What is MAP?

Mycobacterium avium subspecies paratuberculosis (MAP) is a pathogenic bacteria which is the cause of Johne’s disease in ruminants. A human variant of MAP (hMAP) is thought to play a critical role in the development of some immune conditions, including Crohn’s disease, multiple sclerosis and Type 1 diabetes. While the research connecting MAP to Crohn’s disease is the most advanced, the last year has yielded many studies which link MAP to other conditions.

The exact role hMAP plays in disease has yet to be fully elucidated, but many researchers believe there is enough evidence to conclude that it plays an important role in the pathogenesis of Crohn’s disease. Once the mechanism of hMAP in Crohn’s disease is discovered, that knowledge can be applied to related conditions.

MAP vs. hMAP

The term “MAP” is a broad term used to include all of the variations of Mycobacterium avium subspecies paratuberculosis. The are many different strains of MAP, but they generally fall into two categories: Type C (predominately from cattle) and Type S (predominately from sheep and goats). For more information, see this excellent article which details the genetic differences between MAP strains. Researchers have been able to isolate a variety of MAP strains from humans, but only recently has a spheroplastic, cell-wall deficient form been reliably cultured in the human population. We have termed this variant hMAP. For more information about hMAP, please see John Aitken’s presentation from the 2015 Chicago Symposium.

MAP in Crohn’s Disease

The search for a cause and, potentially, a cure for Crohn’s disease has been elusive since the disease was first described over 80 years ago by Dr. Burrill Crohn. Crohn’s disease is one of the major challenges facing gastroenterologists today. However many people, physicians as well as patients, are not aware that the history of the disease goes back over 100 years. In 1913, Dalziel noted the similarities present in the intestines of humans suffering from what came to be known as Crohn’s disease and cattle suffering from Johne’s disease. His findings led him to propose that Johne’s disease and Crohn’s disease may be the same.¹Johne’s disease is an intestinal wasting condition in ruminants that is caused by MAP and behaves clinically much like Crohn’s disease. Nearly 100 years later, Greenstein demonstrated the typical cobblestone appearance of intestinal tissue in both Crohn’s and Johne’s diseases further associating these two conditions.

[Figure A: Crohn’s Disease in Humans. Figure B: Johne’s Disease in Animals. Greenstein Lancet Infectious Disease 2004;3(8):507-14.]

The latest research has revealed that Crohn’s disease is not an auto-immune disorder, but is more correctly classified as an immune mediated disease, with contributing genetic and environmental components. When most people are exposed to MAP through the food chain or environment, their immune systems contain it and they remain healthy. However, Crohn’s disease patients have genetic mutations which do not allow their macrophages (a type of white blood cell) to correctly recognize and rid the body of intracellular pathogens, like the Mycobacterium genus. Genetic mutations, like those found in the NOD2, ATG16L1 and IRGM regions, impair the autophagy (self destruction) response that allows the immune system to destroy intracellular bacteria. hMAP is one such intracellular species.

Where Does MAP Come From?

MAP is present throughout our environment, and infected dairy and meat cattle shed over 1 million infectious doses per day in their feces. One US study of milk bought “off the shelf” in three states demonstrated the presence of MAP in nearly 3 percent of samples.² MAP is not killed by simple pasteurization³ and the role of MAP in humans is one of deep scientific interest. MAP has also been found in water, pastures, aerosols, fruits and vegetables. One study showed that a human variant of MAP survived for up to 4 years inside a culture of amoeba. Currently MAP is not classified as a zoonotic (a disease transmitted from animals to humans) pathogen. Consequently, there are no regulations requiring its removal from the food supply.

Governmental Action

In 1998 the US National Institute of Health invited a number of experienced scientists and physicians to discuss MAP and Crohn’s in a workshop. The results of this meeting indicated that, while a number of Crohn’s patients responded very positively to Anti-MAP therapy, there were significant questions regarding MAP and its role in the development of Crohn’s disease. Further research was recommended, and since that time there have been hundreds of scientific studies published in peer reviewed journals responding to the needs identified at the meeting. Two of the most important areas of interest are described below.

On February 26, 2015, the Advisory Committee on Dangerous Pathogens in the United Kingdom published a review of the latest research on the possible link between Mycobacterium avium, subspecies paratuberculosis (MAP) and Crohn’s disease. The last such review, conducted in 2005, determined that there was no evidence to connect MAP to Crohn’s disease. The current review was requested by Jeremy Hunt, the United Kingdom Secretary of State for Health, following a letter from a patient supporter.

