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]

Genetic disruption of arginase-2 in mouse attenuates the onset of senescence and extends lifespan. [32] [33] Arginase inhibitors have been developed to reduce the effect of NO on intestinal permeability. [33]

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. [34] [35] [36] 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. [37] In mice, exercise reduced the richness of the microbial community, but increased the distribution of bacterial communities. [38]

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 elastic network of a wheat grain's proteins, gliadin and glutenin primarily, that forms readily with the addition of water and often kneading in the case of bread dough. 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 functional gastrointestinal disorder 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.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Gluten-free diet</span> Diet excluding proteins found in wheat, barley, and rye

A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of prolamin proteins found in wheat, as well as barley, rye, and oats. The inclusion of oats in a gluten-free diet remains controversial, and may depend on the oat cultivar and the frequent cross-contamination with other gluten-containing cereals.

Gluten exorphins are a group of opioid peptides formed during the digestion of the gluten protein. These peptides work as external regulators for gastrointestinal movement and hormonal release. The breakdown of gliadin, a polymer of wheat proteins, creates amino acids that stop the gluten epitopes from entering the immune system to activate inflammatory reactions. During this process, gluten does not fully break down, thus increasing the presence of gluten exorphins. Because of this, researchers think this is what might lead to various diseases.

<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">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 has been studied in people with coeliac 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

