For decades, patients were just told to accept the fact that there is no known cause for Crohn’s disease. To rub salt into the wound, there was – and still is – no cure or one treatment that worked consistently for everyone with Crohn’s disease.
But recent research is challenging these long-held beliefs. There is growing evidence that Crohn’s disease could have an infectious cause, which I wrote about in my article, 3 Surprising Microbial Triggers of Crohn’s Disease.
There is one particular microbe that is gaining more and more attention – Mycobacterium avium subspecies Paratuberculosis, better known as MAP. And a MAP infection may be treatable.
What is Mycobacterium avium subspecies Paratuberculosis?
Mycobacterium avium subspecies Paratuberculosis (MAP) is a bacterium belonging to a family of bacteria called Mycobacteriaceae. Does “Paratuberculosis” make you think of any diseases you might be familiar with? If you answered tuberculosis, you’d be correct. MAP is in the same family as the bacteria that cause tuberculosis (Mycobacterium tuberculosis).
MAP is also the cause of Johne’s disease, a systemic infection and chronic inflammation in the intestine of animals, but most commonly in domestic livestock. Johne’s disease sounds a bit like Crohn’s disease, doesn’t it? They share more similarities than their names, though. Both Crohn’s disease and Johne’s disease are forms of Inflammatory Bowel Disease (IBD), and as such, they share some clinical and pathological features (although their similarity has been overstated). Some of their similarities include:
- Chronic diarrhea
- Dull hair
- Weight loss
- Cycle of remission and relapse
- Occasional granulomatous appearance
- Growth of lesions in:
- Esophagus and oral cavity
- Ileum and colon
- Mesenteric lymph nodes
- Rectum, anul
In fact, these similarities are how scientists came to suspect MAP as an infectious cause of Crohn’s disease. So, is it just a coincidence that these two diseases share features, or could they share a common cause, too?
To answer this question, let’s look at how humans are exposed to MAP.
How Are Humans Exposed to MAP?
In ruminants like cows, MAP is transmitted primarily via the fecal-oral route. Most calves are infected within their first month of life. The infection is followed by a long symptom-free period of 3 to 5 years, and only 10% to 15% of calves develop fatal clinical disease. The critical point to make here is that animals infected with MAP can shed the bacteria in their stools, even during the latency period.
And this spells serious trouble for humans.
MAP, along with feces, is deposited onto pastures, where rain can wash it into nearby water sources. In fact, MAP DNA was detected in over 80% of domestic water samples in Ohio! And MAP is one tough bug – studies have found that MAP can survive chlorine disinfection treatment used in drinking water systems.
Other animals, including rabbits and wild ruminants like deer, can also be infected secondarily and shed MAP into the environment. Once shed, MAP can live in the environment for between 12 weeks and a year in soil or water, giving you plenty of opportunity to become infected.
But it doesn’t stop there. MAP can also contaminate our food supply, especially dairy and meat products. Pasteurization can significantly reduce the risk of contamination, but does not eliminate it due to the thick lipid cell wall of MAP that allows it to survive the process. In one study, up to 25% of pasteurized cow’s’ milk tested positive for live MAP during peak periods.
Such a widespread environmental prevalence of MAP can only mean one thing: humans are chronically exposed to MAP. But why does it affect some people more than others? Let’s discuss that next.
Why do Only Some People Exposed to MAP Get Crohn’s Disease?
If so many people are exposed to MAP, wouldn’t there be more people with Crohn’s disease? And why isn’t there an epidemic of MAP infection among dairy farmers?
There are a variety of factors that influence whether an individual develops Crohn’s disease or another disease (like ulcerative colitis) caused by MAP. And not everyone infected by MAP develops a disease caused by the bacterium. Let’s look at a few factors that can determine whether an individual develops a disease when infected with MAP:
- The dose of MAP to which the person is exposed & frequency of exposure: In susceptible individuals, a significant number of MAP can build up over time. High levels of MAP are likely to cause Crohn’s disease.
- The route of infection: Routes of infection that increase the concentration of MAP increase the risk of Crohn’s disease. Examples of such routes include aerosolized water from contaminated rivers and hyperosmolar milk.
- Age of individual infected: It takes less MAP to cause Crohn’s disease in a child than it does in an adult.
- Genetic and acquired susceptibility: Certain genes control how intracellular bacteria are processed in the body, and these seem to have a slight effect on the risk of developing Crohn’s disease. Also, individuals with a history of illness may not be able to handle MAP in the way that health people do. In other words, in a health person, macrophages eat and digest MAP, and T-cells eradicate any cells that contain MAP. When these processes do not occur for whatever reason, a person can develop Crohn’s disease.
- Sex: Infant males and adult females tend to develop Crohn’s disease more often when infected with MAP.
