A new animal study suggests that parasitic worm infestations may be able to restore balance to the erratic gut microbiomes of people with Crohn's Disease. Above, the egg of a human whipworm. CDC/ B.G. Partin
A worm in the gut may help people living with certain types of Crohn’s disease get out of their rut, suggests a new study published Wednesday in Science.
The authors recruited laboratory mice to help explain a persistent mystery of the human gut: Areas of the world where parasitic worm infections are commonplace tend to have much lower rates of autoimmune disorders like Crohn’s and other inflammatory bowel diseases. Understanding how that connection works may help us put our parasitic freeloaders to good use or even devise worm-free ways to treat Crohn's.
The researchers gave specially bred mice lacking Nod2, a gene implicated in some Crohn’s cases, a non-steroidal anti-inflammatory drug that sent their small intestines into disarray and caused a chronic Crohn’s-like inflammation. More specifically, the mucus layer of the small intestine thinned, which seemingly decreased levels of a bacterial family calledClostridiales and increased levels of another common microbe, Bacteroides vulgatus.
Once these mice were infected with the mouse whipworm, though, mucus production picked back up, the levels of B. vulgatus declined as the levels of Clostridiales rose, and inflammation dropped off. A second worm, the nematode Heligmosomoides polygyrus, proved even more effective. And researchers saw a similar effect when they let worm-infested mice live with their uninfected counterparts. After further inspection, the authors concluded the worms had induced a specific immune response known as type 2 immunity, which jumpstarted mucus production and subsequently restored bacterial balance.
“We believe we found one explanation as to why people with parasite infections tend not to develop inflammatory disease,” senior study author Dr. Ken Cadwell, an assistant professor at the Skirball Institute of Biomolecular Medicine at New York Uuniversity, told Medical Daily.“Because we’re getting a glimpse as to how the immune response to parasite infection prevents inflammatory disease, we can now start to ask how we can get this same response and restore a balance in the gut without needing the parasite itself.”
The study only adds further support to the team’s earlier research on a Malaysian village where worm infestation is nearly universal. Back then, they studied the stool samples of people before and after they underwent a deworming treatment, finding that the levels of a related species to B. vulgatus rose significantly as the levels of Clostridiales declined once the worms were gone. Coupled with the present study, that suggests Clostridiales acts as a direct buffer against bacteria belonging to the Bacteroidales family; a sort of microscopic see-saw that can manually be pushed down by intestinal worms.
As the researchers explained, though, Crohn’s is a complicated disease caused by an array of genetic and environmental factors. Though the basic principle is the same — a chronic inflammation at the end of our small intestine caused by a hyperactive immune system — why that happens can dramatically vary from person to person.
According to Cadwell, about a third of Crohn’s sufferers have a defective Nod2 mutation andBacteroidales seems to overly provoke the immune system only in these cases. Similarly, the paper suggests worms may only have a protective effect in people with the mutation, a theory that might explain why clinical human trials using them to treat Crohn’s have failed so far. And while an overabundance of B. vulgatus has been found in the guts of Crohn’s patients, it’s not the only type of bacteria that’s been tied to the disease’s emergence.
“We and others believe that no single bacteria ‘causes’ Crohn’s disease, but the imbalance in the [gut bacteria] population is what contributes to the disease,” he said. “That’s why the field is now interested in ways to restore the balance, either by giving people protective bacteria or inducing a protective immune response.”
For their part, Cadwell and his colleagues are eager to contribute to that goal. “We figured out a lot about how the parasite infection promotes the expansion of beneficial Clostridialesspecies, but we still don’t know exactly how Clostridiales suppresses the inflammatoryBacteroides and restores balance,” he said. “That’s what we want to tackle next.”
Inflammatory bowel disease (IBD) is miserable for anyone, but when it strikes a child under age 5, it’s much more severe, usually causing bloody diarrhea, wrenching abdominal pain and stunted growth. Early-onset IBD is rare, but on the rise: For reasons unknown, its incidence is increasing by about 5 percent per year in some parts of the world.
