For the past 40 years, gastroenterologist David Y. Graham has been researching Mycobacterium avium paratuberculosis (MAP), a bacterium that widely infects cattle and other ruminants. “MAP infection is in 90% of U.S. dairy herds, which means the MAP bacterium is also in our milk, meat and infant formula,” says Graham, a professor at Baylor College of Medicine in Houston who is perhaps best known for his supporting role in the Nobel-winning discovery that the Helicobacter pylori bacterium causes peptic ulcers.  

Like Graham’s work with ulcers, his interest in MAP is tied to a long-standing mystery. In this case the chronic condition is Crohn’s disease, which causes inflammation of bowel tissue and can lead to bouts of pain, fatigue and malnutrition. Crohn’s has no known cause, but Graham and a host of other researchers are convinced that at least some cases are the direct result of MAP infection. A major study from fall 2019 and the launch of trials for a MAP vaccine—suspended by the COVID-19 pandemic but to resume “in a few months,” the investigators hope—may help solve the mystery.

In other animals, MAP can target the intestines and infect key cells of the immune system, particularly white blood cells called macrophages, depleting them of iron—a process that results in chronic inflammation. It has been known for more than a century that MAP infection in cattle can cause Johne’s disease, a wasting gastrointestinal condition characterized by diarrhea and intestinal ulcers that is often fatal.

But trying to draw a line between MAP and Crohn’s disease has been complicated by the difficulty of testing for MAP in humans. In 1984, a team did culture MAP specimens from the blood and tissue of three people with Crohn’s disease. But even current methods can require as many as six months to culture MAP from a human sample—MAP bacterium grows very slowly and has very specific nutritional requirements—and it took another 20 years for the 1984 discovery to be replicated because scientists didn’t have the techniques or appropriate culture media until many years later. “We’re about a year away from developing good screening tests for MAP,” Graham says.

While some research has found that those with Crohn’s disease are more likely to have the MAP bacterium present, the burden of proof has never quite been met to establish a connection. “There is no governmental agency—the Department of Agriculture, the Centers for Disease Control and Prevention—that has declared MAP a zoonotic infection because we only have indirect evidence that MAP causes any human disease,” says Michael T. Collins, professor emeritus at the University of Wisconsin-Madison School of Veterinary Medicine.

Another problem is that it may take a long time for a MAP infection to cause clinical symptoms. As with other microbes that are thought to lead to diseases years or decades later—such as certain viruses suspected of causing cancer—trying to follow the course of the infection runs into hundreds of confounding factors, and running a perfectly controlled experiment may be unachievable. “Direct evidence that MAP causes Crohn’s disease is impossible to obtain, as it would be unethical to infect very young children with MAP, wait 15 years and see what happens,” Collins says.

But there could be back-door approaches to show a MAP connection. One might be to demonstrate that a MAP vaccine keeps the disease from developing. Or, in the shorter term, researchers could use antibiotics to kill MAP, a tack that Graham followed in recent research. In results of a randomized trial that he presented to the American College of Gastroenterology in fall 2019, 39% of Crohn’s patients who received antibiotics known to be effective against MAP had clinical remission after 26 weeks of treatment versus 23% on a placebo, and after a year of treatment, 19% had remission on the study drug versus 9% on a placebo.

“We showed a meaningful, positive response” for anti-MAP therapy, Graham says. “Trials for most drugs now prescribed for Crohn’s disease have a response rate just barely above the placebo rate, and our study drug was a big improvement over placebo.”

Yet some researchers remain skeptical that MAP is the main culprit in Crohn’s disease. Maria Abreu, chief of gastroenterology at the University of Miami Health System who researches microbial causes of inflammatory bowel disease, calls the study’s results “very muted.” “It’s very likely that other bacteria, viruses or fungi prompt infection in patients with inflammatory bowel disease,” says Abreu, who says she believes that the cocktail of antibiotics in Graham’s study may have also acted on those other pathogens. That the remission rate was lower after one year than at 26 weeks was another red flag, she says. “MAP is a difficult-to-treat bacterium, but the response to treatment shouldn’t be lower the longer people take the antibiotics,” she says.

Still, Abreu says she would consider prescribing anti-MAP antibiotics. “It would be fantastic if 25% of patients could be cured in this way,” she says. But better tests for the infection will be key. “I need to know that these patients actually have MAP infection rather than just prescribing antibiotics for all my Crohn’s patients,” she says.

A vaccine against MAP could be a longer-term strategy. The first phase of clinical trials at the Jenner Institute at Oxford was completed before the pandemic hit, and that candidate vaccine uses the same platform as the institute’s potential COVID-19 vaccine, which recently entered phase 3 trials. The MAP vaccine trials are expected to resume by early fall.

If the MAP connection to Crohn’s disease is proved, there may be another way to stop human infection before it happens. “We have the knowledge and diagnostic tools in veterinary medicine to address this,” Collins says. Although treating cattle for MAP isn’t an option—the cost is prohibitive and treated animals’ milk and meat can’t be sold for human consumption—cows could be tested for the pathogen and infected animals then culled from the herd to prevent widespread infection and exposure to people. “But it’s up to the medical community to label MAP as a zoonotic pathogen,” Collins says. “That would give the mandate to government agencies to do the right thing and limit human exposure to MAP.”