Intestinal permeability

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Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances (such as antigens) from leaving the intestine and migrating to the body more widely. [1] In a healthy human intestine, small particles (< 4 Å in radius) can migrate through tight junction claudin pore pathways, [2] and particles up to 10–15 Å (3.5 kDa) can transit through the paracellular space uptake route. [3] There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. [4] The most well understood condition with observed increased intestinal permeability is celiac disease. [5]

Contents

Physiology

Scheme of selective permeability routes of epithelial cells (red arrows). The transcellular (through the cells) and paracellular (between the cells) routes control the passage of substances between the intestinal lumen and blood. Selective permeability routes in epithelium.png
Scheme of selective permeability routes of epithelial cells (red arrows). The transcellular (through the cells) and paracellular (between the cells) routes control the passage of substances between the intestinal lumen and blood.

The barrier formed by the intestinal epithelium separates the external environment (the contents of the intestinal lumen) from the body [6] and is the most extensive and important mucosal surface of the body. [7] However, the intestinal mucin can also be barriers for the host antimicrobial peptides, thus plays a bidirectional barrier for host-microbial interaction. [8] The intestinal epithelium is composed of a single layer of cells and serves two crucial functions. First, it acts as a barrier, preventing the entry of harmful substances such as foreign antigens, toxins and microorganisms. [6] [9] Second, it acts as a selective filter which facilitates the uptake of dietary nutrients, electrolytes, water and various other beneficial substances from the intestinal lumen. [6] Selective permeability is mediated via two major routes: [6]

Modulation

One way in which intestinal permeability is modulated is via CXCR3 receptors in cells in the intestinal epithelium, which respond to zonulin. [4]

Gliadin (a glycoprotein present in wheat) activates zonulin signaling in all people who eat gluten, irrespective of the genetic expression of autoimmunity. This leads to increased intestinal permeability to macromolecules. [4] [12] [5] Bacterial infections such as cholera, select enteric viruses, parasites, and stress can all modulate intestinal tight junction structure and function, and these effects may contribute to the development of chronic intestinal disorders. [4] [13] [12] So called absorption modifying excipients, investigated for the possibility of increasing intestinal drug absorption, can increase the gut permeability. [14]

Clinical significance

Most people do not experience adverse symptoms, but the opening of intercellular tight junctions (increased intestinal permeability) can act as a trigger for diseases that can affect any organ or tissue depending on genetic predisposition. [4] [5] [15]

Increased intestinal permeability is a factor in several diseases, such as Crohn's disease, celiac disease, [16] type 1 diabetes, [17] type 2 diabetes, [16] rheumatoid arthritis, spondyloarthropathies, [18] inflammatory bowel disease, [4] [19] schizophrenia, [20] [21] certain types of cancer, [4] obesity, [22] fatty liver, [23] atopy and allergic diseases, [17] among others. In the majority of cases, increased permeability develops prior to disease, [4] but the cause–effect relationship between increased intestinal permeability in most of these diseases is not clear. [19] [24]

A well studied model is celiac disease, in which increased intestinal permeability appears secondary to the abnormal immune reaction induced by gluten and allows fragments of gliadin protein to get past the intestinal epithelium, triggering an immune response at the intestinal submucosa level that leads to diverse gastrointestinal or extra-gastrointestinal symptoms. [25] [26] Other environmental triggers may contribute to alter permeability in celiac disease, including intestinal infections and iron deficiency. [25] Once established, this increase of permeability might self-sustain the inflammatory immune responses and perpetuate a vicious cycle. [25] Eliminating gluten from the diet leads to normalization of intestinal permeability and the autoimmune process shuts off. [27]

Research directions

In normal physiology, glutamine plays a key role in signalling in enterocytes that are part of the intestinal barrier, but it is not clear if supplementing the diet with glutamine is helpful in conditions where there is increased intestinal permeability. [28]

Prebiotics and certain probiotics such as E. coli strain Nissle 1917 have been found to reduce increased intestinal permeability. [12] Lactobacillus rhamnosus , [29] Lactobacillus reuteri , [29] and Faecalibacterium prausnitzii [30] have also been shown to significantly reduce increased intestinal permeability.

