A complex and controversial question: can M. paratuberculosis infect and cause disease in humans? PREFACE | INTRODUCTION | CLINICAL SIGNS | PATHOLOGY | EPIDEMIOLOGY | DIAGNOSTICS | RESPONSE TO TREATMENT | ANIMAL CHALLENGE STUDIES | LINKS | REFERENCES		Scientific studies convincingly argue both for and against an association of M. paratuberculosis with human disease. Literature in this field is extensive, very technical, controversial and hotly debated among scientists. At the risk of over-simplification, we present here a compilation of findings on this important issue.

The emergence of M. paratuberculosis as a major pathogen of animals in relatively recent microbial history is indicative of the on-going evolution of microbes in our environment. The last hundred years have seen a steady increase in the number of M. paratuberculosis-infected animals within a species, such as dairy cattle, the number of different animal species infected, and the number of countries of the world where this infectious disease has reached economically significant proportions for domestic animal agriculture.

A critical question facing infectious disease biologists today is whether the animal pathogen known as M. paratuberculosis belongs on the list of zoonotic agents, that is: are humans among the animal species that can be infected with M. paratuberculosis? And if infected, does disease result? If it is ever shown that humans become diseased after infection with M. paratuberculosis, then the way veterinarians manage the infection in animals will be significantly changed.

The question of the zoonotic potential of M. paratuberculosis precedes the question of how humans, most of whom live in cities, could be exposed to this domestic agriculture pathogen, i.e., the route of transmission. While questions on transmission are being investigated, they will not be dealt with on this page as the information is incomplete and currently highly speculative. References are provided at the end of this page, however, for the inquisitive reader.

This page of the website attempts to review only the highlights of the complex zoonotic question and lead the visitor to additional more comprehensive information sources. If you are looking here for a firm conclusion to the zoonotic question you will be disappointed.

The cause of Crohn's disease is not known. Many etiologies have been suggested, including autoimmune, genetic, dietary components plus various infectious agents such as the measles virus, Listeria and M. paratuberculosis. The clinical and pathological resemblance of Crohn's disease and Johne's disease was recognized when this chronic inflammatory bowel disease was first recognized in humans by Dalziel in 1913. However, as countless subsequent studies failed to identify a mycobacterial agent, the theory of a mycobacterial etiology fell into disfavor. Diagnostic methods for Johne's disease have steadily improved as this infectious disease has spread in food animals and other ruminants. With new more sophisticated diagnostic tools developed in recent years, the question of whether M. paratuberculosis may be involved in Crohn's disease has been re-examined.

On this web page we can not examine all aspects of this complex subject. Interested readers are directed to recent reviews of the subject published in the Canadian Journal of Gastroenterology (volume 14 pages 521-539, 2000; 369 references), a review in the journal Inflammatory Bowel Diseases (volume 5. pages 183-191, 1999; 92 references) and a report of an EU Commission issued March 2000 having 372 references.

The following sections will try to summarize, in general terms for a lay audience, studies that have searched for evidence of M. paratuberculosis in humans. These studies examine an association (the occurrence at the same time and in the same patient of the organism and Crohn's disease), not a causal relationship (that the organism directly initiated the disease in the patient) since experimental infection of humans is not tolerated. Most of these studies have focused on humans with Crohn's disease due to its clinical and pathological similarity to Johne's disease. This should not be interpreted to mean that Crohn's disease is the only pathological condition that might result from human infection with M. paratuberculosis if it can occur.

Diarrhea and weight loss are the predominant clinical signs of both Johne's disease and Crohn's disease. Abdominal pain is a prominent feature of Crohn's disease in humans but, although difficult to measure in animals, seems absent in cattle and variable in other species. Fever is part of the constellation of signs in Crohn's disease but is not commonly seen in Johne's disease.

Crohn's disease is a chronic inflammatory bowel disease that most frequently involves the ileum. In Crohn's disease patients 64% have ileal involvement, associated with colitis in 41%. Diffuse granulomatous inflammation is the hallmark of microscopic findings. The inflammation may occur as a loose collection of macrophages or it may be a more organized lesion containing multinucleated giant cells, neutrophils, and eosinophils with a small area of central necrosis. Granulomas are found in up to two-thirds of resected tissue specimens from Crohn's disease patients and, in general, the more sections taken, the higher the likelihood granulomas will be found. Transmural inflammation, the presence of lymphoid aggregates in all layers of the intestine including the serosa, is a characteristic but not invariable finding in Crohn's disease. The aphthous ulcer is thought to be the earliest Crohn's mucosal lesion. These pinpoint ulcers are thought to relate to the uptake of particulate antigens or organisms by specialized gastrointestinal cells (M cells).

