The human body has multiple mucosal epithelia that form direct barriers between the environment and the internal host. The gastrointestinal tract has one of the largest of these barriers (Turner, 2009; Helander and Fandriks, 2014). It forms a tight barrier that controls what gets absorbed into the bloodstream.
The “leaky gut” is a simplistic term reflecting intestinal permeability. This term has been reported already in the scientific literature from 1970–1990 (Chadwick et al., 1977; Bjarnason et al., 1983; Hollander et al., 1986). Leaky gut refers to the dysfunction of the intestinal barrier that leads to the generation of leaky gut syndrome (LGS) under chronic states. The term is used to indicate abnormal translocation of big-size molecules from lumen to villi or excessive absorption of such molecules from lumen into systemic circulation, which, in turn, induces various organ disorders (reviewed in Schoultz and Keita, 2020).
STRUCTURE OF INTESTINAL BARRIER
The intestinal barrier includes surface mucus, epithelial layer, and gut microbiota.
The surface mucus. The mucus consists of a highly glycosylated hydrated gel formed by mucin molecules that are secreted by goblet cells. The mucus facilitates passage of the luminal contents along the length of the intestines, protects the epithelial cells from digestive enzymes, and prevents the direct contact of microorganisms with the epithelial layer. The intestinal mucosa protects the body and the gut from uncontrolled translocation of pro-inflammatory molecules, (such as microorganisms, toxins, and antigens) into the circulation. Therefore, it is vital for the maintenance of health and well-being (Turner, 2009; Sánchez de Medina et al., 2014; Lee, 2015).
The intestinal epithelium. The gut epithelium consists of the layer of epithelial cells lining the intestine. The epithelial cells are the strongest determinants of the physical intestinal barrier. They form crucial effective barrier to control the translocation of molecules between cells. Transport of molecules in-between the intestinal epithelial cells is regulated through the presence of junctional complexes. The three most important complexes are tight junctions, adherens junctions and desmosomes (Groschwitz and Hogan, 2009). Tight junctions consist of transmembrane proteins (e.g., claudins, occludin), peripheral membrane proteins (e.g., zonula occludens ZO-1, ZO-2) and regulatory proteins. Adherens junctions are located below the tight junctions and are required for their assembly. Together with desmosomes, adherens junctions provide strong bonds to maintain the integrity of the epithelium. In addition to its protective function, the intestinal epithelium controls the selective uptake of ions, nutrients, and other substances from the gut lumen into the body.
Microbiota. The intestinal microbiota is responsible for a variety of processes, including the breakdown and absorption of nutrients, the production of vitamins and hormones, and the prevention of colonization by pathogens. Few hundred species of gut bacteria fall into two dominant groups, Bacteroidetes and Firmicutes. Dysbiosis and imbalance in maintain this equilibrium between a host and its microbiota has negative consequences for health. Several diseases have been linked to gut dysbiosis, including atopic diseases, inflammatory bowel disease (IBD), diabetes, obesity, and cancer (reviewed in Bischoff et al., 2014).
LEAKY GUT BIOMARKERS
"Leaky gut" is getting a lot of attention in natural medicine, but orthodox medicine does not recognize this condition. The term is somewhat new and most of the research occurs in basic science. Measuring intestinal permeability in humans is difficult. However, the measurement of biomarkers in urine, blood or faeces provides a simple and non-invasive method to evaluate intestinal barrier function. Intestinal permeability can be verified by measuring alpha-1-antitrypsin and zonulin, and the biomarker for inflammatory bowel disease, calprotectin. Claudin protein level has been proposed to be also a suitable candidates for intestinal disruption of the tight junction (Findley and Koval, 2009). Urinary claudin proteins has been found increased in patients with enterocolitis (Blackwood et al., 2015) or IBD (Grootjans et al., 2010). Some of the markers need further investigation.
CAUSES OF INTESTINAL PERMEABILITY
Several factors impact intestinal permeability and may cause leaky gut:
Genetic predisposition. Certain people may be more sensitive to environmental factors that trigger their bodies into inflammatory responses.
Dysbiosis. Bacterial imbalance and small intestine bacterial overgrowth (SIBO), is a leading cause of the LGS.
Poor diet. Diet low in fiber and high in sugar, saturated fats, and genetically modified foods (GMO).
Hypochlorhydria and poor bile flow. Low levels of stomach acid and impaired liver and biliary system functions (e.g., liver diseases, biliary stones, toxin overload, parasites) cause protein and fat indigestion as well as gut dysbiosis leading to an increased gut inflammation.
Heavy alcohol intake.
Chronic stress. Prolonged stressed weakens immune system and inhibits body’s ability to eliminate harmful bacteria and viruses, resulting in inflammation and leaky gut.
Toxin overload. Synthetic chemicals presented in our homes, personal care products, environment as well as food additives and pesticides cause great damage to gut lining.
Various medications. Stomach acid blockers, proton pump inhibitors and antibiotics can all contribute to leaky gut. Antibiotics, while they can be essential, can lead to gut flora imbalance, whereas acid blockers and proton pump inhibitors can decrease gastric acid secretions, necessary for digestion and absorption.
DISEASES ASSOCIATED WITH LEAKY GUT
When the intestinal lining becomes disrupted and irritated, the tight junctions loosen and allow unwanted larger molecules (e.g., microbes, microbial products, and foreign antigens) in the intestines to pass through into the blood. These unwanted substances are recognized by the immune system. Certain immune responses might, in turn, cause cellular damage that could result in further barrier dysfunction (Márquez et al., 2016). Alerted immune system produces antibodies and cytokines. The last once alert white cells to fight foreign particles. This fight results in irritation and inflammation.