The conclusions were that:

Crohn’s disease may be more than one type of disease, MAP susceptibility being one variation.
MAP has been detected in other human conditions, and effects may not be limited to Crohn’s disease.
Individuals with mutations in genes involved in regulating immune responses are at higher risk of developing Crohn’s disease after MAP exposure.
The potential of MAP exposure to humans exists based upon new detection techniques demonstrating the presence of MAP in the environment and dairy associated food products and may affect the youngest, most vulnerable sector of the population.

The governing bodies of Ireland, Australia, Netherlands, the United Kingdom have instituted programs to control Johne’s disease and the spread of MAP. For a brief overview of the applicable laws, please see Dr. Gilles Monif’s article on the Hypothetical Liability of MAP.

Detection of MAP in Crohn’s patients

MAP infects humans and elicits an immune response that initially controls infection similar to infection in cattle. It is then able to break down protective immunity in some subjects leading to clinical disease. MAP is difficult to detect in humans because it often loses its cell wall, making it difficult to detect in feces and tissues using the classic acid fast staining technique. But introduction of DNA testing via PCR has provided a different way of detecting MAP. Eight published studies have shown the presence of MAP in an average of 55% of CD patients.Prof. Saleh Naser of the University of Central Florida successfully grew MAP from the blood of 14 of 28 (50%) patients with Crohn’s disease, 2 of 9 patients (22%) with ulcerative colitis, a closely related intestinal condition, and importantly none of 15 persons who did not have inflammatory bowel disease. Furthermore, MAP DNA was found via PCR in 46% of Crohn’s disease, 45% of UC and 20% of non-IBD patients in this study.⁴

One lab that is leading the world in hMAP testing is Otakaro Pathways in New Zealand. Led by John Aitken, Otakaro Pathways has developed a innovative diagnostic test for Crohn’s disease and other conditions that reliably tests for hMAP. For more information, please see the hMAP Testing page.

The Impact of Treating MAP in Crohn’s Disease Patients

Several studies evaluating the use of Anti-MAP, or Atypical Mycobacterial Antibiotic Therapy (AMAT) to treat patients suffering from Crohn’s disease have been published, and the effectiveness of utilizing AMAT has demonstrated a 67% remission rate in 244 Crohn’s disease patients treated across six studies. Recent work in Israel, Japan, and Ireland has shown that human tissue and white cells can be infected with MAP. These results further indicate that MAP may play a role in Crohn’s disease.

Comparative studies in cattle, the natural host of MAP, show MAP remains controlled by the immune system during the dormant stage of infection and is difficult to isolate from tissues, suggesting a similar condition occurs in humans. It may take up to 12 months to grow under laboratory conditions for both cattle and humans. AMAT must be given for extended periods of time to be effective during all stages of infection with the bacterium and multiple antibiotics in combination must be used to prevent antibiotic resistance. A clinical study evaluating targeted AMAT in 213 Crohn’s disease patients across 20 sites in Australia demonstrated compelling results (the Selby study). Subjects received either antibiotics or placebo and were followed for up to two years. While the author of the study concluded that AMAT was ineffective for treating Crohn’s disease, this was not what the data actually showed.

Of the initial group of patients entering the study 66% of the antibiotic treatment group achieved remission at 16 weeks compared to 50% of the placebo group. Similarly, at the end of one year 41% of the antibiotic group vs. 25% of the placebo group were in remission. Finally, the two year comparison demonstrated 33% remission in the antibiotic group and 18% remission in the placebo group. These comparisons were statistically significant at all three time points, and support the use of AMAT in Crohn’s disease. Unfortunately MAP testing was not available at the time of study and demonstration of causality remains elusive. For a more detailed analysis of the Selby study, see the For Clinicians page.

RedHill Biopharma is currently conducting a large Phase III clinical trial testing one combination of AMAT, RHB-104, in Crohn’s disease patients. RHB-104 is a combination of clarithromycin, rifabutin and clofazimine. The study’s end date is September 2017 with results released in April 2018. For more information on this study, visit the NIH Clinical Trials site. Additionally, a Phase IIa study was recently completed using RHB-104 in multiple sclerosis patients. Interim results were positive, and final results are expected in 2016. See the Treatment of Crohn’s disease with AMAT page for more information.

References

Dalziel, T.K. (1913) Chronic Interstitial enteritis. British Medical Journal, 2, 1068-1070.
Ellingson et al. Detection of viable Mycobacterium avium paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J Food Protection 2005;68(5):966-72.
McDonald, W.L., O’Riley, K.J., Schroen, C.J., Condron, R.J., 2005. Heat inactivation of Mycobacterium avium subsp. paratuberculosis in milk. Appl. Environ. Microbiol.71, 1785–1789.
Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s Disease. Lancet. 2004 Sep 18-24; 364(9439):1039-44