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 attributable 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.