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Intestinal Permeability

Intestinal permeability featured article

A single layer of epithelial cells lines the entire digestive tract, facilitating the exchange of nutrients between the intestine and the bloodstream. This layer, referred to as the intestinal epithelium, must be permeable to nutrients yet impermeable to pathogens.

Increased intestinal permeability (also known as "leaky gut") – a condition in which gaps form between the tight junctions that join enterocytes – allows pathogens to leak through the intestinal barrier and pass directly into the bloodstream, promoting inflammation through a specialized mechanism involving detection by toll-like receptors.

Although commonly associated with gut-related illnesses and autoimmune disorders, disturbed intestinal barrier function is a prominent feature of many chronic diseases via its effects on tissues outside the gut. Intestinal permeability may also contribute to a chronic state of metabolic endotoxemia, which drives...

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Q&A #44 with Dr. Rhonda Patrick (02/04/23)

Posted on February 4th 2023 (over 2 years)

Dr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.

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Q&A #37 with Dr. Rhonda Patrick (7/09/2022)

Posted on July 9th 2022 (almost 3 years)

Dr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.

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Q&A #36 with Dr. Rhonda Patrick (6/04/2022)

Posted on June 4th 2022 (about 3 years)

Dr. Rhonda Patrick answers audience questions on various health, nutrition, and science topics in this Q&A session.

Topic Pages

  • Butyrate

    Butyrate enhances epithelial barrier function, lowering intestinal permeability through HDAC inhibition that upregulates tight-junction proteins.

  • Intestinal permeability

    Intestinal permeability denotes tight-junction–regulated paracellular flux across gut epithelium, whose dysregulation permits antigen translocation and inflammation.

  • Toll-like receptors

    Increased intestinal permeability facilitates luminal PAMP translocation, engaging epithelial and lamina propria Toll-like receptors, triggering MyD88-dependent inflammatory signaling.

News & Publications

  • People with inflammatory bowel disease have 49 percent more microplastics in their feces than healthy people, suggesting a potential link between microplastics and chronic gut inflammation. pubs.acs.org
    Gut Inflammation Pollution Intestinal Permeability

    Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammatory conditions that affect the gut, primarily Crohn’s disease and ulcerative colitis. A growing body of evidence suggests that microplastics – tiny plastic particles ranging between 5 millimeters and 100 nanometers – are pro-inflammatory, potentially contributing to chronic disease. A recent study found that people with inflammatory bowel disease had roughly 49 percent more microplastics in their feces than healthy people.

    Researchers measured microplastic concentrations in the feces of 102 participants. Half of the participants had IBD, and the other half were healthy. Participants completed questionnaires about their plastic usage and exposure.

    The researchers found that the fecal concentration of microplastic particles in the feces of participants with inflammatory bowel diseases averaged 41.8 particles per gram of dry matter. In comparison, healthy participants' concentrations averaged 28.0 particles per gram. The various particles were in sheets, fibers, fragments, and pellets; most were smaller than 300 micrometers. Participants with higher fecal concentrations tended to have more severe IBD. The primary sources of microplastic exposure were plastic packaging (for food and water) and dust.

    These findings suggest that microplastic exposure is linked to the disease process of IBD or that IBD might exacerbate microplastic retention in the body. They also add to the growing evidence suggesting that microplastics influence human health. Scientists have found microplastics throughout the human body, including the sputum, lungs, heart, liver, blood, endometrium, testis, amniotic fluid, and placenta00153-1/fulltext).

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  • Gut barrier dysfunction impairs butyric acid uptake into the blood – potentially increasing the risk of carotid atherosclerosis. www.nature.com
    Gut Butyrate Intestinal Permeability Cardiovascular

    Poor gut barrier function may contribute to carotid atherosclerosis – a narrowing of the blood vessels that supply the brain – according to a new study. People with carotid atherosclerosis demonstrated increased markers of gut barrier damage and inflammation, both of which impair butyric acid uptake into the blood.

    Researchers conducted a study involving 43 people with carotid atherosclerosis and 44 healthy people. They measured butyric acid levels in the participants' blood and feces and assessed their gut health and inflammation.

