Worm infection counters inflammatory bowel disease by drastically changing gut microbiome

The study results support the hygiene hypothesis which, in the case of IBD, argues that the absence of exposure to worms in too-clean modern living spaces has left some with oversensitive, gut-based immune systems vulnerable to inflammatory diseases. Gut worms have helped to train and balance immune systems throughout human evolution, but are now missing in developed nations, which, in turn, have the highest rates of Crohn's disease and ulcerative colitis.

In the newly published study, a team led by researchers from NYU Langone Medical Center found that mice infected with intestinal worms experienced as much as a thousand-fold decrease in Bacteroides -- a group of bacterial species linked by past studies to higher risk for IBD. At the same time, the number of Clostridia, a bacterial species known to counter inflammation, increased tenfold. The investigators argue that the immune response to the worms triggers the growth in Clostridia, which then either outcompete Bacteroides for nutrients or release toxins harmful to Bacteroides.

"Our findings are among the first to link parasites and bacteria to the origin of IBD, supporting the hygiene hypothesis," says study co-senior investigator and parasitologist P'ng Loke, PhD, an associate professor at NYU Langone. Loke says this model may also be applicable to other autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes, in which processes meant to attack foreign invaders instead become oversensitive and react to the body's own cells.

Also among the study's key findings was that people in rural parts of Malaysia, a region known to have low rates of IBD but a high incidence of worm infections, had significantly more Clostridia and fewer Bacteriodes in their microbiomes than people comprising a nearby urban population. In addition, the researchers found that people treated and dewormed had less Clostridia and more Bacteriodes.

"Our study could change how scientists and physicians think about treating IBD," says study co-senior investigator and microbiologist Ken Cadwell, PhD, an assistant professor at NYU Langone and its Skirball Institute of Biomolecular Medicine. "Patient testimonials and anecdotes lead many to think that worms directly cure IBD, while in reality, they act on the gut bacteria thought to cause the disease."

Loke also led a study, published in the journal PLOS Pathogens in 2012, which found that giving worm eggs to monkeys protected them from the simian version of IBD. Worm eggs may be able to trick the immune system into thinking it has a worm infection, and to trigger a specific kind of worm-related response that counters gut inflammation. Along the same lines, future treatments might include giving patients some form of the immune chemicals produced by immune cells in the presence of worm infection, like interleukin 13, Cadwell says. Such treatments may be acceptable to patients as long as they know they cannot possibly get worms in the process.

As part of the new study, the NYU Langone team fed between 10 and 15 parasitic whipworm eggs to mice lacking a gene called NOD2, which is tied to several immune disorders, including IBD. After the worms matured, the investigators measured the amount of Bacteroides and Clostridia in the mice's intestines and stool and noted the presence or absence of IBD. They found that many of the symptoms of IBD, such as intestinal bleeding and ulceration, went away along with almost all Bacteroides, while the Clostridia levels increased.

For another part of the study, the researchers compared the bacteria found in 75 members of the Orang Asli indigenous people in rural Malaysia to those of 20 people living in urban Kuala Lumpur. Researchers found that rural people had much fewer Bacteroides than city dwellers.

Cadwell says he and Loke plan to investigate how Clostridia outcompete Bacteroides, and search for harmless Clostridia species that can still induce this effect. In addition, they intend to explore alterations to gut bacteria by worm infections as the foundation of treatments for several inflammatory diseases.

Funding support for the study was provided by National Institute of Health grants DK103788, DK093668, and AL093811, and by grants from the Burroughs Wellcome Fund and Dr. Bernard Levine.

In addition to Cadwell and Loke, other NYU Langone researchers included Deepshika Ramanan, BS; Rowann Bowcutt, PhD; Zachary Kurtz, BS; Martin Blaser, MD; and Mei San Tang, MD. Further research support was provided by Soo Ching Lee, PhD, and Yvonne Al Lim, PhD, at the University of Malaya in Malaysia; Kenya Honda, PhD, at the Center for Integrative Medical Sciences in Yokohama, Japan; Richard Bonneau at the Simons Foundation in New York; and William C. Cause, PhD, at the Center for Immunity and Inflammation at New Jersey Medical School.