Larazotide acetate (previously known as AT-1001) is a zonulin receptor antagonist that has been probed in clinical trials. It seems to be a drug candidate for use in conjunction with a gluten-free diet in people with celiac disease, with the aim to reduce the intestinal permeability caused by gluten and its passage through the epithelium, and therefore mitigating the resulting cascade of immune reactions. [26] [31]

Decreasing intestinal barrier function with aging can cause increased translocation of microbial products, such as lipopolysaccharide, into the systemic blood circulation that subsequently causes systemic inflammation (inflammaging) and significant clinical outcomes: metabolic syndrome, decreased physical function, and mortality. [32] [33] It has been shown that the loss of intestinal barrier function is associated with an increased formation of nitric oxide (NO) and lower activity of arginase. [34] [35] Genetic disruption of arginase-2 in mouse attenuates the onset of senescence and extends lifespan. [36] [35] Arginase inhibitors have been developed to reduce the effect of NO on intestinal permeability. [35]

Leaky gut syndrome

"Leaky gut syndrome" is a hypothetical, medically unrecognized condition. [19] It has been popularized by some nutritionists and practitioners of alternative medicine who claim that restoring normal functioning of the gut wall can cure many systemic health conditions. However, reliable source evidence to support this claim has not been published. Nor has there been published any reliable evidence that the treatments promoted for so-called "leaky gut syndrome"—including nutritional supplements, probiotics, [12] herbal remedies, (or low-FODMAP diets; low-sugar, antifungal, or gluten-free diets)—have any beneficial effect for most of the conditions they are claimed to help. [19]

Exercise-induced stress

Exercise-induced stress can diminish intestinal barrier function. [37] [38] [39] In humans, the level of physical activity modulates the gastrointestinal microbiota, an increased intensity and volume of exercise may lead to gut dysbiosis, and supplementation may keep gut microbiota in biodiversity, especially with intense exercise. [40] In mice, exercise reduced the richness of the microbial community, but increased the distribution of bacterial communities. [41]

See also

Related Research Articles

<span class="mw-page-title-main">Gluten</span> Group of cereal grain proteins

Gluten is a structural protein naturally found in certain cereal grains. The term gluten usually refers to the combination of prolamin and glutelin proteins that naturally occur in many cereal grains, and which can trigger celiac disease in some people. The types of grains that contain gluten include all species of wheat, and barley, rye, and some cultivars of oat; moreover, cross hybrids of any of these cereal grains also contain gluten, e.g. triticale. Gluten makes up 75–85% of the total protein in bread wheat.

<span class="mw-page-title-main">Coeliac disease</span> Autoimmune disorder that results in a reaction to gluten

Coeliac disease or celiac disease is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barley. Classic symptoms include gastrointestinal problems such as chronic diarrhoea, abdominal distention, malabsorption, loss of appetite, and among children failure to grow normally. Non-classic symptoms are more common, especially in people older than two years. There may be mild or absent gastrointestinal symptoms, a wide number of symptoms involving any part of the body, or no obvious symptoms. Coeliac disease was first described in childhood; however, it may develop at any age. It is associated with other autoimmune diseases, such as Type 1 diabetes mellitus and Hashimoto's thyroiditis, among others.

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the gastrointestinal tract and involve visceral hypersensitivity and motility disturbances.

<span class="mw-page-title-main">Gliadin</span> Protein in wheat & other cereals

Gliadin is a class of proteins present in wheat and several other cereals within the grass genus Triticum. Gliadins, which are a component of gluten, are essential for giving bread the ability to rise properly during baking. Gliadins and glutenins are the two main components of the gluten fraction of the wheat seed. This gluten is found in products such as wheat flour. Gluten is split about evenly between the gliadins and glutenins, although there are variations found in different sources.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">Gut microbiota</span> Community of microorganisms in the gut

Gut microbiota, gut microbiome, or gut flora are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.

<span class="mw-page-title-main">Paneth cell</span> Anti-microbial epithelial cell of the small intestine

Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands and the large eosinophilic refractile granules that occupy most of their cytoplasm.

<span class="mw-page-title-main">Intraepithelial lymphocyte</span>

Intraepithelial lymphocytes (IEL) are lymphocytes found in the epithelial layer of mammalian mucosal linings, such as the gastrointestinal (GI) tract and reproductive tract. However, unlike other T cells, IELs do not need priming. Upon encountering antigens, they immediately release cytokines and cause killing of infected target cells. In the GI tract, they are components of gut-associated lymphoid tissue (GALT).

Zonulin is a protein that increases the permeability of tight junctions between cells of the wall of the digestive tract. It was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of Medicine. As the mammalian analogue of zonula occludens toxin, secreted by cholera pathogen Vibrio cholerae, zonulin has been implicated in the pathogenesis of coeliac disease and diabetes mellitus type 1. Type 2 diabetic patients have shown increased zonulin.

