Crohn’s disease is a devastating inflammatory disorder, characterised by chronic inflammation of the intestines, which can have significant consequences for a patient’s quality of life. Currently there is no cure, but this could all be about to change…

At this time, the etiology of Crohn’s disease is unknown. There are a multitude of hypotheses which have been put forward to explain the underlying cause, but as yet, none have been proven. It is widely believed that a triad of factors are responsible; genetics, environment and an abnormal immune response to antigens [1]. However, there is one particular hypothesis which is gaining substantial traction in the field, known as the “MAP hypothesis”. This suggests that a pathogen called Mycobacterium avium paratuberculosis (MAP) is responsible for causing Crohn’s disease, having fulfilled Koch’s postulates [2]. An excellent article [1] within Expert Review of Gastroenterology & Hepatology by a world leader in this area, Professor David Y Graham, is a great place to begin further reading.

Whether or not MAP is a causative agent in Crohn’s is currently a topic of great debate, with evidence both in support and opposition. Proponents of this hypothesis point to the fact that this bacterium has a causative role in Johne’s disease, a chronic inflammatory condition in cattle with remarkably similar symptoms and presentation as Crohn’s in humans [1]. This offers substantial support to the suggestion it may have a zoonotic effect in humans as a causative agent in Crohn’s. The theory goes that MAP infects humans via ingested milk and meat products from diseased cattle [3]. This is reinforced by MAP being isolated in milk products even following pasteurisation, including powdered infant formula [4,5]. Most people are able to consume these and then identify and destroy MAP as part of a healthy immune response. Crohn’s disease patients however are not able to do this; this is likely due to genetically determined faults in their immune system in addition to other triggers.

Subsequent studies using modern polymerase chain reaction (PCR) techniques have allowed for MAP to be identified in between 50-100% of Crohn’s disease patients, this is significantly more than in healthy individuals [1]. These techniques however, are not perfect. This organism is notoriously difficult to isolate from human samples, due to its ability to hide in a dormant state within human cells and thus not show under microscopy or reliably with PCR [6]. This has led many to discount this hypothesis, arguing that it cannot possibly be causative if it is not present in all patients.

Consequently, both to implicate MAP in the pathophysiology of Crohn’s and also improve diagnosis, there has long been a need for a new method of dependable detection. Multiple groups around the world are currently doing ground-breaking work in this area. Within the UK, a group at Kings College London led by Professor Hermon-Taylor, funded largely by donations, are currently developing a novel blood test which allows for the in-situ visualisation of MAP in the cells of Crohn’s disease patients. Likewise, Quest Diagnostics (London, UK) in collaboration with Israeli pharmaceutical giant RedHill Biopharma are developing a similar test. Early indications from Hermon-Taylor’s group are that MAP has been identified within the cells in the blood of all those patients tested so far, which is highly promising.

It is thought that MAP cloaks itself within our own white blood cells and thus causes destructive inflammatory damage from a safe haven away from the immune system [2]. A device manufactured by Otsuka (Tokyo, Japan), known as Adacolumn certainly provides support to this notion. The device allows for selective macrophage apheresis, meaning certain white blood cells, specifically granulocytes and macrophages, are removed from the blood stream and this induces remission. Alternatively, this effect could simply be explained by removal of the source of pro-inflammatory compounds.

Taking all of this into account, the importance of this diagnostic test cannot be overstated. If the test allows for the reliable visualisation of MAP within infected cells, then our whole understanding of Crohn’s disease may change as a result. Moreover, a quick and relatively simple blood test to aid in a diagnosis of Crohn’s disease would certainly be welcomed by patients and clinicians alike, as opposed to the lengthy, costly and invasive measure currently employed to reach a diagnosis.