Johne's disease also targets the ileum and progresses up and down the gastrointestinal tract, disseminates to regional lymph nodes, and eventually becomes a bacteremic infection (the organism circulates in the blood stream). The primary site of infection is thought to be Peyer's patches with M cells mediating uptake of M. paratuberculosis. Host response to infection is primarily that of a cell-mediated inflammatory response leading to transmural, noncaseating granulomatous inflammation with giant cells. Inflammation causes grossly evident thickening of the intestine but ulceration is not a common finding.

This description of typical Johne's disease pathology is based on what is seen in cattle but actually varies within and among animal species. In sheep for example, intestinal thickening is much less prominent and both paucibacillary (few mycobacteria seen under the microscope, called the tuberculoid form of Johne's disease by pathologists) and multibacillary (many mycobacteria seen under the microscope, called the lepromatous form by pathologists) patterns of the infection occur. In deer/elk, lesions can become caseating making them easily confused with those of tuberculosis (caused by Mycobacterium bovis).

Johne's disease was first described in 1895. Crohn's disease was first recognized 18 years later. The incidence of Crohn's disease in industrialized parts of the world is increasing. From the 1960s to the 1970s the incidence of Crohn's disease rose 100-400%. Scandinavian countries have the best documentation of Crohn's disease cases and provide epidemiological data that likely reflect the changing patterns of this disease in most developed countries. A 1992 study reported a sixfold increase in Crohn's disease in Copenhagen County, Denmark. The adjacent figure, taken from the study of Munkholm et al., shows incidence curves for both men and women from 1962 to 1987. In Olmstead County Minnesota, on January 1, 1991, there was an adjusted Crohn's disease prevalence of 133 per 100,000, equating to 1 in 752 persons. This was 46% higher than that seen in 1980. Crohn's disease attacks people in the prime of life: the highest incidence is found in the age group 15-24 years.

Johne's disease is reported in virtually every country having animal agriculture and the laboratory capability to diagnose the disease. In the U.S. roughly 3-10% of dairy cattle are infected with M. paratuberculosis. The USDA-NAHMS Dairy '96 survey concluded that 22% of U.S. dairy herds had an M. paratuberculosis infection prevalence of >10% based on ELISA (blood) testing. Although comparable surveys were not done earlier, based on clinical reports, diagnostic records, historical records, and animal movements due to recent restructuring of the U.S. dairy industry (notably herd expansions) it seems safe to conclude the incidence of this infection is rising at a fairly rapid rate. The author postulates that the curve for dairy herds in the U.S. may resemble the epidemic pattern shown in the adjacent graph.

The triggering event for Crohn's disease is thought to occur early in life and then be followed by a 15-30 year incubation or latency period. Johne's disease also has a long interval between infection with M. paratuberculosis and onset of clinical signs (2-10 years). Clinical signs in both diseases are seldom seen before sexual maturity. Interestingly, a strong inverse relationship was found between Crohn's disease and gastric cancer using data from 26 countries. Authors of a study reported in the British Medical Journal volume 321, pages 1705-1706, 2000 state that this supports the role of contrasting environmental influences early in life in the etiology of Crohn's disease and gastric carcinoma. The adjacent graph from that study has been reproduced here with permission from the BMJ Publishing Group.

A lack of association between Crohn's disease and exposure to animals is often cited as evidence that M. paratuberculosis is not the cause of Crohn's disease. (That is, it is thought that the number of people diagnosed with Crohn's disease is no greater among dairy farmers who theoretically work with infected animals than people with no exposure to domestic agriculture species). However, no epidemiological study was found that specifically examined whether this association exists or not. The often cited study of Crohn's disease in Olmsted County, Minnesota (1980) indicated that the incidence of Crohn's disease in urban residents was higher than that in rural residents. That study, however, did not characterize the occupation or life style of the rural dwellers nor did it find differences in Crohn's disease rates between urban and rural dwellers statistically significant. What those authors found most intriguing was the rising incidence in Crohn's disease. They interpreted this to indicate that environmental factors more than genetics play a role in the etiology of this disease problem. The data from that study is shown here.