  1. ↑ M. Campieri; C. Fiocchi; S.B. Hanauer (31 March 2002). Inflammatory Bowel Disease: A Clinical Case Approach to Pathophysiology, Diagnosis, and Treatment. Springer. p. 7. ISBN   978-0-7923-8772-5.
  2. ↑ Thoma YM, Anderson JM, Turner JR (2012). "Tight Junctions and the Intestinal Barrier". In Johnson LR, et al. (eds.). Physiology of the Gastrointestinal Tract. Vol. 1. Academic Press. pp. 1043–. ISBN   978-0-12-382027-3.
  3. ↑ Fasano, A. (February 2012). "Leaky Gut and Autoimmune Diseases". Clinical Reviews in Allergy & Immunology (Review). 42 (1): 71–78. doi:10.1007/s12016-011-8291-x. PMID   22109896. S2CID   4088994.
  4. 1 2 3 4 5 6 7 8 Fasano A (Jan 2011). "Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer". Physiological Reviews (Review). 91 (1): 151–75. CiteSeerX   10.1.1.653.3967 . doi:10.1152/physrev.00003.2008. PMID   21248165.
  5. 1 2 3 Leonard MM, Sapone A, Catassi C, Fasano A (2017). "Celiac Disease and Nonceliac Gluten Sensitivity: A Review". JAMA (Review). 318 (7): 647–656. doi:10.1001/jama.2017.9730. PMID   28810029. S2CID   205094729. Previous studies have shown that gliadin can cause an immediate and transient increase in gut permeability. This permeating effect is secondary to the binding of specific undigestible gliadin fragments to the CXCR3 chemokine receptor with subsequent release of zonulin, a modulator of intercellular tight junctions. This process takes place in all individuals who ingest gluten. For the majority, these events do not lead to abnormal consequences. However, these same events can lead to an inflammatory process in genetically predisposed individuals when the immunologic surveillance system mistakenly recognizes gluten as a pathogen.
  6. 1 2 3 4 5 6 Groschwitz KR, Hogan SP (July 2009). "Intestinal barrier function: molecular regulation and disease pathogenesis". The Journal of Allergy and Clinical Immunology. 124 (1): 3–20, quiz 21–2. doi:10.1016/j.jaci.2009.05.038. PMC   4266989 . PMID   19560575.
  7. ↑ Rao JN, Wang JY (2010-01-01). "Intestinal Architecture and Development". Regulation of Gastrointestinal Mucosal Growth. San Rafael, California: Morgan & Claypool Life Sciences. Bookshelf ID NBK54098. Retrieved 15 March 2024– via National Library of Medicine.
  8. ↑ Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, et al. (July 2013). "Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice". Hepatology. 58 (1): 108–19. doi:10.1002/hep.26321. PMC   3695050 . PMID   23408358.
  9. ↑ Khan N, Asif AR (2015-01-01). "Transcriptional regulators of claudins in epithelial tight junctions". Mediators of Inflammation. 2015: 219843. doi: 10.1155/2015/219843 . PMC   4407569 . PMID   25948882.
  10. ↑ Kobayashi N, Takahashi D, Takano S, Kimura S, Hase K (2019). "The Roles of Peyer's Patches and Microfold Cells in the Gut Immune System: Relevance to Autoimmune Diseases". Frontiers in Immunology. 10: 2345. doi: 10.3389/fimmu.2019.02345 . PMC   6794464 . PMID   31649668. Art. No. 2345.
  11. ↑ Näslund E, Hellström PM (September 2007). "Appetite signaling: from gut peptides and enteric nerves to brain". Physiology & Behavior. 92 (1–2): 256–62. doi:10.1016/j.physbeh.2007.05.017. PMID   17582445. S2CID   230872.
  12. 1 2 3 4 Rapin JR, Wiernsperger N (2010). "Possible links between intestinal permeability and food processing: A potential therapeutic niche for glutamine". Clinics (Review). 65 (6): 635–43. doi:10.1590/S1807-59322010000600012. PMC   2898551 . PMID   20613941.
  13. ↑ O'Hara JR, Buret AG (May 2008). "Mechanisms of intestinal tight junctional disruption during infection". Frontiers in Bioscience. 13 (13): 7008–21. doi: 10.2741/3206 . PMID   18508712.
  14. ↑ Dahlgren D, Roos C, Lundqvist A, Tannergren C, Langguth P, Sjöblom M, et al. (December 2017). "Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA". Molecular Pharmaceutics. 14 (12): 4243–4251. doi:10.1021/acs.molpharmaceut.7b00353. PMID   28737406.
  15. ↑ Suzuki T (February 2013). "Regulation of intestinal epithelial permeability by tight junctions". Cellular and Molecular Life Sciences. 70 (4): 631–59. doi:10.1007/s00018-012-1070-x. PMC   11113843 . PMID   22782113. S2CID   16512214.
  16. 1 2 Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM (Nov 18, 2014). "Intestinal permeability--a new target for disease prevention and therapy". BMC Gastroenterology (Review). 14: 189. doi: 10.1186/s12876-014-0189-7 . PMC   4253991 . PMID   25407511.
  17. 1 2 Viggiano D, Ianiro G, Vanella G, Bibbò S, Bruno G, Simeone G, et al. (2015). "Gut barrier in health and disease: focus on childhood" (PDF). European Review for Medical and Pharmacological Sciences. 19 (6): 1077–85. PMID   25855935.
  18. ↑ Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S (Mar 2013). "The role of the microbiome in rheumatic diseases". Current Rheumatology Reports (Review). 15 (3): 314. doi:10.1007/s11926-012-0314-y. PMID   23378145. S2CID   25721240.