It must be stated that even with all of these data pointing towards MAP as a presence in patients, correlation does not equal causation. As a result, in the past, efforts have been made to directly eliminate MAP with anti-tubercular antibiotics. Most notably, a trial headed up by Dr Selby (Royal Prince Alfred Hospital, Sydney, Australia) in Australia in 2007 was focused on this aim. The trial concluded that anti-MAP therapy was no better than placebo [7]. Accordingly, opponents to the theory argued that as all patients did not improve, MAP was not a cause, which became the widely accepted view of the field. Subsequent analyses of the trial however, revealed flaws that could explain the incomplete response in some patients, even revealing that remission rates were actually substantially higher than those of conventional treatments using steroids and immunosuppressants [8]. As a follow on from this, a Phase III trial is currently underway with another anti-MAP therapy, RHB104, taking into account these initial errors in design. The results are hotly anticipated and if these new doses are sufficiently effective, it could answer a lot of the controversy, potentially changing current opinions on the pathophysiology of the disease. Importantly, it would provide patients with another treatment alternative. Current therapies are inadequate and ineffective in some patients, coupled with serious side effects such as those from steroids, or the risks of malignancies from immunosuppressants and biologics. The possibility of a one pill combination treatment is appealing.

Focusing on the future, as with many diseases caused by infection, if this is shown to be the case with Crohn’s disease, then a cure is theoretically possible through therapeutic vaccination. Alongside the diagnostic test, Professor Hermon-Taylor (Kings College London, London, UK), in collaboration with the Jenner Institute has developed such a vaccine. Phase I trials in humans are scheduled to begin in September 2016. This has already been shown to eliminate MAP in infected cattle [9]. It is believed the vaccine will provide the immune systems of Crohn’s disease sufferers the weaponry to eliminate MAP from the body, supplying both an effective treatment and a preventative measure in one.

Hopefully in the coming years the new data being brought to light, along with novel diagnostic tests can drive research to further improve our understanding, allowing the field of gastroenterology to finally unite in curing this debilitating disease. We only need to remember the example of peptic ulcer disease and the original disinclination to accept an infectious underlying mechanism to appreciate that this MAP hypothesis cannot be blindly ignored.

References

[1] McNees AL, Markesich D, Zayyani NR, Graham DY. Mycobacterium paratuberculosis as a cause of Crohn’s disease. Expert Rev Gastroenterol Hepatol 2015; 9: 1523-34.

[2] Gitlin L, Borody TJ, Chamberlin W, Campbell J. Mycobacterium avium ss paratuberculosis-associated Diseases Piecing the Crohn’s Puzzle Together. J Clin Gastroenterol 2012; 46: 649-655.

[3] Lombard JE, Gardner IA, Jafarzadeh SR, Fossler CP, Harris B, Capsel RT, Wagner BA, Johnson. Herd-level prevalence of Mycobacterium avium subsp. paratuberculosis infection in United States dairy herds in 2007. Prev Vet Med 2013; 108: 234-238.

[4] Millar D, Ford J, Sanderson J, Withey S, Tizard M, Doran T, Hermon-Taylor J. IS900 PCR to detect Mycobacterium paratuberculosis in retail supplies of whole pasteurized cows’ milk in England and Wales. Appl Environ Microbiol 1996; 62: 3446-3452.

[5] Botsaris G, Swift BMC, Slana I, Liapi M, Christodoulou M, Hatzitofi M, Christodoulou V, Rees CED. Detection of viable Mycobacterium avium subspecies paratuberculosis in powdered infant formula by phage-PCR and confirmed by culture. Int J Food Microbiol 2016; 216: 91-94.

[6] Hermon-Taylor J. Mycobacterium avium subspecies paratuberculosis, Crohn's disease and the Doomsday Scenario. Gut Pathog 2009; 1: 15.

[7] Selby W, Pavli P Crotty B, Florin T, Radford-Smith G, Gibson P, Mitchell B, Connell W, Read R, Merrett M, Ee H, Hetzel D. Antibiotics in Crohn’s Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology 2007; 132: 2313-2319.

[8] Lipton JE, Barash DP. Flawed Australian CD Study Does Not End MAP Controversy. Gastroenterology 2007; 133: 1745-1746.

[9] Bull TJ, Vrettou C, Linedale R, McGuinnes C, Strain S, McNair J, Gilbert SC, Hope JC. Immunity, safety and protection of an Adenovirus 5 prime - Modified Vaccinia virus Ankara boost subunit vaccine against Mycobacterium avium subspecies paratuberculosis infection in calves. Vet Res; 45: 112.