Intestinal permeability Suggest an improvement to this article

The digestive tract is lined with a single layer of cells called epithelial cells that are responsible for exchanging nutrients between the bloodstream and intestines. In order to fulfill its physiological purpose, this layer, referred to as the intestinal epithelium, must be permeable to nutrients while excluding pathogens. Increased gut permeability (also known as “leaky gut”) – a condition in which gaps form between the tight junctions of the endothelial cells that line the gut – allows pathogens to leak through the intestinal wall and pass directly into the bloodstream, promoting inflammation. The body employs a complex strategy to maintain a selectively permeable barrier that maximizes nutrition and immunity. Disturbed function of the gut barrier is observed in a growing number of health conditions, including:

Crohn's disease, colitis, and other inflammatory bowel diseases

  • Some genotypes are predisposed to higher gut permeability (as determined using twin studies), which may initiate chronic inflammation and the development of inflammatory bowel diseases when an individual encounters certain environmental triggers.[1]

Irritable bowel syndrome

  • In some people with irritable bowel syndrome, the intestinal barrier has too many active T cells and mast cells (white blood cells), compromising gut barrier function and altering function of the gut-brain axis.[2]

Type 1 diabetes

  • Zonulin, a protein that modulates intestinal permeability, is increased prior to the onset of type 1 diabetes, providing a potential link between increased intestinal permeability and the development of autoimmunity in genetically susceptible individuals.[3]

Celiac disease and gluten sensitivities

  • In celiac disease, T cells respond to gluten (due to genetic predisposition) and attack the intestinal barrier, resulting in intestinal atrophy (i.e., shrinkage) and reduced nutrient absorption.[4]

The field exploring intestinal permeability and its relationship with the gut microbiota and disease is quite new. Because of this, there are no established clinical standards for using probiotics or other supplements to treat leaky gut. Therapies to strengthen the gut barrier are under investigation, though, and many lifestyle interventions have been identified as supportive of healthy intestinal permeability:

Fiber

  • Dietary fibers (i.e., carbohydrates that are not digested by human enzymes) are metabolized by gut microbes to produce short-chain fatty acids such as butyrate, which strengthen tight junction proteins and reduce inflammation.[5]

Polyphenols

  • Many polyphenols are poorly absorbed from the diet and are metabolized by the microbiota instead, resulting in the creation of an array of bioactive compounds that regulate inflammation, the gut microbiome, and intestinal barrier function.[6]

Exercise

  • While exercise may lead to short-term gut barrier damage in some people, overall, people who exercise have healthier long-term markers of intestinal permeability at rest.[7]

Probiotics

  • One study has shown that the probiotic Lactobacillus plantarum increases gut barrier integrity through its ability to regulate the tight junction proteins that hold intestinal epithelial cells together.[8]

The gut barrier up close

The gut lining is approximately 320 square feet in surface area (about the size of a small studio apartment). This massive surface area is arranged like shag carpet, with structures called “villi” (villus, singlular) that protrude from the intestine wall. The longer the villus, the greater the number of intestinal epithelial cells (called enterocytes) available to absorb nutrients, such as fat or iron. In addition to the enterocytes, the gut barrier contains goblet cells, which secrete mucus, and paneth cells, which secrete immune factors.[9]

Goblet cells secrete a layer of mucus that sits on top of the intestinal epithelium and acts as a physical buffer between the contents of the digestive tract and the intestinal wall. Paneth cells sample microbial patterns from the gut barrier environment to distinguish friendly bacteria from pathogens. The gut microbiota, the community of microorganisms that inhabits the digestive tract, colonizes space near the mucus layer, crowding out unfamiliar microbes. These layers of defense protect the body from harmful substances that enter the body with food.[9]

Effects of Intestinal Permeability on Aging

Intestinal permeability has implications beyond the digestive tract – it may be linked to accelerated aging. A compromised gut barrier allows bacterial components to infiltrate the bloodstream and trigger the body's innate immune system. While this acute inflammatory response is essential to attack invading pathogens, chronic inflammation is associated with many diseases of aging, a phenomenon termed inflammaging.

