A dose of parasitic whipworms cured monkeys with chronic diarrhea, fixing immune systems gone haywire and offering a snapshot of what worms might do for people.
Whipworms are typically considered a scourge, but there's also reason to think they have benefits. In the monkeys, they seemed to restore intestinal bacterial balance and prevent the monkeys' immune systems from dangerous overreaction.
"If you compare monkeys that had colitis with healthy monkeys, there is a big difference in types of bacteria that are attached to the intestinal wall," said microbiologist P'ng Loke of New York University, co-author of a Nov. 15 PLoS Pathogens study of the worm treatment. "Immune response is calibrated to the presence of worms. In their absence, you get a different response."
Loke is part of a small community of researchers working on an emerging theory of autoimmune diseases, which are characterized by immune malfunction. The researchers hold that humans co-evolved with a host of bacteria, viruses and parasites, and actually rely on exposure to these organisms to properly regulate our immune systems.
A decade ago, this was considered a radical idea. But a large body of research now supports the notion, from population-level observations that worm eradication is often followed by autoimmune disease spikes to animal studies of the mechanisms involved.
Parasites, especially those worms known collectively as helminths, provoke a variety of anti-inflammatory responses, allowing them to stay in our bodies. In the absence of exposure, which from an evolutionary perspective is a recent, radical aberration, immune systems can behave strangely. They overreact to what should be harmless stimuli, from dust and pollen to beneficial bacteria living in our stomachs.
"Helminths awake the regulatory side of the immune system. This helps turn off immune responses that aren't needed," said cell biologist Joel Weinstock of Tufts University, who studies worms as a possible treatment for inflammatory bowel disease. "We're no longer being challenged the way Mother Nature intended. This could be one reason why people are getting more immune-mediated diseases today."
Loke's interest in whipworms was stoked by a 2009 visit from a man with ulcerative colitis who'd treated himself by swallowing the eggs of whipworms, which have been largely exterminated from the United States. The disease went into remission, came back after the worms left his body, and went into remission again after another dose.
One anecdote doesn't make for proof, but by studying the man's immune system Loke's team generated several hypotheses about the whipworm's effects. Those were put to the test in the new experiment, which allowed the researchers to study the effects in a controlled setting.
Tested in the experiment were five rhesus monkeys suffering from idiopathic chronic diarrhea, a common condition in captive monkeys that's considered similar to the human affliction of inflammatory bowel disease. In both conditions, mucous that typically lines intestinal walls becomes thin and patchy, and intestines become dangerously inflamed as cells react to bacteria that live naturally in our gut.
After receiving the worms, four of the five monkeys' conditions improved. Their diarrhea stopped. They started gaining weight. Intestinal mucous production increased. The composition of bacteria inside the monkeys' stomachs changed, coming to resemble the bacterial communities of healthy monkeys.
The researchers also measured a host of immune system-related gene activation patterns resembling what they'd seen in their human subject and also in tests on mice.
These dynamics are difficult to untangle, said Loke, and probably involve multiple immune mechanisms. An increase in mucous makes it easier to flush out the worms. "You're basically trying to sneeze the worm out from the gut," he said. But the mucous also reduces inflammation-causing contact between cell walls and bacteria. At the same time, the types of bacteria present change, perhaps becoming less irritating in the first place.
Loke is already conducting a clinical trial of whipworms for people with ulcerative colitis. Other worm trials involve multiple sclerosis, Crohn's disease and even autism, some cases of which may be triggered by immune malfunction.
If the clinical trials succeed, worms could become a standard autoimmune disease treatment, or even be used in children to prevent disease – a strange thought, at first, but there's precedent. After all, many vaccines are made with live viruses.
There are also potential downsides to using worms. In the absence of proper medical care, parasites can be deadly. But Loke and Weinstock say it's possible to keep the side effects under control. It might also be possible to replicate the worms' activity with drugs, or to design worms that offer health benefits without problems.
"Helminths have been neglected," said Weinstock. "When you look at all the discoveries made from plants, bacteria and fungi, helminths have definitely been overlooked. They have such amazing powers, and they've barely been studied."
Citation: "Therapeutic Helminth Infection of Macaques with Idiopathic Chronic Diarrhea Alters the Inflammatory Signature and Mucosal Microbiota of the Colon." By Mara Jana Broadhurst, Amir Ardeshir, Bittoo Kanwar, Julie Mirpuri, Uma Mahesh Gundra, Jacqueline M. Leung, Kirsten E. Wiens, Ivan Vujkovic-Cvijin, Charlie C. Kim, Felix Yarovinsky, Nicholas W. Lerche, Joseph M. McCune, P'ng Loke. PLoS Pathogens, 15 November 2012.