Several studies have shown a strong familial association for Crohn's disease. In Sweden and Denmark, studies showed that first-degree relatives had a 10 to 21-times higher risk of having CD. In a Canadian study, children with inflammatory bowel disease (IBD) had significantly (P=0.00004) more IBD in their families than did controls. That study also reported that among all children with IBD in their family, IBD was found significantly (P=0.0073) more often on the mother's side of the family than on the father's side. While such data have been interpreted to indicate a genetic predisposition to Crohn's disease in some families, they could also be interpreted as epidemiological evidence of an infectious etiology (i.e. family members are exposed to the same pathogens). In May 2000 a research group in Florida reported isolation of M. paratuberculosis from breast milk of woman with Crohn's disease providing a possible infectious disease explanation for the familial association observation.

Traditionally thought of as an infection of ruminant animals, the natural host range of M. paratuberculosis is large and growing. Scottish scientists have convincingly demonstrated paratuberculosis in rabbits, foxes, stoats, weasels, mice, and voles. The source of infection for these animals is presumed to have been infected domestic livestock. Whether these wild animals are dead-end hosts or have the potential and opportunity to transmit the infection back to domestic animals or simply sustain M. paratuberculosis in the ecosystem remains to be determined. Two reports of spontaneous M. paratuberculosis infection in nonhuman primates, stump-tail macques in 1987 and a mandrill baboon in 1994, indicate that these too may be on the list of animals susceptible to M. paratuberculosis infection.

Histopathology with special stains. Special stains of tissue slides for mycobacteria do not reveal the organism in tissues of Crohn's disease patients. This lack of visual evidence of M. paratuberculosis remains one of the more influential facts arguing against involvement of this agent in Crohn's disease.

Microbiology. The first reported isolation of M. paratuberculosis from Crohn's disease patients was by R. Chiodini et al. in 1984. Since then M. paratuberculosis has been sporadically but not consistently isolated through culture methods from Crohn's disease patients by other investigators. In their 1996 review article evidence on whether M. paratuberculosis is a zoonotic agent, Chiodini and Rossiter reported culture of M. paratuberculosis from10 of 135 (7.4%) Crohn's disease patients as compared to 1 of 121 (0.8%) control subjects. (The ten successful culture results were compiled from eight independent laboratories).

Molecular diagnostics. Detection of the genetic material from M. paratuberculosis in resected bowel tissues from Crohn's disease patients using molecular techniques (called IS900 PCR probe) occurs more consistently than isolation of the living organism by culture. While the detection of the M. paratuberculosis genetic material does not imply that the organism in living in the patient, these genetic probe findings suggest an association of M. paratuberculosis with Crohn's disease. Ten studies reporting IS900 PCR on intestinal tissue samples obtained from full gut resections are summarized in the table below. Seven of these 10 studies reported a statistically significant association between M. paratuberculosis and Crohn's disease as compared to control patients (generally people who had intestinal resection due to cancer). Publications from which this data are derived are provided in the list of references at the end of this page.

Year	First author	Country	Crohn's %positive	Controls %positive	Statistical Significance
1992	Sanderson	England	65%	12%	p<0.0001
1994	Dell'Isola	France	72%	29%	p<0.01
1994	Lisby	Denmark	46%	11%	p<0.01
1994	Fidler	England	13%	0%	p<0.05
1995	Suenaga	Japan	100%	87%	nsd
1995	Rowbotham	England	0%	0%	nsd
1996	Dumonceau	Belgium	0%	0%	nsd
1996	Mishna	USA	100%	0%	p<0.0001
1998	Del Prete	Italy	47%	2%	p<0.0001
2000	Collins	USA	29%	5%	p<0.01

nsd = not significantly different
p values indicate results were significantly different between groups.

Serology. Tests for serum antibodies to M. paratuberculosis in Crohn's disease patients dating back to the 1980s have reported divergent results, but more recent studies report a positive association. Serodiagnostic methods for M. paratuberculosis in animals improved dramatically in the late 1990s. When purified M. paratuberculosis antigens to detect antibodies to M. paratuberculosis were used with serum from Crohn's disease patients, several investigators found a significant association. In December 2000, using an adaptation of a commercial ELISA for diagnosis of paratuberculosis in cattle, Collins et al. reported that 13.4% of 142 U.S. Crohn's disease patients were test-positive for paratuberculosis as compared to 2.6% of healthy blood donors.This difference was statistically significant.

