From Ayurveda to the teachings of Hippocrates, medicine’s earliest traditions advanced a belief that the gut was the foundation of all health and disease. It wasn’t until recently, however, that Western medicine has adopted the notion of gut-barrier dysfunction as a pathologic phenomenon critical to not only digestive health but also chronic allergic, inflammatory, and autoimmune disease.
To learn more, Medscape contributor Akash Goel, MD, interviewed Elena Ivanina, DO, MPH, an integrative gastroenterologist, on the role of the gut barrier. Ivanina is the founder of the Center for Integrative Gut Health and the former director of Neurogastroenterology and Motility at Lenox Hill Hospital in New York. She runs the educational platform for all things gut health, gutlove.com.
What is the role of the gut barrier in overall health and disease?
The gut contains the human body’s largest interface between a person and their external environment. The actual interface is at the gut barrier, where there needs to be an ideal homeostasis and selectivity mechanism to allow the absorption of healthy nutrients, but on the other hand prevent the penetration of harmful microbes, food antigens, and other proinflammatory factors and toxins.
The gut barrier is made up of the mucus layer, gut microbiome, epithelial cells, and immune cells in the lamina propria. When this apparatus is disrupted by factors such as infection, low-fiber diet, antibiotics, and alcohol, then it cannot function normally to selectively keep out the harmful intraluminal substances.
Gut-barrier disruption leads to translocation of dangerous intraluminal components, such as bacteria and their components, into the gut wall and, most importantly, exposes the immune system to them. This causes improper immune activation and dysregulation, which has been shown to lead to various diseases, including gastrointestinal inflammatory disorders such as inflammatory bowel disease (IBD) and celiac disease, systemic autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and metabolic diseases such as obesity and diabetes.
Is disruption of this barrier what is usually referred to as “leaky gut”?
Leaky gut is a colloquial term for increased intestinal permeability or intestinal hyperpermeability. In a 2019 review article, Dr Michael Camilleri exposes leaky gut as a term that can be misleading and confusing to the general population. It calls upon clinicians to have an increased awareness of the potential of barrier dysfunction in diseases, and to consider the barrier as a target for treatment.
Is leaky gut more of a mechanism of underlying chronic disease or is it a disease of its own?
Intestinal permeability is a pathophysiologic process in the gut with certain risk factors that in some conditions has been shown to precede chronic disease. There has not been any convincing evidence that it can be diagnosed and treated as its own entity, but research is ongoing.
In IBD, the Crohn’s and Colitis Canada Genetic, Environmental, Microbial Project research consortium has been studying individuals at increased risk for Crohn’s disease because of a first-degree family member with Crohn’s disease. They found an increased abundance of Ruminococcus torques in the microbiomes of at-risk individuals who went on to develop the disease. R torques are mucin degraders that induce an increase in other mucin-using bacteria, which can contribute to gut-barrier compromise.
In other studies, patients have been found to have asymptomatic intestinal hyperpermeability years before their diagnosis of Crohn’s disease. This supports understanding more about the potential of intestinal hyperpermeability as its own diagnosis that, if addressed, could possibly prevent disease development.
The Many Possible Sources of Gut-Barrier Disruption
What causes leaky gut, and when should physicians and patients be suspicious if they have it?
There are many risk factors that have been associated with leaky gut in both human studies and animal studies, including acrolein (food toxin), aging, alcohol, antacid drugs, antibiotics, burn injury, chemotherapy, circadian rhythm disruption, corticosteroids, emulsifiers (food additives), strenuous exercise (≥ 2 hours) at 60% Vo2 max, starvation, fructose, fructans, gliadin (wheat protein), high-fat diet, high-salt diet, high-sugar diet, hyperglycemia, low-fiber diet, nonsteroidal anti-inflammatory drugs, pesticide, proinflammatory cytokines, psychological stress, radiation, sleep deprivation, smoking, and sweeteners.
Patients may be completely asymptomatic with leaky gut. Physicians should be suspicious if there is a genetic predisposition to chronic disease or if any risk factors are unveiled after assessing diet and lifestyle exposures.
What is the role of the Western diet and processed food consumption in driving disruptions of the gut barrier?
The Western diet reduces gut-barrier mucus thickness, leading to increased gut permeability. People who consume a Western diet typically eat less than 15 grams of fiber per day, which is significantly less than many other cultures, including the hunter-gatherers of Tanzania (Hadza), who get 100 or more grams of fiber a day in their food.
