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Treating auto immune diseases with intestinal worms

Treating auto immune diseases with intestinal worms
August 04
14:37 2017

It takes a hookworm four to six weeks to travel through the human body and reach the gut, where it latches onto the small intestine and sucks blood to sustain itself.

That doesn’t just sound gross; it also sounds like a situation that would outrage the immune system into action. But if you take an endoscope and film these worms once they are ensconced in a human gut, says Alex Loukas, a molecular parasitologist at James Cook University, the area appears healthy rather than inflamed.

This bizarre observation hints that being worm-infested might have its upsides. To survive in the human body, hookworms and other gut-dwelling beasties have to be able to calm inflammation. Loukas and other researchers are investigating whether intestinal worms might be able to treat autoimmune and inflammatory conditions, from celiac disease to autism to allergies. The idea behind this experimental worm therapy is that squirmy creatures called helminths evolved alongside us and actually benefit our immune system.

“It looks like it could save a tremendous amount of human pain and suffering,” says William Parker, an associate professor of surgery at the Duke University School of Medicine. “But it needs to be investigated.”

Worm therapy has a mixed record in clinical trials. For years, people have opted not to wait for FDA approval, using worms to self-treat their illnesses at home. Still, researchers are continuing to study the benefits of worm therapy. Others are entranced by the notion of using the worms as inspiration for new, improved medications.

“What we’re trying to conserve isn’t friendly…It’s not a little baby doe with those big eyes or a baby fur seal,” says Garin Aglietti, owner of wormtherapy.com, a Mexico-based helminth provider. “But they’re an important part of ecosystems.”

Scientists, doctors, and those who self-treat are exploring what roles helminths might play in the human ecosystem.

A worm by any other name

Intestinal worms have been our boon companions for many thousands of years. Today, around 24 percent of the world’s population is infected with soil-transmitted helminths. When people carry only a few worms, they’re often harmless. But in larger numbers, the parasites can cause problems such as abdominal pain and weakness. Hookworms can leave people anemic. In many parts of the world, children are often infected early in life—building up heavy burdens of worms. “It can have disastrous consequences on their physical and mental development,” Loukas says.

These worms don’t transmit directly from person to person. Instead, their eggs pass out of the body in feces and contaminate the soil in areas with poor sanitation. Nowadays, people in high-income countries rarely encounter parasitic worms.

Yet in these countries, diseases related to an overactive immune system are on the rise; more than 23.5 million Americans are now affected by autoimmune diseases.

It’s widely accepted that the composition of our gut microbial community is easily and commonly disrupted, contributing to many health problems. Perhaps, some scientists argue, the absence of intestinal worms is also a factor. Before the agricultural revolution, humans lived in less crowded conditions. This meant it was harder to pick up harmful numbers of helminths, Parker says. Our immune systems were, however, used to a small number of worms in their midst.

Over time, human and worm coevolved. Eventually, the thinking goes, our immune system came to rely on having helminths around to “train” it to develop properly. Without worms, the immune system is more likely to go rogue.

“They have been given a blanket label of parasites,” Parker says. Yet the same creature that acts as a parasite in high numbers may help us in small doses.

Not everyone is convinced. Helena Helmby, an immunologist at the London School of Hygiene & Tropical Medicine, is skeptical that an increase in autoimmune and inflammatory diseases is related to missing worms. A disrupted microbial community is more plausible, she says. “Worms are not the only answer.” Another possibility is that worms are beneficial largely because they’re manipulating the microbiota.

What we do know is that helminths are adept at influencing the immune system. In order to ensure their own survival, these worms must dampen the immune response that would otherwise wipe them out. They do this in part by secreting molecules with anti-inflammatory properties.

That is where the promise of worm therapy lies.

An uneven record

Humans have turned leeches, maggots, and bacteria into medicinal tools. Why not worms?

Helminths are appealing because they don’t appear to suppress the immune system across the board—rather, they tune it. “The immune function gets more specific and targeted at the actual danger to us, and less inflammatory in general,” Parker says. “The immune system without helminths can be much like a police force that has only hand grenades. There’s a tremendous amount of force there but it’s not very specific and not targeted.”

This is an advantage over the anti-inflammatory medications we currently use to treat autoimmune diseases. These drugs are immunosuppressive, putting people at heightened risk for infections and cancer.