Cellular immunity assays. Only one study has thus far reported results of diagnostic assays for cellular immune responses (the cytokine gamma interferon released after stimulation of leukocytes with antigenic extracts) to M. paratuberculosis in Crohn's disease patients. That study found a significant association between a response to M. paratuberculosis (hyporesponsiveness) and Crohn's disease (Collins et al., 2000).

Collectively, few studies have reported attempts to treat Crohn's disease patients with antimycobacterial dugs and the results of the few studies are conflicting. However, the pattern of results parallels that of serological studies: early studies report treatment failure and thus are not supportive of a mycobacterial infection theory while more recent studies, using different drugs and prolonged therapy protocols do report treatment success and argue in favor of mycobacterial involvement in Crohn's disease.

For example, the 1984 study of Shaffer et al. reported no improvement of 14 Crohn's disease patients treated for 12 months with rifampicin and ethambutol (two drugs used to treat tuberculosis which is another mycobacterial disease). A critical premise of these early clinical trials using antimicrobial drugs was that drugs effective in treatment of tuberculosis also would be effective against other mycobacteria, in particular M. paratuberculosis. The concluding sentence of the 1992 paper by Rutgeerts et al. is illustrative of this point:

"The strength of the present study lies in the fact that all patients were studied endoscopically and histologically and that it was established unequivocally that the macroscopic and histologic lesions of Crohn's ileitis do not improve with antimycobacterial therapy, which is certainly effective against M. paratuberculosis." *** underlining added for emphasis by the author of this web page ***

The fact is that Rutgeert et al. did not perform M. paratuberculosis drug susceptibility testing nor did they cite any such data to support their choice of drugs for their clinical trial. Laboratory studies actually indicate that M. paratuberculosis is quite resistant to first line anti-tuberculosis drugs. This could explain the treatment failure Rutgeert et al. observed.

A small placebo-controlled study by Graham et al. in 1995 found prolonged remission (>1 year) in 8 of 15 CD patients treated with clarithromycin for 6 months. In 1997, Gui et al. reported a study attempting treatment of Crohn's disease patients with a combination of two drugs, rifabutin and one of two macrolides (clarithromycin or azithromycin), for >18 months. They reported that clinical remission was induced in >93% of 46 patients.

More studies are needed to define which antimicrobial drugs are most effective against M. paratuberculosis, and then well-controlled studies using these drugs are needed before any definitive statement about the value of directing therapy for Crohn's disease against M. paratuberculosis or any other mycobacterial agent can be made.

Two studies have reported attempts to infect animals using isolates (strains) of M. paratuberculosis derived from humans with Crohn's disease. Infant goats were reportedly infected orally with a single strain ("Linda") of M. paratuberculosis in 1986. A 1991 report found that chickens could be infected by multiple exposure routes using the same M. paratuberculosis strain. The first author of both studies is the same author who recently wrote the article titled "Lack of support for a common etiology in Johne's disease of animals and Crohn's disease in humans" (Inflammatory Bowel Diseases volume 5, pages 183-191, 1999). Clearly more research is needed in this area.

Virtually all known mycobacterial pathogens of animals are transmissible to humans and have the capacity to cause disease. That is they are zoonotic. Thus, it is plausible that M. paratuberculosis also is a potential human pathogen. If, when, or how M. paratuberculosis has the opportunity to infect humans remains a puzzle. However, given the expanding epidemic of paratuberculosis in multiple animal species, it is likely that the burden of M. paratuberculosis in the environment is increasing.

A standard for scientific proof of disease causation by microbes is called Koch's postulates, referring to the pioneering work of Robert Koch who discovered the cause of tuberculosis in humans in 1882. There is debate among scientists as to whether these postulates are appropriate for proving causation of more complex and chronic disease problems facing medicine today. For two divergent perspectives on this issue, interested readers are encouraged to read the article by R.M Krause titled "Microbes and Emerging Infections: The Compulsion to Become Something New" (ASM News volume 67, pages 15-20, 2001), and the book "Plague Time: How Stealth Infections Cause Cancers, Heart Disease, and other Deadly Ailments" by P. W. Ewald (The Free Press, New York, 2000); see pages 50-52 in particular.