Some people are genetically predisposed and may be more sensitive to changes in the digestive system. Moreover, modern life may actually be the main driver of gut inflammation. LGS has been observed concomitantly with gut inflammation. Intestinal barrier dysfunction is thought to be precondition for and exacerbating factor of numerous gastrointestinal conditions, including food allergies, IBD, irritable bowel syndrome (IBS), celiac disease, non-alcoholic fatty liver disease and non-steroidal anti-inflammatory drugs (NSAIDs)-induced ulceration (Chadwick et al., 1977; Bjarnason et al., 1983; Hollander et al., 1986; Groschwitz and Hogan, 2009; Yan et al., 2013; Sánchez de Medina et al., 2014).
Several other non-gastrointestinal diseases have been associated with leaky gut, including asthma, autism, Parkinson’s disease, multiple sclerosis, eczema, psoriasis, fibromyalgia, depression, chronic fatigue syndrome, obesity, metabolic syndrome, pancreatitis, and rheumatoid arthritis (reviewed in Odenwald and Turner, 2013). The concept of a leaky gut in non-gastrointestinal diseases is supported by evidence of dysfunctional gut mucosal barrier in stress-associated conditions, associations of disease states with altered intestinal permeability and gut dysbiosis. However, the con of this hypothesis is that most of the scientific data comes from in vitro data and animal models. There is limited scientific data in humans that a leaky gut resulting in increased intestinal permeability causes symptoms outside the gastrointestinal tract. Many authors indicate that altered gut permeability can occur simultaneously with other disease or condition (but it is not directly related to it) because any inflammatory process, dietary components, stress, or factors such as bile acids may impair barrier integrity (reviewed in Camilleri, 2019). More research must be performed to find out how intestinal barriers effect different body systems and disease development and/or progression. Nevertheless, it is important to keep in mind what Hippocrates: “all disease begins in the gut” and addressing the gut health should be included in patients treatment and recovery.
CONCLUSIONS
LGS, also called intestinal permeability, is classified by malfunction in the intestinal tight junctions in the digestive tract. When this occurs, inflammatory immune responses can increase, leading to several health issues. Dietary habits and lifestyle factors have a clear impact on intestinal permeability with known detrimental effects for a western diet, high alcohol intake, stress, and certain medications. Clinical and scientific data support a central role of intestinal barrier dysfunction in IBD, Celiac disease and non-alcoholic fatty liver disease. LGS has also be linked with depression, autism, joint pain, skin inflammation, autoimmune disease and more.
REFERENCES
Bischoff SC, Barbara G, Buurman W, et al. (2014). Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol. 14:189.
Bjarnason I, Peters TJ, Veall N. (1983). A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test. Lancet. 1:323–325.
Blackwood BP, M D, Wood DR, B S, Yuan CY, B S, et al. (2015). Urinary Claudin-2 Measurements as a Predictor of Necrotizing Enterocolitis: A Pilot Study. J Neonatal Surg. 4(4):43.
Büning C, Geissler N, Prager M, et al. (2012). Increased small intestinal permeability in ulcerative colitis: rather genetic than environmental and a risk factor for extensive disease? Inflamm Bowel Dis. 18(10):1932–1939.
Camilleri M. (2019). Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 68(8):1516–1526.
Chadwick VS, Phillips SF, Hofmann AF. (1977). Measurements of intestinal permeability using low molecular weight polyethylene glycols (PEG 400). II. Application to normal and abnormal permeability states in man and animals. Gastroenterology. 73:247–451.
de Magistris L, Familiari V, Pascotto A, et al. (2010). Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 51(4):418–424.
Findley MK, Koval M. (2009). Regulation and roles for claudin-family tight junction proteins. IUBMB Life. 61(4):431–437.
Grootjans J, Thuijls G, Verdam F, Derikx JP, Lenaerts K, Buurman WA. (2010). Non-invasive assessment of barrier integrity and function of the human gut. World J Gastrointest Surg. 2(3):61–69.
Groschwitz, KR, Hogan, SP. (2009). Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis. The Journal of Allergy and Clinical Immunology. 124(1):3–22.
Helander HF, Fandriks L. (2014). Surface area of the digestive tract - revisited. Scandinavian journal of gastroenterology. 49(6):681–689.
Hollander D, Vadheim CM, Brettholz E, et al. (1986). Increased intestinal permeability in Crohn’s patients and their relatives: an etiological factor. Ann Intern Med. 105:883–885.
Lee, SH. (2015). Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases. Intestinal Research. 13(1):11–18.
Márquez, M; Fernández Gutiérrez, Del Álamo C; Girón-González, JA (2016). Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity. World J. Gastroenterol. 22(4):1433–1448.
Odenwald MA, Turner JR. (2013). Intestinal permeability defects: is it time to treat? Clin Gastroenterol Hepatol. 11:1075–1083.
Sánchez de Medina, F., Romero-Calvo, I., Mascaraque, C., Martínez-Augustin, O. (2014). Intestinal inflammation and mucosal barrier function. Inflammatory Bowel Diseases. 20(12):2394–2404.
Schoultz, I and Keita, Å.V. (2020). The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells. 9(8):1909.
Turner JR. (2009). Intestinal mucosal barrier function in health and disease. Nature reviews. Immunology. 9(11):799–809.
Yan, L, Yang, C, Tang, J. (2013). Disruption of the intestinal mucosal barrier in Candida albicans infections. Microbiological Research. 168(7): 389–395.