The Two Forms of MAP
Paradoxically, children who come into contact with farm animals are less likely to develop juvenile Crohn’s disease. Part of the reason is that occupational exposure to the bacterium increases the antibody levels. But there’s more to the answer – MAP exists (and can switch between) in two forms:
- ZN-positive phenotype (physical characteristics): Mycobacteria are acid-fast organisms, meaning they have cell walls that enables them to be resistant to acid-based decolorization used in many bacteria staining procedures. These organisms need to be stained by a process called Ziehl-Neelsen (ZN) staining and are thus said to have an “encapsulated” or ZN-positive phenotype. It is this phenotype of MAP that can live outside of other cells and is excreted by infected animals. However, humans are not susceptible to it, and may even acquire natural immunity to disease as a result of the exposure.
- ZN-negative phenotype: When MAP is taken up into a host’s white blood cells, MAP sheds its “capsule.” This “naked” from is called a ZN-negative phenotype, which means the gold standard ZN staining cannot be used to detect it. Even without its “capsule,” MAP is extremely tough and can resist many chemical and enzymatic efforts to break it down. It is also much more virulent to humans and is the form found in most people with Crohn’s disease.
How to Test for MAP
This is where already frustrated patients run into more doors – standard methods for detection of MAP, such as ELISA assays, have notoriously low sensitivity and specificity, which makes them unreliable. As discussed above, the ZN-negative phenotype found in most Crohn’s disease patients renders traditional bacteria staining tests useless.
To add to these difficulties, ordinary microscopes can’t see MAP. Fecal cultures can identify the presence of the bacterium, but MAP grows very slowly – it can take 3 months or more just for colonies to appear on a bacterial culture dish.
Some studies have used molecular techniques such as polymerase chain reaction (PCR) to overcome these challenges. However, the availability of such tests is extremely limited for many patients.
But there is another way. Otakaro Pathways, a New Zealand-based company, has developed a highly reliable test for the detection of MAP, and the kit is available to patients. All you need to do is send a sample of your blood, and the results will be delivered to you by e-mail in 30 days. Essentially, this test acts as a biomarker (a measurable indicator) to support the diagnosis of Crohn’s disease or other autoimmune diseases.
Can MAP Infections Be Treated?
The goal of traditional Crohn’s disease treatment is to reduce the inflammation that triggers the symptoms and to limit complications. A treatment plan for Crohn’s disease can include various agents, such as:
- Anti-inflammatory drugs (ex: corticosteroids, oral 5-aminosalicylates)
- Immune system suppressors
- Pain relievers
- Iron supplements
- Vitamin B-12, calcium, and/or vitamin D supplements
- Nutrition therapy
Unfortunately, therapy for Crohn’s disease is imperfect, and relapses are common even after surgery.
And there’s another issue with the conventional treatment: It doesn’t treat the cause of Crohn’s disease. For patients with active MAP infections, unless the MAP is treated, doctors are only addressing the mechanism of the disease.
How Do You Treat a MAP Infection?
MAP is a member of the M. avium complex (MAC), a group of atypical bacteria that is notoriously difficult to treat with the traditional antimicrobial drugs. In a 5-year study, treatment of patients with Crohn’s disease using anti-tuberculosis drugs (isoniazid, ethambutol, and rifampicin) failed to demonstrate consistent improvement.
There are, however, some evidence to suggest that MAP-specific treatments can result in at least a partial remission of Crohn’s disease. The current therapy includes a combination of antimicrobials that have demonstrated impressive activity against mycobacterial species:
- Rifabutin (RIF)
- Clarithromycin (CLA)
- Clofazimine (CLO)
This combination therapy has been tested in several clinical trials, which have reported clinical remission rates ranging from 44% to almost 90%.
The Landmark Study
The “landmark study” among anti-MAP clinical trials is considered to be that conducted by Selby et al. in 2007. This was a two-year, phase 3, parallel-group, placebo-controlled, double-blind trial designed to assess the combination therapy of a steroid and CLA, CLO, and RIF in 213 patients with active Crohn’s disease.
Although remission was induced within the first 16 weeks for 66% of patients receiving the antibiotic therapy, there was no evidence for a long-term benefit. This was a huge blow. For many, this failure was considered to be the “final nail in the coffin” for the MAP/Crohn’s hypothesis.
However, there were many weaknesses in the trial’s design and analysis. For example, the investigators did not test patients to confirm a MAP infection before the start of the trial and did not use the optimal therapeutic doses for the three antibiotics used. Had the investigators included only patients with a MAP infection in the study, the benefits would likely have been more substantial.
In fact, when the results were re-analyzed using an “intent-to-treat” analysis, the combination of the 3 antibiotics and steroids performed significantly better than the placebo. In contrast to Selby et al.’s report that benefits peaked at 16 weeks and declined afterwards, the authors of the reanalysis observed that the benefits continued through week 104.