Koch's postulates as traditionally reported state that to prove disease causation by a microbe one must accomplish all four of the following (adapted from Fundamentals of Microbiology, 9^th edition):

1. Find the infectious agent consistently associated with the disease and in a logical pathological relationship to the symptoms and lesions.

2. Isolate the organism from victims of the disease in pure culture.

3. When the pure culture is inoculated into a susceptible host, it must reproduce the disease (most often an animal, not a human, for obvious ethical reasons).

4. The organism must be re-isolated in pure culture from such experimental infections.

Examining the preponderance of evidence regarding M. paratuberculosis as a cause of Crohn's disease in light of Koch's postulates we find:

1. M. paratuberculosis can often be shown to be associated with Crohn's disease, but not always. The association is primarily by molecular (genetic) but not other diagnostic methods. However, the association is logical given the type of pathology this agent induces in other animals.

2. M. paratuberculosis can be isolated in pure culture from Crohn's disease patients, but not very often.

3. Only two successful attempts to infect animals with human strains of M. paratuberculosis have been reported (resulting in Johne's disease, not Crohn's disease). The primary author of those publications now argues against a causal association of M. paratuberculosis with Crohn's disease.

4. M. paratuberculosis was re-isolated from animals challenged with a human strain of M. paratuberculosis in both published studies.

Clearly more research is needed before solid scientific conclusions can be made as to whether M. paratuberculosis is zoonotic. If it is, it could be an emerging disease problem that must be urgently addressed.

European Commission report, March 2000.
Possible links between Crohn's disease and paratuberculosis
http://europa.eu.int/comm/food/fs/sc/scah/out38_en.pdf

Paratuberculosis Awareness and Research Association (P.A.R.A.)
http://crohns.org

Paratuberculosis and Crohn’s disease: Got Milk?
Michael Greger, MD; Updated January 2001.
This document contains 424 references.

Note to readers: This list is not intended to be comprehensive. It is a representative list of 80 pertinent references. It is only starting point for those interested in pursuing more information. Scientific publications in this area of science come from a diverse array of disciplines are therefore somewhat harder to locate. It is hoped that this list will help partially alleviate that problem. Publications are listed in reverse chronological order to more quickly lead readers to the most recent literature.

Chamberlin, W. M. and S. A. Naser . 2006. Integrating theories of the etiology of Crohn's Disease On the etiology of Crohn's Disease: Questioning the Hypotheses. Med. Sci. Monit. 12:RA27-RA33.

Dow, C. T. 2006. Paratuberculosis and Type I diabetes Is this the trigger? Med.Hypotheses 67:782-785.

Nakase, H., A. Nishio, H. Tamaki, M. Matsu ura, M. Asada, T. Chiba, and K. Okazaki . 2006. Specific antibodies against recombinant protein of insertion element 900 of Mycobacterium avium subspecies paratuberculosis in Japanese patients with Crohn's disease. Inflamm. Bowel Dis. 12:62-69.

Pozler, O., J. Malay, O. Bonova, P. Dedek, P. Frühauf, A. Havlickova, T. Janatova, F. Jimramovsky, L. Klimova, D. Klusacek, D. Kocourkova, A. Kolek, R. Kotalova, D. Marx, J. Nevoral, R. Petro, O. Petru, I. Plasilova, Z. Seidl, I. Sekyrova, N. Semendak, I. Schreierova, J. Stanek, J. Sykora, A. Sulakova, L. Toualkova, R. Travnickova, V. Volf, L. Zahradnicek, and I. Zenisková . 2006. Incidence of Crohn's disease in the Czech Republic in the years 1990 to 2001 and assessment of pediatric population with inflammatory bowel disease. J.Ped.Gastroenterol.Nutr. 42:186-189.

Sieswerda, L. E. and R. M. Bannatyne . 2006. Mapping the effects of genetic susceptibility and Mycobacterium avium subsp. paratuberculosis infection on Crohn's disease: Strong but independent. J.Clin.Microbiol. 44:1204-1205.

Autschbach, F., S. Eisold, U. Hinz, S. Zinser, M. Linnebacher, T. Giese, T. Loffler, M. W. Buchler, and J. Schmidt . 2005. High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn's disease. Gut 54:944-949.