Scientists and people who self-treat with worms have honed in on a few candidates. Several, including pig whipworm (Trichuris suis) and rat tapeworm (Hymenolepis diminuta) are adapted to other mammals and generally can’t survive to their adult stage in humans. Human hookworm (Necator americanus) is another popular choice. They can stick around for more than a year, making them cheaper for self-treaters. But they are also more likely to cause side effects (typically cramping or anemia). Very rarely, the worms that don’t usually colonize humans can make existing psychiatric issues worse, Parker says. Fortunately, it’s easy to get rid of worms with anthelmintic drugs.

So far, worms have shown promise in animal studies and small trials with humans. When scientists take the soup of proteins and other molecules secreted by worms and inject it into rodents, they can prevent all sorts of ailments like inflammatory bowel disease, asthma, rheumatoid arthritis, Loukas says.

And Parker and his colleagues have shown that when rat pups are born from a mother colonized with helminths, their brains are more protected against inflammation induced elsewhere. He believes that, accordingly, helminths may eventually help with anxiety disorders, migraine headaches, and depression. Scientists now suspect that inflammation plays a role in many of these conditions. He also suspects that helminths are more effective in preventing an overactive immune response from happening than turning off an ongoing reaction. So they would show more promise for treating seasonal allergies than those caused by irritants people are constantly exposed to, like dust.

The work of Joel Weinstock, then a gastroenterologist at the University of Iowa, launched much of the nascent field when he and his colleagues found that pig whipworm seemed to ease the symptoms of inflammatory bowel disease. In another trial, scientists at the University of Wisconsin-Madison saw pig whipworm apparently reduce the number of lesions on the nerve cells of people with multiple sclerosis. Another multiple sclerosis trial in the United Kingdom using hookworms has recently concluded.

During a trial with celiac disease, Loukas and his colleagues saw that hookworms appeared to reverse gluten sensitivity; the participants were ultimately able to eat a bowl of pasta with no adverse effects.

In autoimmune diseases, there’s typically an overabundance of a type of T cells—a kind of white blood cell—that pump out inflammation-causing chemicals. When the gut in people with celiac disease encounters gluten, there’s a boost in the numbers of these cells. But when people with celiac disease had hookworms in their guts, these cells did not increase after they slowly reintroduced gluten. Instead, the numbers of a different “peacekeeping” T cell that calms inflammation rose. It appears that the worms prompt an increase in these soothing cells, which can travel around the body to quiet down the immune response, Loukas says. He’s now about two-thirds done enrolling people for a larger, 70-person clinical trial on celiac disease led by colleagues John Croese and Paul Giacomin.

However, “There’s a checkered history recently in terms of clinical trials,” he says. In 2013, two large clinical trials on irritable bowel disease using pig whipworm failed to show any benefit. One speculation about why these trials may not have worked is because the company changed the solution the eggs were stored in, perhaps in a way that made them ineffective, Parker says. Regardless of the reason, since this major setback pharmaceutical companies have been reluctant to get onboard with helminth therapy, although smaller trials have continued.

DIY

Helminths aren’t approved by the U.S. Food and Drug Administration to combat any illness. It’s not legal to sell them in this country to treat a disease, and that is unlikely to change anytime soon.

Some people with debilitating autoimmune conditions are taking matters into their own hands. They travel to other countries where helminths are available and bring back a personal supply to the United States, or order from the black market online.

“Basically the whole thing is now stuck in this no man’s land where it continues to grow in the underground,” says Judy Chinitz, a co-founder of Biome Restoration, which provides the larvae of rat tapeworm in the United Kingdom.

Parker estimates that between 6,000 and 7,000 people worldwide use worms to manage the symptoms of their illnesses, including both adults and children. He and his colleagues have spent years surveying the self-treating community, the physicians supervising people who had decided to self-treat, and companies that sell the eggs or larvae. “We’ve gotten more than 10 percent of everybody on planet Earth who’s ever tried a helminth for therapy,” he says. Talking doctors has allowed them to build a picture that includes people who tried worm therapy and found it ineffective or unpleasant, as well as people who are pleased with their internal guests.

“We initially thought that people aren’t going to go for this,” Parker says. But, “If somebody’s sick [and] especially if somebody’s child is sick, they will try just about anything.” Many self-users feel that helminths have boosted their quality of life, although others detect no improvement. Journalist Moises Velasquez-Manoff tried hookworms to see if they might help his alopecia and hay fever. Ultimately, the worms did not pan out and the side effects were unpleasant.

necator americanus

Necator americanus

WormTherapy.com

Velasquez-Manoff picked up his worms in Mexico, from Aglietti. There are a few other well-known providers that operate around the world; generally they strongly recommend that you involve a physician if you are determined to take helminths, or provide their own, Parker says.

