The parasitic worms that lurk in some people’s intestines may be revolting, but they seem to forestall Crohn’s disease and other types of inflammatory bowel disease (IBD). A new study might explain how, revealing that the worms enable beneficial microbes in the intestines to outcompete bacteria that promote inflammation. The results could lead to new ways of treating gut diseases by mimicking the effects of the parasites.
“It’s a beautifully done paper,” says immunologist Joel Weinstock of Tufts University in Boston, who wasn’t connected to the work. “It had not been previously shown that one of the mechanisms [of IBD] is through changes in the intestinal flora.”
In people with IBD, inflammation in the digestive tract results in symptoms such as diarrhea and bleeding and can sometimes lead to intestinal obstructions or other severe complications. Because parasitic worms, or helminths, can be harmful, they appear to be unlikely allies against these diseases. “They are called parasites for a reason,” says immunologist Ken Cadwell of the New York University School of Medicine in New York City, a co-author on the new study. However, IBD is rare in parts of the world where helminths are prevalent, and it is surging in more developed countries, where few people now carry the intestinal intruders. That difference suggests, researchers say, that they are protective.
To determine how the worms could be our frenemies, Cadwell and colleagues tested mice with the same genetic defect found in many people with Crohn’s disease. Mucus-secreting cells in the intestines malfunction in the animals, reducing the amount of mucus that protects the gut lining from harmful bacteria. Researchers have also detected a change in the rodents’ microbiome, the natural microbial community in their guts. The abundance of one microbe, an inflammation-inducing bacterium in the Bacteroides group, soars in the mice with the genetic defect.
The researchers found that feeding the rodents one type of intestinal worm restored their mucus-producing cells to normal. At the same time, levels of two inflammation indicators declined in the animals’ intestines. In addition, the bacterial lineup in the rodents’ guts shifted, the team reports online today in Science. Bacteroides’s numbers plunged, whereas the prevalence of species in a different microbial group, the Clostridiales, increased. A second species of worm also triggers similar changes in the mice’s intestines, the team confirmed.
To check whether helminths cause the same effects in people, the scientists compared two populations in Malaysia: urbanites living in Kuala Lumpur, who harbor few intestinal parasites, and members of an indigenous group, the Orang Asli, who live in a rural area where the worms are rife. A type of Bacteroides, the proinflammatory microbes, predominated in the residents of Kuala Lumpur. It was rarer among the Orang Asli, where a member of the Clostridiales group was plentiful. Treating the Orang Asli with drugs to kill their intestinal worms reversed this pattern, favoring Bacteroides species over Clostridiales species, the team documented.
Cadwell and colleagues also asked whether Clostridiales and Bacteroides microbes were at odds in other people. They analyzed two sets of data on the frequencies of different intestinal microbes, which include results for healthy U.S. residents and kids in North America who have IBD. They saw the same relationship—when Clostridiales species are up, Bacteroides varieties are down, and vice versa.
The study’s findings suggest that parasitic worms deliver their benefits indirectly through their impact on the microbial mixture in the intestines. Worms are “having an anti-inflammatory effect by kicking out something that is inflammatory,” Cadwell says. Members of the Clostridiales group may get a boost when worms are around, he says, because the intestines produce more mucus, which the bacteria feast on.
“This is a good proof of concept,” says immunologist Gabriel Nunez of the University of Michigan, Ann Arbor, who wasn’t connected to the research. It supports “the principle that some of these diseases may be related to changes in the microbiome.” But he cautions that researchers still need direct evidence that Bacteroides species are responsible for Crohn’s disease.
Turning the results into a treatment for IBD could be difficult. Two recent clinical trials of helminth treatment for Crohn’s disease, in which participants drank a solution containing the worms’ eggs, stopped early because the results were disappointing. These studies may not be the last word, however. Cadwell says that worm therapy might work in the roughly 30% of Crohn’s patients who have the same genetic flaw as the mice. And Weinstock notes that if researchers can determine how the parasites trigger the shift in microbe composition, “we may be able to bypass the worms and develop a small molecule drug to get the effect in a safe way.”