What does all of this mean? It simply means that the largest anti-MAP clinical trial was unreliable and therefore, it holds little significance. It also revealed the desperate need for a well-designed clinical trial for anti-MAP therapy.
And we didn’t get this trial for a long time – until very recently.
RHB-104 – A Groundbreaking Therapy for Crohn’s Disease?
Based on the increasing evidence supporting the MAP/Crohn’s disease hypothesis, RedHill Biopharma developed RHB-104, a novel formulation that combines CLA, CLO, and RIF in a single pill at lower dosages.
The low dose of each antibiotic was an important factor in developing RHB-104. Data from pre-clinical trials showed that at combined low doses, the three antibiotics exerted a synergistic antibacterial activity against MAP, an effect that was not seen when they were tested individually or in pairs. This simply means that when the three antibiotics are combined at low doses, their effect is greater than a higher dose of an individual antibiotic.
The lower concentrations were beneficial in other ways as well, including a more tolerable dose regimen and a decreased risk for bacterial resistance.
Following these encouraging preclinical trial results, RHB-104 was tested in a multicenter, randomized, double-blind, placebo-controlled, parallel group phase III trial involving about 331 patients with moderate to severe active Crohn’s disease. Patients were divided into two treatment groups as follows:
- Patients receiving 5 RHB-104 capsules orally twice daily (95 mg CLA, 45 mg RIF, and 10 mg CLO)
- Patients receiving 5 placebo capsules orally twice daily
Patients took the medication or placebo for 26 weeks and were monitored for an additional 26 weeks for a total of 52 weeks. At weeks 16, 26, and 52, the investigators evaluated patients for clinical remission, defined as a value less than 150 on the Crohn’s Disease Active Index (CDAI). Each time, RHB-104 demonstrated clear superiority over the placebo. At the one-year mark of the study, 25% of the anti-MAP recipients and 12% of the placebo recipients were in clinical remission.
More information about this phase III MAP trial can be found at clinicaltrials.gov.
The Fight Against MAP – A Success Story
I had the privilege of working with a young female patient in her 20s. She had been diagnosed with rheumatoid arthritis and Crohn’s disease, but was having a hard time finding relief from her chronic, severe pain. On a scale from 1 to 10 (with 10 being excruciating pain), her pain was about at 8 – she was in agony all the time.
From my experience, I’ve learned to consider the possibility of an infection whenever a patient is suffering from significant pain. First, I did the typical Crohn’s disease workup – the stool sample, the blood tests to check for deficiencies and infection, etc. We also sent a blood sample to Otakaro Pathways, and results showed she indeed had a MAP infection.
With this information, we began treatment with two antibiotics. As mentioned previously, a MAP infection is normally treated with a combination therapy of 3 antibiotics. In this case, however, I only used two antibiotics because the patient could not tolerate a third.
Within 30 to 60 days, the patient was pain-free and symptom-free – it was an incredible, dramatic turnaround! I had her continue taking the antibiotics for 9 months. The patient did well for about 6 months after stopping the therapy, but recently experienced a small relapse due to the high stress of wedding planning. We decided to put her back on a short-term antibiotic therapy, and I am happy to report that she is doing very well.
I firmly believe that the patient would have stayed in remission had it not been for the stress of wedding planning.
Now, I know many of you are probably shocked. What in the world could I be thinking putting a patient on a 9-month course of antibiotics? And you’re right. Typically, I am not a fan of antibiotics. When used excessively and irresponsibly, antibiotics can do irreversible damage to your gut microbiome.
However, in cases such as this where a patient is suffering from chronic illnesses that would otherwise have no cure, antibiotics can have a life-changing and curative effect. Of course, I carefully monitor my patients during long courses of antibiotics and do everything I can to protect the gut, including:
- High-doses of probiotics (100–600 billion CFU/day)
- Strengthening the gut through natural supplements like Gut Immune
- Checking for signs of gastritis or pain
- Advising patients to take antibiotics with food
- Using antifungals if signs of a fungal or yeast infection are present
I think this was a good lesson in learning to think outside of the box. Had this young lady not been diagnosed with a MAP infection, she would have continued living in chronic pain.
Has the Mystery of Crohn’s Disease Been Solved?
Less than two decades ago, experts were still debating about MAP’s roles in Crohn’s disease. Many argued that there were insufficient data to support the hypothesis that MAP could cause the disease or that it was a significant human pathogen.
But the possibility that MAP causes human disease can no longer be ignored. Crohn’s disease has become a worldwide epidemic, and there is growing evidence that it is not an autoimmune disease as previously thought.
We need reliable methods of detecting, diagnosing, and treating MAP, and the acknowledgement of its role as a cause of Crohn’s disease could be the first step in solving this complex disease.
The possibility of MAP as a cause of Crohn’s disease isn’t new, but do you think it’s the sole cause? What are your thoughts about MAP and its role in Crohn’s disease? Share your thoughts in the comments below!