However, helminth production is generally not regulated or inspected as a drug would be. People who self treat do run risks not incurred by those who sample worms through a clinical trial. And because ongoing treatment with helminths is so expensive, some unscrupulous providers offer cheap versions that may be produced in non-sterile conditions or come from unreliable sources.

In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency allows Biome Restoration to produce their larvae as a non-pharmaceutical product. Recently, the European Union has updated its rules for what is considered a novel food. Chinitz and Detlev Goj, owner and CEO of Tanawisa, a Thailand-based provider of pig whipworm eggs, are interested in seeking approval to have their helminths classified under this category in Europe (in Thailand, they are considered a natural medicine).

Hookworm larvae are delivered through a patch on the skin, while the eggs or larvae of other species are ingested. The dose varies, depending on the species and illness. But it’s typical for people to take 25 or so hookworms at a time to eventually build up a colony of around 100, Parker says. Other species must be consumed every few weeks. For pig whipworm, this means swallowing thousands of eggs at a time. Goj, who has tried this himself, says that experience was “Nothing special. It was like drinking juice.”

Worm in a pill

Some researchers believe that a more promising avenue lies in the molecules helminths secrete.

“They are pathogens, I think people need to be realistic about that,” Helmby says. “We would be much better off not using live infection, but actually harnessing the product these parasites produce and then using them for anti-inflammatory treatments.”

Loukas and his colleagues feel similarly. “Evolution has taken care of drug design for us,” he says. As in his clinical trials, he is focusing on hookworms. He and his colleagues have identified the 100 most abundant proteins that the worms produce. They’ve selected a protein called AIP-2 that seems especially promising and protects against asthma in mice. It’s not clear yet how it exactly it works, although it does boost inflammation-calming T cells. He’s working with pharmaceutical companies to develop it as a treatment for inflammatory bowel disease and other ailments in humans.

Loukas views his trials with lives worms as evidence the worms can influence the immune system, rather than that they are the ideal vehicle for treatment. A minority of the volunteers Loukas has worked with did experience intense gut pain when the worms first arrived, although this typically disappears after 12 to 16 weeks. That said, the volunteers are offered a deworming drug after their trial, but most don’t take it. “In almost every scenario the patients have refused the drug and have kept their worms. They love them,” Loukas says.

Intestinal worms are not particularly charismatic to most people, though. “There’s still that ick factor,” Loukas says. And producing live worms is complicated. One must collect feces from volunteers, recover the eggs, raise them to the larval stage, and clean them up so they won’t transmit any germs to the person they infect. It’s not really possible to scale up this process to the point where you’d be able to treat millions of people, Loukas says.

Developing a pill or injectable from worm proteins will be a formidable challenge, however. “There’s so many molecules that are secreted by the helminth…and there’s a lot going on there that would be impossible to recapitulate with a single pharmaceutical,” Parker says. “You’d have to reinvent the whole worm basically.”

Worm proteins haven’t been tested in people yet; a clinical trial is probably two to three years away. Medications based on individual worm proteins, or combinations of a few different ones, probably won’t be on the market for more than 10 years.

Onwards and inward

To move forward and gain FDA approval, worm therapy will need large clinical trials, and it’s hard to raise funds for those without backing from pharmaceutical companies. Parker is afraid that worm therapy will languish for decades like fecal transplants, which were actually tested in 1958 but have only recently become popular to treat pernicious gut infections. “It has interest, but it’s also got baggage from these failed trials,” he says.

Still, there are small signs of progress. “One of the big roadblocks is having the parasites that the FDA will allow you to infect people with,” says John Hawdon, vice president of the American Society of Parasitologists and a researcher at the George Washington University. He and his colleagues are applying for permission to grow hookworm larvae to standards fit for testing in humans. Currently, there is no place in the United States where this is allowed; Hawdon anticipates a lengthy application process.

“As a long-term goal we may be the place to get the larvae to do the clinical trials to determine if this works or not,” he says. “It’s got a lot of promise, but we’re just not there yet, to say whether it works or not, and I don’t recommend people doing it on their own.”

Helminths must still be thoroughly investigated to determine if and when worms or worm-inspired drugs would be effective, what doses and species are most beneficial, that it is safe, and to seek approval and regulation. That worm-filled future is a long way off, though. In the meantime, people will continue to colonize themselves with helminths. After all, we are far from being able to offer people with these lifelong conditions any cures. Most researchers don’t advise self-treating, but they can understand why people choose to do it. “Until more work is done, individuals are left with the uncomfortable task of making that determination for themselves,” Parker said in email.

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