Nav: Home

Mass. General researchers provide evidence linking 'leaky gut' to chronic inflammation

April 20, 2017

With the help of genetically engineered mice, scientists at the Massachusetts General Hospital (MGH) are moving closer to establishing the role that increased intestinal permeability, sometimes called a "leaky gut," plays in chronic inflammatory conditions. Regulated by a protein called zonulin, elevated intestinal permeability has been associated with several chronic conditions including autoimmunity, metabolic disorders, neurodegenerative diseases and even cancer.

In an article published in Annals of the New York Academy of Sciences, lead author Craig Sturgeon, a graduate student in the Mucosal Immunology and Biology Research Center (MIBRC) at MGH, and colleagues provide a direct link between increased permeability of the small intestine and chronic inflammatory disease. They describe how inducing colitis in transgenic mice with two copies of the zonulin-producing gene variant led to significantly more severe symptoms and increased mortality compared with inducing colitis in animals without the zonulin gene.

"This is the first time that we have been able to mechanistically link zonulin-dependent modulation of small-intestinal permeability and the resulting enhanced antigen trafficking to the development of an inflammatory disease," says Alessio Fasano, MD, director of the MIBRC and senior author of the article. "When we exposed these two groups of mice to inflammatory stress, the zonulin transgenic mice showed a remarkable increase in colon inflammation and in mortality -- up to 70 percent -- compared to normal mice."

In a related finding that Fasano calls "even more remarkable," adding a zonulin inhibitor -- AT1001, also called larazotide acetate -- to the drinking water of the transgenic mice completely protected the animals from colonic inflammation and death, reducing permeability of the small intestine to normal levels, despite continued zonulin expression.

Fasano's group discovered zonulin, which controls the opening of "tight junctions" between cells lining the digestive tract, in 2000. Since then it has been the subject of numerous studies implicating intestinal permeability in chronic inflammatory disease. In 2001 while at the University of Maryland School of Medicine, Fasano developed AT1001 as a therapeutic agent for celiac disease. The zonulin-blocking agent is set to undergo Phase III clinical trials later this year, according to Innovate BioPharmaceuticals, which has licensed development of the drug from Alba Therapeutics, a company co-founded by Fasano.

A professor of Pediatrics at Harvard Medical School, Fasano explains that, while some alternative health care practitioners use the term "leaky gut syndrome" to describe a variety of health problems ranging from gastrointestinal complaints to neurological symptoms, he prefers the concept of loss of intestinal barrier function. "Leaky gut syndrome has been blamed by some non-mainstream practitioners as the reason for almost everything that is wrong with a person. With the development of this mouse model to study inflammation, we'll be able to separate science from speculation," he says.

Lead author Sturgeon adds, "Use of these mice will allow us to gain insight into specific mechanisms by which zonulin-dependent increased intestinal permeability can affect disease onset, clinical severity and outcomes, and even possible prevention." Jinggang Lan, PhD, of the MIBRC is also a co-author of the Annals of the New York Academy of Science paper. The study was supported by National Institutes of Health grant DK048373.
-end-
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Inflammatory Disease Articles:

Researchers identify a possible cause and treatment for inflammatory bowel disease
In a study published online in PNAS on Jan. 20, 2020, Prof.
Does inflammatory bowel disease carry certain risks during pregnancy?
Pregnant women with inflammatory bowel disease (IBD) are more likely to undergo delivery by Caesarean section and face certain risks during pregnancy, according to an analysis published in Alimentary Pharmacology & Therapeutics.
Inflammatory bowel disease appears to impact risk of Parkinson's disease
Amsterdam, NL, November 14, 2019 - Relatively new research findings indicating that the earliest stages of Parkinson's disease (PD) may occur in the gut have been gaining traction in recent years.
Are steroids used too much for patients with inflammatory bowel disease?
Steroid therapy is commonly used to treat acute attacks of the inflammatory bowel diseases ulcerative colitis and Crohn's disease; however, because it does not provide long-term benefits and it carries a risk of serious side effects, it should not be used to treat inflammatory bowel disease for more than three months.
FODMAPs diet relieves symptoms of inflammatory bowel disease
New research from King's College London has found that a diet low in fermented carbohydrates has improved certain gut symptoms and improved health-related quality of life for sufferers of inflammatory bowel disease (IBD).
The diet-microbiome connection in inflammatory bowel disease
A change in diet is a go-to strategy for treating inflammatory bowel diseases like Crohn's.
Edinburgh is global hotspot for inflammatory bowel disease rates
Edinburgh has some of the highest known rates of inflammatory bowel disease in the world and the figure is expected to rise in the next 10 years.
Medication linked to increased risk of inflammatory bowel disease
Medications that target tumor necrosis factor alpha (TNFα), a protein involved in inflammation, have revolutionized the management of certain autoimmune diseases, but paradoxically, these agents might provoke the development of other autoimmune conditions.
Sunshine may decrease risk of inflammatory bowel disease
Children who spend half an hour a day outside in the sun reduce their risk of inflammatory bowel disease (IBD), according to new research from The Australian National University (ANU).
Investigational cream may help patients with inflammatory skin disease
A study published in the British Journal of Dermatology indicates that an investigational nonsteroidal topical cream (PAC-14028) may be effective for treating atopic dermatitis, one of the most common inflammatory skin diseases.
More Inflammatory Disease News and Inflammatory Disease Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Teaching For Better Humans 2.0
More than test scores or good grades–what do kids need for the future? This hour, TED speakers explore how to help children grow into better humans, both during and after this time of crisis. Guests include educators Richard Culatta and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Space
One of the most consistent questions we get at the show is from parents who want to know which episodes are kid-friendly and which aren't. So today, we're releasing a separate feed, Radiolab for Kids. To kick it off, we're rerunning an all-time favorite episode: Space. In the 60's, space exploration was an American obsession. This hour, we chart the path from romance to increasing cynicism. We begin with Ann Druyan, widow of Carl Sagan, with a story about the Voyager expedition, true love, and a golden record that travels through space. And astrophysicist Neil de Grasse Tyson explains the Coepernican Principle, and just how insignificant we are. Support Radiolab today at Radiolab.org/donate.