    The people who had carotid atherosclerosis had higher levels of butyric acid in their feces but not in their blood, despite robust gut microbial production of butyric acid. They also had higher levels of markers that indicate gut barrier damage and inflammation and tended to be heavier, carry more weight around their waist, have poor blood glucose control, and have higher markers of inflammation.

    The researchers hypothesized that the participants' higher fecal (but not blood) levels of butyric acid were due to poor gut barrier function, which could impair butyric acid absorption and in turn reduce its uptake into the blood. Other research has found that high fecal levels of butyric acid are associated with intestinal permeability, obesity, metabolic dysfunction, and high blood pressure.

    Butyric acid, a short-chain fatty acid, is best known for its roles in maintaining gut barrier function and preventing intestinal permeability. However, butyric acid also protects the vascular endothelium – the lining of the blood vessels. Having low butyric acid levels in the blood could contribute to the risk of developing carotid atherosclerosis.

    [Learn about butyrate, a compound related to butyric acid, in our overview article.] (https://www.foundmyfitness.com/topics/butyrate)

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  • Visceral fat may cause pathogenic obesity reinforced through a cycle of chronic inflammation www.sciencedaily.com
    Obesity Inflammation Metabolic Syndrome Intestinal Permeability Visceral Fat

    Scientist proposes that the bodies decision to promote visceral fat rather than subcutaneous fat may be due to underlying biological switches triggered partly by malnutrition.

    The evolutionary advantage of visceral fat:

    Sometimes called “the abdominal policeman,” a VAT-rich structure called the omentum, a loosely hanging fold of the membrane lining the abdominal cavity, sticks to wounds, foreign objects such as shrapnel and infection sites like a bandage full of antibiotics. In fact, surgeons sometimes use pieces of omentum to control severe postoperative infections. VAT surrounds the small intestine, defending the body from ingested pathogens and toxins.

    […]

    In the past, the role of visceral fat as part of the immune system may have been more widely important than it is today because starvation and infections were more common. West-Eberhard proposes that in fetuses subject to nutritional stress, more energy may be stored as fat around the abdominal organs rather than as fat under the skin (subcutaneous fat or SAT).

    Chronic inflammatory feedback loop promotes development of visceral fat:

    In overweight individuals, a dangerous feedback loop may develop: increased VAT leads to increased chronic inflammation, which, in turn, leads to increased insulin resistance leading to further VAT storage and increased susceptibility to disease.

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  • Reduced expression of genes involved in integrity of blood-brain barrier, intestinal barrier in autism: 75% have reduced barrier-forming components www.sciencedaily.com
    Brain Microbiome Autism Intestinal Permeability Endotoxemia Blood-Brain Barrier

    From the article:

    The group analyzed postmortem cerebral cortex and cerebellum tissues from 33 individuals – 8 with ASD, 10 with schizophrenia and 15 healthy controls. Altered expression of genes associated with blood-brain-barrier integrity and function and with inflammation was detected in ASD tissue samples, supporting the hypothesis that an impaired blood-brain barrier associated with neuroinflammation contributes to ASD.

    In keeping with the hypothesis that the interplay within the gut-brain axis is a crucial component in the development of neurodevelopmental disorders, the group also analyzed intestinal epithelial tissue from 12 individuals with ASD and 9 without such disorders. That analysis revealed that 75 percent of the individuals affected by ASD had reduced expression of barrier-forming cellular components, compared with controls, and 66 percent showed a higher expression of molecules that increase intestinal permeability.

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  • Increased permeability of the blood brain barrier www.sciencedaily.com
    Brain Intestinal Permeability Endotoxemia

    “Endothelial cells of blood vessels of the central nervous system (CNS) constitute blood-CNS barriers. Barrier properties are not intrinsic to these cells; rather they are induced and maintained by CNS microenvironment. Notably, the abluminal surfaces of CNS capillaries are ensheathed by pericytes and astrocytes. However, extrinsic factors from these perivascular cells that regulate barrier integrity are largely unknown. Here, we establish vitronectin, an extracellular matrix protein secreted by CNS pericytes, as a regulator of blood-CNS barrier function via interactions with its integrin receptor, α5, in endothelial cells. Genetic ablation of vitronectin or mutating vitronectin to prevent integrin binding, as well as endothelial-specific deletion of integrin α5, causes barrier leakage in mice. Furthermore, vitronectin-integrin α5 signaling maintains barrier integrity by actively inhibiting transcytosis in endothelial cells. These results demonstrate that signaling from perivascular cells to endothelial cells via ligand-receptor interactions is a key mechanism to regulate barrier permeability.”