Cheng, J., T. J. Bull, S. Cen, C. Finlayson, and J. Hermon-Taylor . 2005. Mycobacterium avium subspecies paratuberculosis in the inflamed gut tissues of patients with Crohn's disease in China and its potential relationship to the consumption of cow's milk: a preliminary study. World Journal of Microbiology & Biotechnology 21:1175-1179.

Ellingson, J. L. E., J. L. Anderson, J. J. Koziczkowski, R. P. Radcliff, S. J. Sloan, S. E. Allen, and N. M. Sullivan . 2005. Detection of viable Mycobacterium avium subsp. paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J.Food Prot. 67:966-972.

Grant, I. R. 2005. Zoonotic potential of Mycobacterium avium ssp. paratuberculosis: the current position. J.Appl.Microbiol. 98 :1282-1293.

Romero, C., A. Hamdi, J. F. Valentine, and S. A. Naser . 2005. Evaluation of surgical tissue from patients with Crohn's disease for the presence of Mycobacterium avium subspecies paratuberculosis DNA by in situ hybridization and nested polymerase chain reaction. Iflamm.Bowel Dis. 11:116-125.

Sartor, R. B. 2005. Does Mycobacterium avium subspecies paratuberculosis cause Crohn's disease? Gut 54:896-898.

Sechi, L. A., A. M. Scanu, P. Molicotti, S. Cannas, M. Mura, G. Dettori, G. Fadda, and S. Zanetti . 2005. Detection and isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn's disease in Sardinia . Am. J. Gastroenterol. 100:1529-1536.

Sechi, L. A., M. Gazouli, J. Ikonomopoulos, J. C. Lukas, A. M. Scanu, N. Ahmed, G. Fadda, and S. Zanetti . 2005. Mycobacterium avium subsp. paratuberculosis, genetic susceptibility to Crohn's disease, and Sardinians: the way ahead. J.Clin.Microbiol. 43:5275-5277.

Whan, L., H. J. Ball, I. R. Grant, and M. T. Rowe . 2005. Occurrence of Mycobacterium avium subsp. paratuberculosis in Untreated Water in Northern Ireland . Appl.Env.Microbiol. 71:7107-7112.

Whittington, R. J., I. B. Marsh, and L. A. Reddacliff . 2005. Survival of Mycobacterium avium subsp. paratuberculosis in dam water and sediment. Appl.Env.Microbiol. 71:5304-5308.

Barta, Z., I. Csipo, G. Mekkel, M. Zeher, L. Majoros, C. N. Bernstein, and M. T. Collins . 2004. Seroprevalence of Mycobacterium paratuberculosis in patients with Crohn's disease. J.Clin.Microbiol. 42:5432-5433.

Bernstein, C. N., J. F. Blanchard, P. Rawsthorne, and M. T. Collins . 2004. Population-based case control study of seroprevalence of Mycobacterium paratuberculosis in patients with Crohn's disease and ulcerative colitis. J.Clin.Microbiol. 42:1129-1135.

Ghadiali, A. H., M. Strother, S. A. Naser, E. J. B. Manning, and S. Sreevatsan . 2004. Mycobacterium avium subsp. paratuberculosis strains isolated from Crohn's disease patients and animal species exhibit similar polymorphic locus patterns. J.Clin.Microbiol. 42:5345-5348.

Naser, S. A., G. Ghobrial, C. Romero, and J. F. Valentine . 2004. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease. Lancet 364:1039-1044.

Ryan, P., R. G. Kelly, G. Lee, J. K. Collins, G. C. O'Sullivan, J. O'Connell, and F. Shanahan . 2004. Bacterial DNA within granulomas of patients with Crohn's disease-detection by laser capture microdissection and PCR. Am. J. Gastroenterol. 99:1539-1543.

Sechi, L. A., M. Mura, E. Tanda, A. Lissia, G. Fadda, and S. Zanetti . 2004. Mycobacterium avium sub. paratuberculosis in tissue samples of Crohn's disease patients. New Microbiol 27:75-77.

Bull, T. J., E. J. McMinn, K. Sidi-Boumedine, A. Skull, D. Durkin, P. Neild, G. Rhodes, R. Pickup, and J. Hermon-Taylor . 2003. Detection and verification of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic mucosal biopsy specimens from individuals with and without Crohn's disease. J.Clin.Microbiol. 41:2915-2923.

