The digestive tract is lined with a single layer of epithelial cells (called enterocytes) that are responsible for exchanging 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 metabolic and physiological consequences that may have far-reaching consequences on immunity, brain, and even aging. To learn more, see the metabolic endotoxemia section of our toll-like receptor overview.
The field of exploring intestinal permeability and its relationship with the gut microbiota and disease is relatively new. Consequently, there are no established clinical standards for using probiotics or other supplements to treat increased intestinal permeability. Therapies to strengthen the gut barrier are under investigation, though, and many lifestyle interventions have been identified as supportive of healthy intestinal barrier function:
The intestinal lining is approximately 320 square feet in surface area,[6] which is about the size of a small studio apartment. This massive surface area resembles a shag carpet, with enterocyte-covered structures called “villi” (villus, singular) that protrude from the intestine wall. The longer the villus, the greater the number of enterocytes available to absorb nutrients, such as fat or iron. Interspersed among the enterocytes are goblet cells and paneth cells.[7]
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 intestinal 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 multiple layers of defense protect the body from harmful substances that enter the body with food or beverages.[7]
Intestinal permeability has been implicated in the pathogenesis of many conditions that affect the health of the gut as well as non-gut-related disorders, including:
Having increased intestinal permeability increases a person’s risk for chronic diseases, many of which may be related to exposure to lipopolysaccharide (LPS), an endotoxin present in the cell walls of Gram-negative bacteria. LPS exploits intestinal permeability to gain access to the bloodstream. There, pattern-recognition molecules called toll-like receptors detect its presence and activate an immune response that drives the expression of an array of proinflammatory proteins and mediators. This cascade of events, starting with the loss of barrier function and culminating with immune activation, likely plays roles in the pathogenesis of many chronic disorders, including cardiovascular disease, neurodegenerative disease, metabolic dysfunction, behavioral disorders, and cancer.[12]
Increased intestinal permeability may be involved in the pathogenesis of atherosclerosis. Circulating LPS can bind to lipoproteins, facilitating their absorption in the liver during LDL recycling, effectively removing LPS from circulation and lowering systemic inflammation. However, small, dense lipoproteins are not easily recycled. When bound to LPS, they remain in circulation and eventually insert themselves into arterial walls, triggering an immune response. Immune factors engulf the particles, creating foam cells and initiating the process of atherosclerosis.[13]
The intestinal barrier shares many similarities with the blood-brain barrier, consisting of cells held together by tight junctions and supported by other cell types, including astrocytes, pericytes, and microglia cells, the brain's resident immune cells. Microglia protect the brain following acute brain injury and help maintain brain homeostasis. LPS can bind to toll-like receptors on microglial cells, switching them from "protect" to "attack" mode and initiating a vicious cycle of blood-brain barrier breakdown and neuroinflammation. The loss of blood-brain barrier function is particularly evident during aging, with markers of barrier breakdown preceding the formation of tau tangles and amyloid-beta plaques in early cognitive dysfunction.[14]
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, people with metabolic diseases tend to have higher blood levels of LPS, leading to chronic activation of TLR4 and its downstream pro-inflammatory pathways. Excessive TLR4-mediated innate immune activation can result in chronic inflammation, which advance hallmarks of aging, a phenomenon referred to as inflammaging. LPS plays a role again, as even a low-dose exposure to the endotoxin can drive inflammaging, increasing inflammatory markers as much as a hundredfold.[15]
Compelling evidence suggests that the relationship between inflammation and depression is indeed causal, and LPS may play a role. In studies in which participants receive LPS injections, their circulating levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha (which are downstream of toll-like receptor activation), increase markedly. Interestingly, depressive symptoms, anxiety, feelings of social disconnection, and anhedonia (a lack of reactivity to pleasurable stimuli) increase, as well, coinciding with the peak of the proinflammatory response.
Intestinal permeability has implications for accelerated aging, as well. A compromised intestinal 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 promotes the hallmarks 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 proteins, called 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 LPS.
Learn more about toll-like receptors in our overview article.