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  • TLR4 exacerbates necrotizing enterocolitis, a leading cause of death in premature newborns, by stopping enterocytes from closing wounds in intestines www.sciencedaily.com
    Inflammation Immune System Intestinal Permeability Toll-Like Receptors

    View full publication:

    Blocking signals from a key molecular receptor that normally switches on the intestine’s immune response but instead becomes too intense in the presence of stress and toxins may help reverse necrotizing enterocolitis (NEC), a leading cause of death in premature newborns.

    […]

    But Hackam’s group found that the stresses of oxygen deprivation and bombardment by bacterial toxins, conditions that can occur in premature infants with underdeveloped lungs, stimulate too much production of TLR4. Like an unstoppable alarm, the increased numbers of TLR4 blare out signals that eventually tip the cells into cellular suicide. They also stop enterocytes from migrating to close wounds in the intestines.

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  • TLR4 receptor involved in recognizing and triggering the innate immune system in response to bacteria may be involved in reinforcing binge drinking www.sciencedaily.com
    Brain Gut Alcohol Immune System Behavior Intestinal Permeability

    Genetic activation of TLR4 in the brain reduced binge drinking. What makes this so interesting is that alcohol consumption itself promotes intestinal permeability, which increases systemic activation of TLR4, potentially resulting in negative cardiovascular outcomes, among other things.

    From the article:

    One of the study’s most novel findings concerns TLR4’s important role in binge drinking. Science has traditionally considered TLR4 to be an innate immunity receptor involved with neuroinflammation in the brain. Scientists associated TLR4 with microglia, cells that support inflammatory responses in the brain. “What makes this finding particularly important for the field of neuroscience is that we’re showing that TLR4 plays a significant role in neurons, specifically, the neurons that are connected to the GABA receptor,” says Dr. June.

    To establish the connection between the GABA receptors, TLR4 and alcohol, the scientists manipulated this pathway in the binge drinking rodents. Dr. Aurelian was a pioneer in developing a method to inhibit gene expression, helping scientists to pinpoint the role of individual genes in the body. […] The scientists found that when they artificially stimulated the GABA receptors and TLR4 in order to simulate the good feelings binge drinkers feel when drinking alcohol, the rats lost interest in alcohol for two weeks after the procedure.

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  • Rebalancing gut microbiome with butyrate lengthens survival in mouse model of ALS by repairing intestinal permeability www.sciencedaily.com
    Brain Aging Microbiome Neurodegeneration Butyrate Intestinal Permeability

    From the article:

    In a mouse model of ALS, the compound butyrate helped correct a gut microbiome imbalance and reduced gut leakiness – both symptoms of ALS. The treated mice lived also longer compared to mice that weren’t given butyrate.

    […]

    When the researchers fed the ALS-prone mice butyrate in their water, starting when the mice were 35 to 42 days old, the mice showed a restored gut microbiome profile and improved gut integrity. Butyrate-treated mice also showed improved neuromuscular function and delayed onset of ALS symptoms. Treated mice showed symptoms at 150 days old compared to control mice at about 110 days. Treated mice also lived an average 38 days longer than mice not given butyrate.

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  • Polyphenols prevent leaky gut syndrome. www.eurekalert.org
    Gut Microbiome Green Tea Polyphenol Intestinal Permeability Lipopolysaccharide

    Intestinal hyper-permeability, often referred to as “leaky gut,” is a condition in which the gaps between the cells that line the gut expand. These gaps allow pathogens such as bacteria or endotoxins (i.e., lipopolysaccharide, a major component of the cell membrane of gram-negative bacteria) to leak through the intestinal wall and pass directly into the bloodstream. Leaky gut is common among older adults, putting them at risk for many acute and chronic diseases. Findings from a recent study suggest that a polyphenol-rich diet reduces the risk of leaky gut in older adults.