Greenstein, R. J. 2003. Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease. The Lancet Infectious Diseases 3:507-514.

Kugathasan, S., R. H. Judd, R. G. Hoffmann, J. Heikenen, G. Telega, F. Khan, S. Weisdorf-Schindele, P. W. San, Jr., J. Perrault, R. Park, M. Yaffe, C. Brown, M. T. Rivera-Bennett, I. Halabi, A. Martinez, E. Blank, S. L. Werlin, C. D. Rudolph, D. G. Binion, and Wisconsin Pediatric Inflammatory Bowel Disease Alliance. 2003. Epidemiologic and clinical characteristics of children with newly diagnosed inflammatory bowel disease in Wisconsin : a statewide population-based study. J.Pediatr. 143:525-531.

Motiwala, A. S., M. Strother, A. Amonsin, B. Byrum, S. A. Naser, J. R. Stabel, W. P. Shulaw, J. P. Bannantine, V. Kapur, and S. Sreevatsan . 2003. Molecular epidemiology of Mycobacterium avium subsp. paratuberculosis: Evidence for limited strain diversity, strain sharing, and identification of unique targets for diagnosis. J.Clin.Microbiol. 41:2015-2026.

Olsen, I. , H. G. Wiker, E. Johnson, H. Langeggen, and L. J. Reitan . 2003. Elevated antibody responses in patients with Crohn's disease against MPP14, a 14 kDa secreted protein purified from Mycobacterium avium subsp. paratuberculosis. Acta Vet.Scand. 44:287.

Phavichitr, N., D. J. S. Cameron, and A. G. Catto-Smith . 2003. Increasing incidence of Crohn's disease in Victorian children. J. Gastroenterol. Hepatol. 18:329-332.

Corti, S. and R. Stephan . 2002. Detection of Mycobacterium avium subspecies paratuberculosis specific IS900 insertion sequences in bulk-tank milk samples obtained from different regions throughout Switzerland . BMC Microbiology 2:15.

Hermon-Taylor, J. and T. J. Bull . 2002. Crohn's disease caused by Mycobacterium avium subspecies paratuberculosis: a public health tragedy whose resolution is long overdue. J.Med.Microbiol. 51:3-6.

Hermon-Taylor, J. 2002. Treatment with drugs active against Mycobacterium avium subspecies paratuberculosis can heal Crohn's disease: more evidence for a neglected public health tragedy. Digest.Liver Dis. 34:9-12.

Naser, S. A., I. Shafran, D. Schwartz, F. El Zaatari, and J. Biggerstaff . 2002. In situ identification of mycobacteria in Crohn's disease patient tissue using confocal scanning laser microscopy. Molecular & Cellular Probes 16:41-48.

Ryan, P., M. W. Bennett, S. Aarons, G. Lee, J. K. Collins, G. C. O'Sullivan, J. O'Connell, and F. Shanahan . 2002. PCR detection of Mycobacterium paratuberculosis in Crohn's disease granulomas isolated by laser capture microdissection. Gut 51:665-670.

Chamberlin, W., D. Y. Graham, K. Hulten, H. M. El Zimaity, M. R. Schwartz, S. Naser, I. Shafran, and F. A. El Zaatari . 2001. Review article: Mycobacterium avium subsp. paratuberculosis as one cause of Crohn's disease. Aliment.Pharmacol.Ther. 15:337-346.

El Zaatari, F. A., M. S. Osato, and D. Y. Graham . 2001. Etiology of Crohn's disease: the role of Mycobacterium avium paratuberculosis. Trends in Molecular Medicine 7:247-252.

Harris, J. E. and A. M. Lammerding . 2001. Crohn's disease and Mycobacterium avium subsp. paratuberculosis: current issues. J.Food Prot. 64:2103-2110.

Hulten, K., H. M. T. El Zimaity, T. J. Karttunen, A. Almashhrawi, M. R. Schwartz, D. Y. Graham, and F. A. K. El Zaatari . 2001. Detection of Mycobacterium avium subspecies paratuberculosis in Crohn's diseased tissues by in situ hybridization. Am.J.Gastroenterol. 96:1529-1535.

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