A recently identified form of early-onset IBD shows up within months of birth, causing severe inflammation in the large intestine and abscesses around the anus. Recently linked to genetic mutations in the cellular receptor for a signaling protein, interleukin-10 (IL-10), it can also lead to lymphoma later in life.
As with all early-onset IBD, IL-10-receptor deficiency has no good treatment. A bone marrow transplant is actually curative, but carries many risks, especially in infants.
“We’ve been trying to understand why IBD in these children is so severe and presents so early,” says Dror Shouval, MD, a pediatric gastroenterologist at Boston Children’s Hospital and a fellow in the lab ofScott Snapper, MD, PhD. The beginnings of such an understanding—detailed recently in the journalImmunity—could lead to a new treatment approach for this and perhaps other kinds of early-onset IBD.
Of mice and macrophages
Working through its receptor, IL-10 quiets inflammatory immune responses when they’re not needed to protect against infection. Working with mouse models, Shouval, Snapper and colleagues showed that when innate immune cells near the intestine didn’t receive IL-10 signals, the mice developed rapid, severe intestinal inflammation and weight loss.
Delving further, they showed that without the ability to sense IL-10, the mice could not produce the kinds of immune cells that tend to temper inflammation. They churned out plenty of pro-inflammatory macrophages, but far fewer macrophages with anti-inflammatory properties, and those they made didn’t work well. As a result, they also produced fewer T-regulatory cells, another type of “calming” immune cell; again, those they did make functioned poorly.
Simply put, their intestinal immune responses were out of whack.
“Loss of IL-10 signaling disrupts the delicate balance in the intestine between pathogenic and regulatory immune cells,” says Snapper, who directs the Inflammatory Bowel Disease Center at Boston Children’s
The researchers then tapped a worldwide patient cohort study of early-onset IBD, known as NEOPICS, which serves as a clearinghouse for research and on which Snapper is a co-principal investigator. “We get an email or phone call at least once a week from physicians around the world who are struggling with the work-up and management of patients who developed IBD very early in life,” says Shouval. “Based on the clinical presentation, we tailor a specific diagnostic plan to try to find the cause.”
Using the NEOPICS database, Shouval and Snapper identified seven children from the U.S., Canada, Israel, Saudi Arabia, Brazil, Germany and the Netherlands—all with IBD and IL-10-receptor mutations—and studied their disease in a dish.
“Like in the mice, their macrophages are much more aggressive and lead to an exaggerated immune response,” says Shouval. “The generation and function of anti-inflammatory macrophages are also decreased.”
Bench to bedside?
The mouse studies had another, more hopeful finding. By transferring anti-inflammatory macrophages into the IL-10-receptor-deficient mice, the researchers were able to ameliorate their IBD.
“If you can modulate macrophage function, it could be a new avenue for IBD treatment,” says Shouval. “This is very preliminary, but what we hope to do is take monocytes from the patient’s blood, stimulate them in the lab, create more anti-inflammatory macrophages, and give them to the patient.”
This type of cell transplant would be milder than a full bone marrow transplant, which requires immunosuppressive medications that can have severe side effects in young children, including cancer.
And, Shouval and Snapper believe, it could potentially work for children with early-onset IBD who don’t have an IL-10-receptor deficiency. “Many pathways may converge to this IL-10 signaling pathway, and other patients might have blunted responses to anti-inflammatory signals like IL-10, so we think it might be possible to use this in a broader way,” Shouval says. “There is a great need to develop new therapies for IBD, and we hope that the knowledge gained by these experiments will lead to drug discovery and improved treatment options.”
AbbVie (ABBV) Affirms Receipt of Positive EMA CHMP Opinion for HUMIRA in Crohn's Disease
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AbbVie (NYSE: ABBV) announced that the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has granted a positive opinion for HUMIRA (adalimumab) for the treatment of moderately to severely active Crohn's disease in pediatric patients (from six years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator, or who are intolerant to or have contraindications for such therapies.