Immune cells bear specialized proteins embedded within their membranes that recognize specific microbial molecular patterns. These toll-like receptors detect the presence of bacterial components and signal the body to secrete inflammatory cytokines. Humans have ten functional toll-like receptors, each recognizing distinct microbial patterns, for example, the TLR4 receptor detects lipopolysaccharide (LPS), an endotoxin present in the cell walls of Gram-negative bacteria.

Increased intestinal permeability is a feature of metabolic diseases such as obesity, non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. As a result, patients with metabolic diseases tend to have higher blood levels of endotoxin, leading to chronic activation of TLR4 and its downstream pro-inflammatory pathways. Excessive TLR4-mediated innate immune activation can result in chronic inflammation and inflammaging.

Summaries

Below is a selection of summaries from current research investigating the role of intestinal permeability in health and disease.

Polyphenols improve gut microbiota quality and butyrate production, preventing leaky gut syndrome.

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. Findings from one study suggest that a polyphenol-rich diet reduces the risk of leaky gut in older adults. Leaky gut is common among older adults, putting them at risk for many acute and chronic diseases.

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 dietary 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' ages, 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 the consumption of polyphenol-rich foods throughout the lifespan.

Sugar binges increase risk of inflammatory bowel disease.

Approximately 3 million people living in the United States have inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis. The Western diet – a dietary pattern that is high in unhealthy fats and refined sugar and low in fiber – has been implicated in the pathogenesis of IBD. Findings from one study suggest that even short-term exposure to a high-sugar diet increases susceptibility to ulcerative colitis.

The study involved mice that were fed either regular mouse chow or a diet that was high in sugar (approximately 50 percent sucrose). After two days, the mice were treated with dextran sodium sulfate, a chemical that induces colitis. The mice were then assessed for changes in the diversity of their gut microbiota, disease severity, gut permeability, and the concentration of short-chain fatty acid (SCFA), which are products of microbial fermentation that dampen inflammation in the gut.

The mice that ate the high sugar diet exhibited decreased diversity among their gut microbiota, increased gut permeability, and lower concentrations of SCFAs. They were much more likely to develop colitis than the mice that ate the regular chow. These findings suggest that even short-term exposure to a high sugar diet can influence susceptibility to IBD.

Supplementing with butyrate reduces the aggressiveness of ALS by strengthening the gut barrier.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive loss of voluntary muscle control due to motor neuron dysfunction. A growing body of evidence implicates the gut microbiota in the development of neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, and ALS. Findings from one study demonstrate that feeding butyrate, a bacterial metabolic product, regulates the immune system and reduces the aggressiveness of ALS.

The authors of the report used normal mice and mice who are genetically predisposed to developing ALS in their study. They gave the mice normal drinking water or drinking water with two percent butyrate added and watched them for signs of ALS for several weeks.

Butyrate supplementation delayed the onset of ALS symptoms in genetically susceptible mice from 110 days in the group drinking normal water to 150 days in the butyrate-supplemented group. Mice who developed ALS had a reduced abundance of butyrate-producing microbes in their gut microbiota at the time their ALS symptoms appeared; however, butyrate supplementation restored the population of butyrate-producing bacteria. Butyrate supplementation corrected abnormal tight junction proteins, which are responsible for connecting gut epithelial cells to each other. This improved but barrier integrity and reduced gut inflammation.

These findings demonstrate a significant relationship between butyrate-producing bacteria in the gut and the development and progression of ALS, potentially guiding the development of new therapeutic strategies for the disease.

Frequently Asked Questions

Q: Are there supplements that help prevent leaky gut?

A: Fiber, polyphenols, and probiotics are all under investigation for their health benefits, which include strengthening the gut barrier and preventing leaky gut. Whole foods such as vegetables, fruits, and nuts are the best way to get adequate amounts of fiber and polyphenols, although these nutrients can be found in supplements as well. Probiotics can be found in fermented foods such as yogurt and kimchi and are also available as supplements. Because this field of research is so new and because individuals vary in their responses to supplements, data to support the use of any probiotic or supplement for leaky gut or other gastrointestinal tract disorders are not yet available.

Q: Oats contain a protein called "avenin" that is similar in structure to gluten. Should I be worried about oats causing leaky gut?