    Polyphenols are bioactive compounds present in fruits and vegetables. Evidence suggests that polyphenols influence the composition and function of the gut microbiota, have beneficial effects on gut metabolism and immunity, and exert anti-inflammatory properties.

    The randomized, controlled, crossover trial involved 51 adults (60 years and older) who were living in a residential care facility and had elevated zonulin, a biomarker of impaired gut barrier function. Half of the participants followed their typical diet, but they substituted some items with polyphenol-rich foods while maintaining the same caloric and nutrient intake for eight weeks. The other half consumed their normal diet with no substitutions. After eight weeks, the two groups switched to the opposite diet. Participants underwent physical exams before, during, and after the study and provided blood and fecal samples for analysis.

    The polyphenol-rich foods included berries, blood oranges (and their juice), pomegranate juice, green tea, apples, and dark chocolate. On average, participants who ate the polyphenol-rich diet consumed 1391 milligrams of polyphenols per day, while those who ate a typical diet consumed only 812 milligrams of polyphenols per day. The study investigators noted that participants on the polyphenol-rich diet had higher levels of beneficial gut bacteria than those on the typical diet. They also noted that metabolites from cocoa and green tea polyphenols were associated with having higher levels of butyrate (a short-chain fatty acid that benefits gut health) and lower levels of zonulin. These changes improved overall gut health in the study participants, but the participants' age, baseline zonulin levels, and numbers of beneficial gut bacteria, especially those of the Porphyromonadaceae family, influenced the extent of benefit.

    These findings suggest that polyphenol-rich foods improve gut health and reduce the risk of leaky gut in older adults. They also underscore the importance of developing dietary habits that promote consumption of polyphenol-rich foods throughout the lifespan. For an easy way to get more polyphenols in your diet, try this polyphenol-rich smoothie.

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  • Daily apple consumption decreases multiple markers of obesity-associated inflammation. academic.oup.com
    Diet Obesity Inflammation Polyphenol Intestinal Permeability Endotoxemia Lipopolysaccharide IL-6

    Obesity is characterized by chronic low-grade inflammation, which contributes to the development of cardiovascular disease. While processed foods and beverages high in saturated fats and simple sugars are associated with a higher risk of cardiovascular disease, diets rich in plant-based foods, including fruits, are associated with a lower risk. Findings of a recent report detail the effects of daily apple consumption on inflammation, endotoxemia, and metabolism.

    Causes of obesity-associated inflammation include leaky gut, a condition where the intestinal barrier is compromised, leading to increased levels of bacterial endotoxin (toxins that are released when bacteria die) in the bloodstream (called endotoxemia). This increase in endotoxin levels activates white blood cells to secrete pro-inflammatory cytokines such as interleukin (IL)-6 and IL-17. Plant foods such as apples are beneficial for people with obesity because they are rich in bioactive compounds that decrease inflammation and dietary fibers that strengthen the gut barrier.

    The researchers recruited 46 participants with overweight and obesity and directed them to avoid foods and beverages rich in polyphenols and/or dietary fibers (e.g., coffee, vegetables, grains, beans, and red/purple/blue fruits) for two weeks. Next, they assigned half of the participants to consume three Gala apples per day for six weeks or to avoid apples. Both groups continued to eat a diet with limited polyphenols and dietary fibers. Participants provided blood samples for the collection of white blood cells and measurement of pro-inflammatory cytokines. After isolating the white blood cells, the researchers stimulated them with endotoxin and measured their response.

    Apple consumption decreased plasma C-reactive protein (a pro-inflammatory cytokine) by 17 percent, IL-6 by 12 percent, and endotoxin-binding protein by 20 percent compared with no apple consumption. White blood cells from participants who consumed apples secreted 28 percent less IL-6 and 11 percent less IL-17. While apple consumption increased total antioxidant capacity in blood by 10 percent, it had no effect on cardiovascular disease markers.

