats and humans, and has shown its spread to several northeastern states. These events confirm the establishment of West Nile virus endemically in the United States.

A clustering of Crohn's disease in Mankato, Minnesota

Infrequently, clusterings of Crohns disease (CD) occur that suggest it is transmissible. We studied such a clustering. Graduates of the Mankato West High School Class of 1980 were contacted by mail and asked to respond, by self-addressed postcard, to a six-item questionnaire about inflammatory bowel disease and CD. Responses were followed-up by telephone contact and additional mailings. Two visits were made to Mankato, Minnesota, to interview individuals with CD, to obtain medical records, radiographs, and sera, and to study environmental risk factors. Of the 320 graduates of the class of 1980, 285 were contacted. Seven cases of CD were identified, the equivalent of a prevalence of 2,400/100,000. Concerns were discovered that CD may have emanated from recreational swimming. Fecal coliform counts in excess of 200/dL, the standard above which water is regarded as unsafe for recreational use, had been recorded year after year for the Blue Earth River at Mankato and for the Minnesota River. Recent fecal coliform counts (1993–1995) of Lake Washington, Lake German/Jefferson, and Lake Shetek were greater than 200/dL in 57%, 65%, and 62% of water samples. This clustering, in unrelated individuals, argues against a genetic cause for CD and suggests that environmental transmission occurred.

Canine Colitis Comparable to Regional Enteritis and Mucosal Colitis of Man

Eight cases of spontaneous canine ileitis, colitis, and proctitis were studied. Clinical, laboratory, radiological, and pathological data were examined for correlation with human ileitis and colitis. Individual case reports document canine counterparts of specific forms of human colitis, and the spectrum of colitides found in purebred dogs is shown to be substantially similar to the spectrum seen in man. As in human colitis, familial (breed) predisposition is considered a significant etiological factor.