A: Unfortunately, there isn't much research into the effects of avenin on the gut barrier. One study found that avenin, unlike gluten, did not activate the pathways implicated in celiac disease development in cells in culture. In fact, a separate study conducted in rats found that oats improved gut leakiness caused by alcohol exposure. It is reasonable, given the amount of fermentable fiber found in oats that can be utilized by gut microbes to produce butyrate, to think that oats may reduce gut leakiness in humans as well, although research has yet to investigate this. However, because some oat products are prepared or packaged in areas where gluten-containing grains may be present, people with gluten sensitivity should exercise caution when consuming oats.

Topics

  • Toll-like receptors are specialized receptors that detect the presence of bacterial components in the bloodstream and trigger the body to secrete inflammatory cytokines. Prolonged immune stimulation mediated by toll-like receptors contributes to aspects of aging known as inflammaging.

  • Polyphenols are plant nutrients that improve the gut barrier and enhance health in a number of other ways; learn more from our overview article on the topic.

  • The blood-brain barrier is another membraneous barrier in the body that loses its integrity with age. Increased microbial toxins in the blood as a result of increased intestinal permeability is a source of stress for the blood-brain barrier, injuring neurons and promoting disease.

Episodes & Clips

  • Time-restricted eating may be one strategy for strengthening the gut batter. Expert Dr. Satchin Panda discusses how time-restricted eating affects leaky gut and systemic inflammation in this clip from the FoundMyFitness podcast.
  1. ^ Gut Barrier Dysfunction A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition Journal of Crohn s and Colitis , April 2018. https://doi.org/10.1093/ecco-jcc/jjy045.
  2. ^ Cellular and Molecular Basis of Intestinal Barrier Dysfunction in the Irritable Bowel Syndrome Gut and Liver 6, no. 3 (July 2012): 305–15. https://doi.org/10.5009/gnl.2012.6.3.305.
  3. ^ The role for gut permeability in the pathogenesis of type 1 diabetes - a solid or leaky concept? Pediatric Diabetes 16, no. 7 (August 2015): 485–92. https://doi.org/10.1111/pedi.12305.
  4. ^ Celiac Disease: Role of the Epithelial Barrier Cellular and Molecular Gastroenterology and Hepatology 3, no. 2 (March 2017): 150–62. https://doi.org/10.1016/j.jcmgh.2016.12.006.
  5. ^ Microbial butyrate and its role for barrier function in the gastrointestinal tract Annals of the New York Academy of Sciences 1258, no. 1 (June 2012): 52–59. https://doi.org/10.1111/j.1749-6632.2012.06553.x.
  6. ^ Polyphenols and Intestinal Permeability: Rationale and Future Perspectives Journal of Agricultural and Food Chemistry 68, no. 7 (June 2019): 1816–29. https://doi.org/10.1021/acs.jafc.9b02283.
  7. ^ Exercise and intestinal permeability: another form of exercise-induced hormesis? American Journal of Physiology-Gastrointestinal and Liver Physiology 319, no. 4 (October 2020): G512–G518. https://doi.org/10.1152/ajpgi.00232.2020.
  8. ^ Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and protective effects on the epithelial barrier American Journal of Physiology-Gastrointestinal and Liver Physiology 298, no. 6 (June 2010): G851–G859. https://doi.org/10.1152/ajpgi.00327.2009.
  9. ^ a   b Homeostasis of the gut barrier and potential biomarkers American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 3 (March 2017): G171–G193. https://doi.org/10.1152/ajpgi.00048.2015.

Topics related to Intestinal permeability

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  • Polyphenols
    Polyphenols are bioactive plant compounds with a wide range of health benefits.
  • Butyrate
    A short-chain fatty acid produced by microbes in the gut. Microbial production of butyrate occurs in the colon during the fermentation of dietary fibers.
  • Beta-hydroxybutyrate
    Beta-hydroxybutyrate (BHB) is a ketone body and source of cellular energy produced via the breakdown of fats during times of carbohydrate scarcity and fasting.
  • Toll-like receptors
    Toll-like receptors are a family of pattern recognition receptors expressed on the surface of immune and other cells that play an important role in intestinal permeability and inflammaging.