HUMIRA is currently approved in the European Union for the treatment of severe active Crohn's disease in pediatric patients (from six years of age) who have had an inadequate response to conventional therapy including primary nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant to or have contraindications for such therapies.2
"The positive CHMP opinion represents a significant milestone for the pediatric gastroenterology community as we move closer to European approval of HUMIRA in pediatric patients with moderately to severely active Crohn's disease, a chronic condition with no known cure that affects a growing number of children worldwide," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "AbbVie is committed to the ongoing study and innovation of HUMIRA, and we look forward to expanding this treatment option, once approved, to help more children with this debilitating illness during a vulnerable time in their lives."
"There is no known cure for children and adolescents affected by Crohn's disease, therefore treatment options are important," said Jeffrey S. Hyams, M.D., head, Division of Digestive Diseases, Hepatology and Nutrition, Connecticut Children's Medical Center. "A large-scale investigation such as the IMAgINE trial showcases the safety and efficacy profile of HUMIRA in the moderately to severely active pediatric Crohn's disease population."
Pediatric Crohn's disease is characterized by periods in which the disease flares up, is active and causes symptoms.1,3 These episodes can be followed by times of remission—periods in which symptoms disappear or decrease.1,3 In addition to signs and symptoms such as abdominal pain, weight loss and diarrhea, pediatric Crohn's disease can affect children in several ways unique to this age group, including delayed growth and/or puberty.1
The positive opinion is based on the results of the IMAgINE-1 study, the largest multi-center, randomized, open-label induction, followed by double-blind maintenance trial in patients six to 17 years of age with moderately to severely active Crohn's disease to date.4,5 Moderately to severely active Crohn's disease was defined by a Pediatric Crohn's Disease Activity Index (PCDAI) > 30 at baseline.5
The study found that 63 patients (33.5 percent) were in clinical remission at week 26 and a greater proportion of patients in the standard-dose HUMIRA group (36/93) achieved clinical remission compared to the low-dose HUMIRA group (27/95; P=0.075). Clinical remission was defined as a PCDAI score of less than 10. At week 52, the proportion of patients in clinical remission in the HUMIRA standard-dose group (31/93) was greater compared with the low-dose HUMIRA group (22/95; P=0.100).5
In the study, HUMIRA therapy was initiated with a 4-week induction period consisting of 80 mg and 40 mg administered subcutaneously at weeks 0 and 2, respectively, for patients with bodyweight <40 kg or 160 mg and 80 mg at weeks 0 and 2, respectively, for patients with bodyweight >40 kg. Following the induction period, 188 patients were randomized 1:1 to standard-dose or low-dose double-blind HUMIRA treatment (standard-dose: 20 mg every other week for patients with bodyweight <40 kg or 40 mg every other week for patients with bodyweight >40 kg; low-dose: 10 mg every other week for patients with bodyweight <40 kg or 20 mg every other week for patients with bodyweight >40 kg).5
The review of the variation to the Marketing Authorization (MA) is being conducted under the centralized licensing procedure. If approved, the authorization will be valid in all 28 member states of the European Union, as well as Iceland, Liechtenstein and Norway.
Since first gaining approval more than 13 years ago for rheumatoid arthritis, HUMIRA has been approved in more than 90 countries and is currently being used to treat more than 955,000 patients worldwide6 across 13 globally approved indications.2,7
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Team Intestinal Fortitude does not recommend the use of medical marijuana without the advice and consent of your GI doctor. We also oppose the medication in smoking form when edible forms and oils are available and safer for a patient's respiratory system. Non "high" versions of the medicine are available and we assume doctors can guide you as to the earliest age use is suggested such as 18 or 21 years old. Team Intestinal Fortitude also believes the federal government should be declassified from a Class I Controlled Substance so that further testing may take place in the United States and so that the federal government is on the same page as those states which permit medical marijuana.