Learn more about inflammaging in our hallmarks of aging overview
Fiber undergoes microbial fermentation in the gut to produce butyrate, a short-chain fatty acid that, under normal physiological circumstances, provides more than 70 percent of the energy consumed by to colonocytes, the cells that line the colon.[16] Whole grains are the primary dietary sources of fermentable fiber, but non-gluten-containing sources include a wide range of fruits and vegetables that provide pectin, beta-glucans, inulin, and resistant starch, such as apples, sunflower seeds, oats, and potatoes, among others. Evidence from animal models suggests that a microbiota that is enriched in butyrate-producing bacteria prevents intestinal permeability and atherosclerosis. Factors that may contribute to increased numbers of butyrate-producing bacteria include time-restricted eating,[17] aerobic exercise,[18] and the consumption of omega-3 fatty acids.[19]
The overall quality of the fats in a person's diet can influence intestinal permeability, as well. For example, a trial found that postprandial LPS increased markedly after consumption of saturated fat. However, providing 500 milligrams of omega-3 fatty acid (DHA) with a meal reduced postprandial LPS.[20]
A meta-analysis of studies investigating the effects of dietary fats on intestinal permeability revealed that whereas saturated fats tend to promote postprandial LPS leakage, omega-3 fatty acids tend to prevent it. This may be because omega-3s increase intestinal alkaline phosphatase, an enzyme that degrades LPS. Omega-3s also alter the makeup of the gut microbiota, favoring butyrate-producing species. However, some of the studies on which these conclusions are based used processed oils and provided refined carbohydrates with the test meals, confounding the analysis.[21]
Byproducts of omega-3 fatty acid metabolism, called specialized pro-resolving mediators (SPMs) resolve inflammation.[22] The three families of omega-3-derived SPMs, which include the resolvins, protectins, and maresins, promote apoptosis, regulate leukocyte activity, and reduce the production of proinflammatory molecules. Omega-3 fatty acids promote dose-dependent increases in blood SPM levels that persist for up to 24 hours.[23]
Surprisingly, no evidence suggests higher levels of LPS leak into circulation during a ketogenic diet, likely due to the profound metabolic changes induced during ketosis. In addition, beta-hydroxybutyrate, a ketone produced during a ketogenic diet, may travel to the colon and nourish the colonocytes.[24]
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.[25] A diet rich in polyphenols, especially those from cocoa and green tea, may reduce the risk of intestinal permeability in older adults. These benefits may arise from the compounds' capacity to support populations of butyrate-producing bacteria in the gut.[26]
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 ulcerative colitis, a type of inflammatory bowel disease. Evidence from a study in mice suggests 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 that ate the high-sugar diet exhibited decreased diversity among their gut microbiota, increased intestinal permeability, and lower concentrations of gut-produced short-chain fatty acids. They were also much more likely to develop colitis than the mice that ate the regular chow.[27]
Evidence suggests that providing supplemental butyrate regulates the immune system and reduces the aggressiveness of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease. In a study in which mice that are genetically predisposed to developing ALS received either regular water or butyrate-supplemented water, butyrate supplementation delayed the onset of ALS symptoms by more than 40 days. Mice that developed ALS had few butyrate-producing microbes in their gut microbiota when their ALS symptoms appeared; however, butyrate supplementation restored the population of butyrate-producing bacteria. Butyrate supplementation also corrected abnormal tight junction proteins, improving barrier integrity and reducing gut inflammation.[28]
Q: Are there supplements that help prevent leaky gut?
A: Fiber, polyphenols, and probiotics are all under investigation for their health benefits, including strengthening the gut barrier and preventing leaky gut. Whole foods such as vegetables, fruits, and nuts are the best way to obtain 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.[29] In fact, a separate study conducted in rats found that oats improved gut leakiness caused by alcohol exposure.[30] 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.
Q: Why do conditions of the gut often seem to have an impact on qualities of cognition and mood?
A: The intestinal barrier and blood-brain barrier share many characteristics and common causes for dysfunction, such as aging, hyperglycemia, and inflammation. An emerging body of evidence supports the existence of a gut-brain axis, which describes the bi-directional communication between the central nervous system (CNS) and enteric nervous system (ENS). The ENS contains a number of neurones equal to or greater than the spinal cord and is described as quasi-autonomous because it is the only part of the peripheral nervous system (PNS) that has neural circuits capable of local, autonomous function – meaning not under CNS control.[31] These circuits control motor functions, local blood flow, mucosal transport and secretion, and modulation of immune and endocrine functions. [32] The gut-brain axis connects centers of cognition and emotion in the brain with the physiology of the gut, placing the ENS at the center of many diseases of the brain and digestive tract.[33]
Topics
Butyrate - A short-chain fatty acid produced by bacterial fermentation of dietary fiber in the gut. Butyrate increases tight-junction protein assembly, strengthening the gut barrier.[34]
Toll-like receptors - TLRs 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 - 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.
Blood-brain barrier - Another membranous barrier in the body that loses its integrity with age. Increased microbial toxins in the blood because of increased intestinal permeability is a source of stress for the blood-brain barrier, injuring neurons and promoting disease.
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