Recently, I came across an article in a local newspaper that raised concerns about cattle as a source of zoonotic pathogens, in particular with regard to Mycobacterium avium subspecies paratuberculosis (MAP) – the causative agent of Johne’s disease in cattle and other ruminants.
While the topic merits discussion, the author of the newspaper article, who holds a master’s degree in public health, drew conclusions that were quite alarmist and asserted that there was mounting evidence that MAP can spread to humans. Like many of us, I had heard about the association between human Crohn’s disease and MAP, but I had never examined the actual evidence. Intrigued, I started digging. This article offers some background and summarizes scientific evidence on the long-debated association between Johne’s disease in cattle and Crohn’s disease in people.
The longstanding debate on whether MAP plays a role in Crohn’s disease in people started more than a century ago. But, let us start with some background information on the cattle disease, which MAP is responsible for. Johne’s disease is a widespread chronic infectious disease affecting cattle and other ruminants. The fecal-oral route is the most important way of transmission in cattle. Susceptibility decreases with age, and there is a long latent period when animals appear completely normal. In fact, only a fraction of infected cattle will go on to develop clinical disease. The immune system appears to be able to limit the infection for years, similar to infections with Mcyobacterium tuberculosis in humans, where only 5% to 10% of those infected go on to develop clinical tuberculosis. Over 90% of dairy herds in the U.S. are estimated to be infected with MAP today.
One of the questions people outside the cattle industry might have is: Why aren’t we doing anything about Johne’s disease?
Cattle producers would love to get rid of Johne’s disease, but it is difficult to eradicate from a herd, and few tools are available. There is no cure for Johne’s disease. Testing to find infected animals is challenging because animals in the early stages of infection often test negative on diagnostic tests. Use of a vaccine is tightly regulated because vaccinated animals will test positive on a tuberculosis test, and the vaccine has not shown to be very effective. One available tool to reduce Johne’s disease in cattle herds involves the use of a risk assessment of management practices and several years of commitment to risk reduction through hygiene and biosecurity, testing, isolation and timely removal of positives. Some infected animals become supershedders that contaminate the environment at a high rate. This fact, together with MAP’s ability to persist in the environment for years in a vegetative state, can make eradication difficult and frustrating. The USDA promotes control of the disease to limit its spread, but there is no national eradication program for Johne’s disease in the U.S.
Let’s now talk about why MAP has been linked to Crohn’s disease in people. Crohn’s disease is an inflammatory bowel disease affecting approximately 1.4 million people in North America that can cause diarrhea, weight loss and malnutrition in affected patients, and its causes are not well understood. The discussion on MAP’s role in Crohn’s disease started a long time ago, in 1913, when Scottish surgeon Thomas Kennedy Dalziel noted similarities between the cattle and human disease presentations. Early attempts at culturing MAP from Crohn’s patients were unsuccessful, but more modern techniques have often been able to show that the bacterium is present in Crohn’s patients on average about seven times more frequently than in healthy controls. The fact that MAP is also found in healthy people is not reason enough to exclude it as a cause, as these individuals could be subclinically infected. Controversy surrounding the consistency of results stems from the difficulty of culturing the fastidious organism in the laboratory or the way polymerase chain reaction-based assays that look for DNA or RNA specific to MAP have been applied. Either way, showing the presence of MAP in people is technically challenging, and available evidence is difficult to interpret.
Why hasn’t this evidence convinced us to assume that MAP is also causing Crohn’s disease?
The reason why MAP hasn’t universally been accepted as a causative agent of Crohn’s disease goes back to the premise that an association does not prove causation, meaning that just because two things happen together does not mean that one causes the other. One of the most important ways to show that a certain exposure causes a disease is temporality, i.e., the exposure must happen before the disease. A sort of litmus test for whether a suspected pathogen causes a disease requires that a suspected pathogen is isolated from a sick individual, grown in the lab and then causes the same disease when a healthy individual is experimentally infected. Animals experimentally infected with MAP have developed Johne’s disease, but for obvious ethical reasons, we cannot perform these tests in people. Most of the studies on MAP and Crohn’s disease are so-called case-control studies, where patients with the disease are matched to controls without the disease, or with a different disease, and their exposures or risk factors are compared. Case-control studies cannot show temporality because the case participants already have the disease, so it is impossible to say whether they became sick after they were infected with MAP or the other way around. Although case-control studies are a valuable epidemiological tool, they are vulnerable to bias because cases may differ from controls in ways that confound results and can be hard to detect. Furthermore, results from these studies have not been consistent, leaving some questions as to the robustness of the findings.
A concept that would strengthen an association to show causation is dose response, which means if exposure increases, risk goes up as well. Studies that assessed the risk of Crohn’s disease in those with the highest exposure to MAP (i.e., cattle producers and veterinarians) found no increase in risk for Crohn’s disease for members of these groups. On the other hand, the so-called hygiene hypothesis speculates that improved hygiene in developed countries, resulting in decreased exposure to infectious agents in early life, leads to increased risk of allergic disorders. The hygiene hypothesis may offer an explanation for why high environmental exposures to MAP could actually result in some protective immunity. On the flip side, there are reports of increased incidence of Crohn’s disease in areas with suspected high MAP burden in water sources from agricultural runoff.
A more definitive answer to the question of causality is expected from randomized controlled trials with antimicrobials to eliminate MAP from Crohn’s patients. If those in the treatment group have better outcomes (i.e., fewer symptoms or longer remission) than those in the placebo group, and there is evidence that MAP has been eliminated from their bodies, it could be regarded as evidence that MAP is indeed playing a role in the disease. The results of at least one such study are expected to be published in the near future.
On their webpage, the Crohn’s & Colitis Foundation lists genetics and living in developed countries in an urban environment in a northern climate as risk factors for Crohn’s disease. They explain that in people with Crohn’s disease, “harmless bacteria are mistaken for foreign invaders, and the immune system mounts a response. The inflammation caused by the immune system does not go away. This leads to chronic inflammation, ulceration, thickening of the intestinal wall and, eventually, symptoms of Crohn’s disease.” There is no mention of a link between MAP and Crohn’s disease on their webpage.
This brings us to our last question: Are cattle on public lands, or in places where contact with the public is likely, a health threat because some of them are shedding MAP, as described in the article mentioned in the beginning?
Zoonotic pathogens are a serious problem that should not be brushed off. We know about pathogens from livestock (e.g., E. coli O157:H7, cryptosporidium, campylobacter, salmonella), and we have many safeguards in place to minimize exposure to these pathogens (e.g., milk pasteurization and hazard analysis and critical control point principles during carcass processing). In the case of MAP, pasteurization reduces, but does not completely eliminate, viable bacteria in milk. Anyone who consumes milk or other dairy products is very likely exposed to MAP on a regular basis, especially if the milk is consumed raw. MAP can also often be found in drinking water because it resists chlorination. Exposure to MAP is widespread, yet cases of Crohn’s disease are relatively rare, and a large study from 2016 actually found a decreased risk of developing Crohn’s disease for people with higher milk consumption. Warnings against contact with cattle to reduce MAP seem, therefore, unfounded.
In conclusion, although some evidence suggests an association between MAP and Crohn’s disease, our current knowledge does not support a definitive causative role of MAP in the disease. What leads to Crohn’s disease is still not well understood. Future studies may be able to more definitively explain what role MAP is playing in Crohn’s disease.
