Doctors who treat patients with Crohn’s disease have long regarded the illness as a biological version of friendly fire, where people’s own immune systems mistakenly attack the digestive tract. But Washington State University researcher William Davis said its cause may originate outside the human body - from a germ that sickens cattle.
Working with scientists internationally, Davis is developing a vaccine that could head off the problem.
Why a rod-shaped bacterium that infects cattle is turning up in the intestines of humans warrants far more investigation than it is getting, said Davis, a professor in WSU’s Department of Veterinary Microbiology and Pathology. A new vaccine could save cattle, the livelihood of dairy farmers and ranchers, and lend a measure of protection to humans against the potentially harmful germ, he said.
That germ, Mycobacterium avium subspecies paratuberculosis, or MAP, is related to the microbe that causes tuberculosis.
It causes Johne’s (pronounced yo-nees) disease in the intestines of cattle and other ruminants. This produces symptoms similar to those experienced by people with Crohn’s disease, including drastic weight loss, chronic diarrhea and malnutrition, according to numerous studies on the two disorders.
MAP has infected a staggering number of cattle during the past 100 years. It is secreted in their feces and milk, said Davis, who has been researching the bacterium for two decades. In 2003, he co-authored a report for the National Academy of Sciences on its diagnosis and control.
So when it was identified in the intestines of humans, he and scientists from Canada to Europe paid attention. The theory that it might be making people sick is controversial. If proven, it means modern medicine’s understanding of Crohn’s disease is incorrect and a harmful bacterium is being transmitted via the human food chain.
"We know the incidence of Johne’s is on the rise, as is the incidence of Crohn’s,” said Davis, whose research has included collaboration with physicians and immunologists. "The problem is too important and the theory is sufficiently plausible that we need to be taking a closer look. More research is necessary to resolve exactly what the link is.”
The idea that MAP may be making people sick is not new. In their 2003 report to the National Academy of Sciences, Davis and seven other scientists proposed a possible link to Crohn’s disease.
"This has been a controversial subject attracting strong adherents to both positions, but its resolution is essential for the development of rational approaches to disease management and prevention,” they wrote.
In 2006, the U.S. Department of Agriculture issued a fact sheet acknowledging researchers’ concerns that MAP is being transmitted to humans in undercooked meat, unpasteurized milk and water.
"Because of continued potential public-health concerns related to Johne’s disease, animal-production industries must give it more attention,” the document says.
In 2008, a report by the American Academy of Microbiology said that people with Crohn’s disease are "seven-fold more likely” to have MAP in their gut tissues. While the cause of Crohn’s is unknown, the authors wrote, "the possible role of this bacterium, which could conceivably be passed up the food chain to people, has received too little attention from the research community.”
And just last year, Davis and another WSU researcher published a analysis funded by the National Institutes of Health citing more cases of MAP found in the human population, making further research on cattle essential. More precise testing tools reveal MAP is present in healthy humans as well, said Davis – a finding that "tells us that all humans are susceptible to MAP infection but that its presence doesn’t always lead to disease. While not destroying MAP, the human immune system is keeping it in check.”
Similarly, not all cattle come down with Johne’s, said Davis. Those that do apparently keep MAP under control for two years or so, staying symptom free until something triggers a breakdown in immunity and allows the disease to progress.
"There’s no cure so, from then on, they get sicker and sicker,” he said. "For dairy farmers, it can be a devastating loss.”
Culprit or innocent bystander?
It’s not unusual to find foreign microbes living inside the human gut where thousands of others reside naturally. But how to determine if MAP is harmful or simply hanging out? That’s what further research can establish, said Davis, who wants to investigate the immune response in animal models. It takes extensive study to determine whether a bacterium is primary or secondary, he said.
As for all the people walking around with MAP anchored in their intestines who aren’t ill, the reason is the presence of protective immunity - similar to what’s seen with MAP in cattle, said Davis.
MAP is a mycobacterium known to cause serious illnesses in mammals – just like its cousin, M. tuberculosis, which causes pulmonary tuberculosis.
"Just because an infectious agent is present doesn’t mean everyone will get sick from it,” Davis said, pointing to M. tuberculosis. "Ninety percent of the world’s population infected with M. tuberculosis exhibit no symptoms because their immune systems control infection.
"But we also know that if their immune systems get weakened, such as in the elderly or people with HIV, the disease can become active,” he said. "The situation is most likely the same for infection with MAP.”
‘A huge deal’
Skeptics insist that MAP be consistently found in all Crohn's patients before they will consider it as a potential cause of the disease, according to medical literature critical of the MAP-link theory. But physician and researcher William Chamberlin - who sees Crohn’s patients almost daily - doesn’t need that kind of evidence, he said.
"This is a classic case of the 800 pound gorilla in the living room that’s easier to ignore than to do something about,” said Chamberlin, a gastroenterologist who, in 2011, co-authored a review in the journal Clinical Immunology concluding that Crohn’s is caused by infections, not an autoimmune disorder.
Backing the 2008 report by the American Academy of Microbiology suggesting that Crohn’s isn’t a single disease but a syndrome with different causes, "MAP is but one of them,” said Chamberlin in an interview.
"The idea that MAP triggers a syndrome in humans that we call Crohn’s is a huge deal,” he said. "From a medical treatment perspective, we need to be strengthening the body’s defense, not suppressing it with steroids and other drugs.”
Parallels to ulcer discovery
Chamberlin was an associate professor of gastroenterology at Texas Tech University before moving to Billings, Mont., to treat patients at St. Vincent Hospital.
He likens the MAP controversy to the one that ensued over the link between H. pylori and stomach ulcers 30 years ago. Doctors entrenched in the belief that stress and spicy foods caused ulcers resisted an Australian physician’s evidence that the real culprit was a bacterial infection.
Desperate to prove his point, the physician drank a test tube of the bacteria and swiftly developed an ulcer. Then, instead of using the customary antacids to treat it, he took antibiotics – today considered the standard treatment for most stomach ulcers.
Gulping down a vial of MAP might not lead to disease. But if it did, Crohn’s symptoms are more serious and chronic than stomach ulcers, said Chamberlin.
"Believe me, no one wants to get Crohn’s disease,” said Chamberlin, whose center-stage treatment for the ailment is a cocktail of antibiotics. Properly selected antibiotics are reducing symptoms in many of his patients, he said.
"Philosophers like to say that we never know anything for certain and that truth is based on probabilities,” he said. "That said, with the amount of evidence that has accrued, the probability of MAP being one of the agents that causes Crohn’s symptoms meets my threshold.”
New vaccine to protect
And so, as science moves in fits and starts and skepticism continues to percolate, Davis will soon enter his third decade of MAP research on cattle. In the meantime, seemingly healthy cows continue to transmit the germ into the human food chain.
If scientists can’t reach a consensus on whether this is safe or harmful, Davis hopes to plow ahead by studying the effectiveness of the vaccine that he and a group of international scientists developed by altering MAP’s DNA. Preliminary tests, published in 2011, show that it keeps MAP from launching the biological chaos of infection inside the intestines of cattle and goats, he said.
If scientific scrutiny shows that the vaccine works and it is then administered to cattle, will fewer people get struck by that painful, incurable disease we call Crohn’s?
"I’m not an alarmist; I’m a realist,” said Davis. "That would be the moment of truth.”