<span class="mw-page-title-main">Gluten-related disorders</span> Set of diseases caused by gluten exposure

Gluten-related disorders is the term for the diseases triggered by gluten, including celiac disease (CD), non-celiac gluten sensitivity (NCGS), gluten ataxia, dermatitis herpetiformis (DH) and wheat allergy. The umbrella category has also been referred to as gluten intolerance, though a multi-disciplinary physician-led study, based in part on the 2011 International Coeliac Disease Symposium, concluded that the use of this term should be avoided due to a lack of specificity.

Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase protein. Detection is considered abnormal, and may indicate one of several conditions.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.

The immunochemistry of Triticeae glutens is important in several inflammatory diseases. It can be subdivided into innate responses, class II mediated presentation, class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In gluten sensitive enteropathy, there are four types of recognition, innate immunity, HLA-DQ, and antibody recognition of gliadin and transglutaminase. With idiopathic gluten sensitivity only antibody recognition to gliadin has been resolved. In wheat allergy, the response pathways are mediated through IgE against other wheat proteins and other forms of gliadin.

<span class="mw-page-title-main">Microbial symbiosis and immunity</span>

Long-term close-knit interactions between symbiotic microbes and their host can alter host immune system responses to other microorganisms, including pathogens, and are required to maintain proper homeostasis. The immune system is a host defense system consisting of anatomical physical barriers as well as physiological and cellular responses, which protect the host against harmful microorganisms while limiting host responses to harmless symbionts. Humans are home to 1013 to 1014 bacteria, roughly equivalent to the number of human cells, and while these bacteria can be pathogenic to their host most of them are mutually beneficial to both the host and bacteria.

FODMAPs or fermentable oligosaccharides, disaccharides, monosaccharides, and polyols are short-chain carbohydrates that are poorly absorbed in the small intestine and ferment in the colon. They include short-chain oligosaccharide polymers of fructose (fructans) and galactooligosaccharides, disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols), such as sorbitol, mannitol, xylitol, and maltitol. Most FODMAPs are naturally present in food and the human diet, but the polyols may be added artificially in commercially prepared foods and beverages.

Non-celiac gluten sensitivity (NCGS) or gluten sensitivity is a controversial disorder which can cause both gastrointestinal and other problems.

<span class="mw-page-title-main">Alessio Fasano</span> Medical doctor and researcher on celiac disease

Alessio Fasano is an Italian-born medical doctor, pediatric gastroenterologist and researcher. He currently holds many roles, including professor of pediatrics at Harvard Medical School and professor of nutrition at Harvard T.H. Chan School of Public Health, both in Boston. He serves as director of the Center for Celiac Research and Treatment at MassGeneral Hospital for Children (MGHfC) and co-director of the Harvard Medical School Celiac Research Program. In addition, he is director of the Mucosal Immunology and Biology Research Center at MGHfC, where he oversees a research program with approximately 50 scientists and staff researching a variety of acute and chronic inflammatory diseases, including cystic fibrosis, celiac disease, enteric infections and necrotizing enterocolitis. A common theme of these programs is the study of the emerging role of the gut microbiome in health and disease. Fasano is also the scientific director of the European Biomedical Research Institute of Salerno (EBRIS) in Italy. Along with these leadership positions, he is a practicing outpatient clinician in pediatric gastroenterology and nutrition and the division chief.

Larazotide is a synthetic eight amino acid peptide that functions as a tight junction regulator and reverses leaky junctions to their normally closed state. It is being studied in people with celiac disease.

<span class="mw-page-title-main">Intestinal mucosal barrier</span>

The intestinal mucosal barrier, also referred to as intestinal barrier, refers to the property of the intestinal mucosa that ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and circulatory system from exposure to pro-inflammatory molecules, such as microorganisms, toxins, and antigens is vital for the maintenance of health and well-being. Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: food allergies, microbial infections, irritable bowel syndrome, inflammatory bowel disease, celiac disease, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, and septic shock.

References

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  41. ↑ Yan, Qiuyu; Zhai, Wenhui; Yang, Chenghao; Li, Zihao; Mao, Longfei; Zhao, Mingyi; Wu, Xiushan (12 October 2021). "The Relationship among Physical Activity, Intestinal Flora, and Cardiovascular Disease". Cardiovascular Therapeutics. 2021: 1–10. doi: 10.1155/2021/3364418 . PMC   8526197 . PMID   34729078. Open Access logo PLoS transparent.svg
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