With a fiber-depleted diet, gut microbiota that normally feed on fiber gradually disappear and other commensals shift their metabolism to degrade the gut-barrier mucus layer.
A low-fiber diet also decreases short-chain fatty acid production, which reduces production of mucus and affects tight junction regulation.
Emerging Evidence on Causality
New evidence is demonstrating that previous functional conditions of the gastrointestinal tract, like functional dyspepsia, are associated with abnormalities to the intestinal barrier. What is the association between conditions like functional dyspepsia and irritable bowel syndrome (IBS) with gut-barrier disruption?
Conditions such as functional dyspepsia and IBS are similar in that their pathophysiology is incompletely understood and likely due to contributions from many different underlying mechanisms. This makes it difficult for clinicians to explain the condition to patients and often to treat without specific therapeutic targets.
Emerging evidence with new diagnostic tools, such as confocal laser endomicroscopy, has demonstrated altered mucosal barrier function in both conditions.
In patients with IBS who have a suspected food intolerance, studies looking at exposure to the food antigens found that the food caused immediate breaks, increased intervillous spaces, and increased inflammatory cells in the gut mucosa. These changes were associated with patient responses to exclusion diets.
In functional dyspepsia, another study, using confocal laser endomicroscopy, has shown that affected patients have significantly greater epithelial gap density in the duodenum compared with healthy controls. There was also impaired duodenal-epithelial barrier integrity and evidence of increased cellular pyroptosis in the duodenal mucosa.
These findings suggest that while IBS and functional dyspepsia are still likely multifactorial, there may be a common preclinical state that can be further investigated as far as preventing its development and using it as a therapeutic target.
What diagnostic testing are you using to determine whether patients have disruptions to the gut barrier? Are they validated or more experimental?
There are various testing strategies that have been used in research to diagnose intestinal hyperpermeability. In a 2021 analysis, Dr Michael Camilleri found that the optimal probes for measuring small intestinal and colonic permeability are the mass excreted of 13C-mannitol at 0-2 hours and lactulose during 2-8 hours or sucralose during 8-24 hours. Studies looking at postinfectious IBS have incorporated elevated urinary lactulose/mannitol ratios. Dr Alessio Fasano and others have looked at using zonulin as a biomarker of impaired gut-barrier function. These tests are still considered experimental.
Is there an association between alterations in the gut microbiome and gut-barrier disruption?
There is an integral relationship between the gut microbiome and gut-barrier function, and dysbiosis can disrupt gut-barrier functionality.
The microbiota produce a variety of metabolites in close proximity to the gut epithelium, impacting gut-barrier function and immune response. For example, short-chain fatty acids produced by Bifidobacterium, Bacteroides, Enterobacter, Faecalibacterium, and Roseburia species impact host immune cell differentiation and metabolism as well as influence susceptibility to pathogens.
Studies have shown that sodium butyrate significantly improves epithelial-barrier function. Other experiments have used transplantation of the intestinal microbiota to show that introduction of certain microbial phenotypes can significantly increase gut permeability.
Practical Advice for Clinicians and Patients
How do you advise patients to avoid gut-barrier disruption?
It is important to educate and counsel patients about the long list of risk factors, many of which are closely related to a Western diet and lifestyle, which can increase their risk for leaky gut.
Once one has it, can it be repaired? Can you share a bit about your protocols in general terms?
Many interventions have been shown to improve intestinal permeability. They include berberine, butyrate, caloric restriction and fasting, curcumin, dietary fiber (prebiotics), moderate exercise, fermented food, fish oil, glutamine, quercetin, probiotics, vagus nerve stimulation, vitamin D, and zinc.
Protocols have to be tailored to patients and their risk factors, diet, and lifestyle.
What are some tips from a nutrition and lifestyle standpoint that patients can follow to ensure a robust gut barrier?
It is important to emphasize a high-fiber diet with naturally fermented food, incorporating time-restricted eating, such as eating an early dinner and nothing else before bedtime, a moderate exercise routine, and gut-brain modulation with techniques such as acupuncture that can incorporate vagus nerve stimulation. Limited safe precision supplementation can be discussed on an individual basis based on the patient’s interest, additional testing, and other existing health conditions.
Dr Akash Goel is a clinical assistant professor of medicine at Weill Cornell in gastroenterology and hepatology. His work has appeared on networks and publications such as CNN, The New York Times, Time Magazine, and Financial Times. He has a deep interest in nutrition, food as medicine, and the intersection between the gut microbiome and human health.
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