    These findings suggest that six weeks of daily Gala apple consumption helped mitigate inflammation in those consuming a diet low in polyphenols and fiber, a common feature of the Western diet pattern. Apple consumption may decrease cardiovascular disease risk in those with obesity, even without weight loss.

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  • Leaky gut decreases the beneficial effects of dietary polyphenol compounds in older adults. pubs.acs.org
    Gut Microbiome Polyphenol Intestinal Permeability

    Polyphenols are a group of bioactive compounds found in plant-based foods that have beneficial effects in the body. Bacteria in the human gut break down polyphenols into smaller compounds to increase their absorption. Authors of a recent study aimed to measure the relationship between gut health and the absorption of beneficial polyphenols in older adults.

    As humans age, the quality of the population of microbes that comprise the gut microbiota decreases, leading to poor gut barrier integrity and causing contents of the gut to leak into the bloodstream, a condition commonly referred to as “leaky gut.” This leaking of toxins, viruses, and bacteria is associated with increased inflammation and disease risk. In addition to causing a leaky gut, poor microbiota quality may decrease the beneficial effects of polyphenol-rich plant foods.

    The authors tested the effects of a polyphenol-rich diet in 51 adults (greater than 60 years of age) residing in an assisted living setting. Participants consumed either the normal menu prepared by their facility for eight weeks or a menu that included three servings of polyphenol-rich fruits, teas, and cocoa for eight weeks and then switched to the opposite diet. The researchers collected blood samples to measure serum zonulin, a marker of gut barrier integrity, and urine samples to analyze polyphenol metabolite content before and after each diet period.

    Overall, serum zonulin decreased following eight weeks of a polyphenol-rich diet, meaning that gut barrier integrity improved. Participants who started the trial with better gut barrier integrity had a significantly greater increase in blood levels of polyphenol metabolites compared to participants with leakier guts. The metabolites found in the group with greater gut barrier integrity were microbial-derived, suggesting these participants had a more health-promoting gut microbiota.

    Based on these results, the authors hypothesize that changes in the gut microbiota damage the gut barrier and cause a subsequent reduction in the absorption of dietary polyphenol compounds. They conclude that personalized diet plans could be effective for managing leaky gut in older adults.

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  • Compounds in e-cigarettes trigger inflammation, promoting a leaky gut. ucsdnews.ucsd.edu
    Gut Intestinal Permeability Lipopolysaccharide

    In recent years, vaping, or smoking electronic cigarettes (e-cigarettes), has emerged as a popular substitute for smoking tobacco-containing cigarettes. E-cigarettes produce a vapor that may contain nicotine as well as a variety of toxic substances, including some carcinogens. Findings from a new study suggest that some compounds in e-cigarettes trigger inflammation, promoting a leaky gut.

    Leaky gut, otherwise known as intestinal permeability, is a condition in which gaps form between the tight junctions between the endothelial cells that line the gut. These gaps allow pathogens like bacteria or endotoxins (toxins that are released when bacteria die) to leak through the intestinal wall and pass directly into the bloodstream. Leaky gut has been linked with a number of chronic diseases, including Alzheimer’s disease and cardiovascular disease.

    The authors of the study exposed mice to e-cigarette vapors for one hour per day and then they examined the animals' colons at one week and three months after the chronic exposure. Then they measured gene expression in the colons. They also built gut enteroids – three-dimensional tissue models that incorporate many of the features of human gut tissue, including an epithelial layer surrounding a functional lumen and all of the cell types normally found in the gut. They exposed the enteroids to e-cigarette vapor (with or without nicotine).

    They found that exposure to e-cigarette vapor promoted leaky gut, increasing the susceptibility of the gut lining to bacterial infections, and triggering gut inflammation. Use of the two models established that the primary components in the vapor responsible for the harmful effects were propylene glycol and vegetable glycerol, compounds present in more than 99 percent of all e-cigarettes. They also found that e-cigarette vapor altered expression of genes involved in the cellular response to stress, infection, and inflammation.

    These findings demonstrate that commonly used substances present in e-cigarettes promote leaky gut and drive inflammation and provide insights into the long-term health effects of e-cigarettes. They also underscore public health efforts to reduce e-cigarette use.

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