  19. 1 2 3 4 "Leaky gut syndrome". NHS Choices. 26 February 2015. Archived from the original on 2018-02-11. Retrieved 15 August 2016.
  20. ↑ Yarandi SS, Peterson DA, Treisman GJ, Moran TH, Pasricha PJ (2016). "Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases". Journal of Neurogastroenterology and Motility (Review). 22 (2): 201–12. doi:10.5056/jnm15146. PMC   4819858 . PMID   27032544. In patients with schizophrenia, there are increased intestinal permeability and change in intestinal function
  21. ↑ Severance EG, Yolken RH, Eaton WW (2016). "Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling". Schizophrenia Research (Review). 176 (1): 23–35. doi:10.1016/j.schres.2014.06.027. PMC   4294997 . PMID   25034760.
  22. ↑ Teixeira TF, Collado MC, Ferreira CL, Bressan J, Peluzio Mdo C (September 2012). "Potential mechanisms for the emerging link between obesity and increased intestinal permeability". Nutrition Research (Review). 32 (9): 637–47. doi:10.1016/j.nutres.2012.07.003. PMID   23084636.
  23. ↑ Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A (November 2014). "Gut microbiota and metabolic syndrome". World Journal of Gastroenterology (Review). 20 (43): 16079–16094. doi: 10.3748/wjg.v20.i43.16079 . PMC   4239493 . PMID   25473159.
  24. ↑ Kiefer D, Ali-Akbarian L (2004). "A brief evidence-based review of two gastrointestinal illnesses: irritable bowel and leaky gut syndromes". Alternative Therapies in Health and Medicine. 10 (3): 22–30, quiz 31, 92. PMID   15154150.
  25. 1 2 3 Heyman M, Abed J, Lebreton C, Cerf-Bensussan N (September 2012). "Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis". Gut (Review). 61 (9): 1355–64. doi:10.1136/gutjnl-2011-300327. PMID   21890812. S2CID   42581980. Changes in intestinal paracellular and transcellular permeability appear secondary to the abnormal immune reaction induced by gluten. Gliadin was suggested to increase junction permeability to small molecules through the release of prehaptoglobin-2. Environmental triggers of CD other than gliadin may also promote changes in permeability. Intestinal infection and iron deficiency can stimulate the expression of the transferrin receptor (TfR) CD71 in enterocytes. ... Once established, the alterations in intestinal permeability, notably the retro-transport of IgA-gliadin peptides, might self-sustain the inflammatory immune responses and perpetuate a vicious circle.
  26. 1 2 Khaleghi S, Ju JM, Lamba A, Murray JA (January 2016). "The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate". Therapeutic Advances in Gastroenterology (Review. Research Support, N.I.H., Extramural). 9 (1): 37–49. doi:10.1177/1756283X15616576. PMC   4699279 . PMID   26770266.
  27. ↑ Fasano A (October 2012). "Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications". Clinical Gastroenterology and Hepatology (Review). 10 (10): 1096–100. doi:10.1016/j.cgh.2012.08.012. PMC   3458511 . PMID   22902773.
  28. ↑ Akobeng AK, Elawad M, Gordon M (February 2016). "Glutamine for induction of remission in Crohn's disease" (PDF). The Cochrane Database of Systematic Reviews. 2016 (2): CD007348. doi:10.1002/14651858.CD007348.pub2. PMC   10405219 . PMID   26853855.
  29. 1 2 Lopetuso LR, Scaldaferri F, Bruno G, Petito V, Franceschi F, Gasbarrini A (2015). "The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors". European Review for Medical and Pharmacological Sciences. 19 (6): 1068–1076. PMID   25855934.
  30. ↑ Ganesan K, Chung SK, Vanamala J, Xu B (2018). "Causal Relationship between Diet-Induced Gut Microbiota Changes and Diabetes: A Novel Strategy to Transplant Faecalibacterium prausnitzii in Preventing Diabetes". International Journal of Molecular Sciences. 19 (12): E3720. doi: 10.3390/ijms19123720 . PMC   6320976 . PMID   30467295.
  31. ↑ Crespo Pérez L, et al. (Jan 2012). "Non-dietary therapeutic clinical trials in coeliac disease". European Journal of Internal Medicine (Review). 23 (1): 9–14. doi:10.1016/j.ejim.2011.08.030. PMID   22153524.
  32. ↑ Xiong Y, Yepuri G, Montani JP, Ming XF, Yang Z (2017). "Arginase-II Deficiency Extends Lifespan in Mice". Front Physiol. 8: 682. doi: 10.3389/fphys.2017.00682 . PMC   5596098 . PMID   28943853. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  33. 1 2 Brandt A, Baumann A, Hernández-Arriaga A, Jung F, Nier A, Staltner R, Rajcic D, Schmeer C, Witte OW, Wessner B, Franzke B, Wagner KH, Camarinha-Silva A, Bergheim I (December 2022). "Impairments of intestinal arginine and NO metabolisms trigger aging-associated intestinal barrier dysfunction and 'inflammaging'". Redox Biol. 58: 102528. doi:10.1016/j.redox.2022.102528. PMC   9649383 . PMID   36356464.
  34. ↑ Clark, Allison; Mach, Núria (5 January 2016). "Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes". Journal of the International Society of Sports Nutrition. 13 (1): 346–349. doi: 10.1186/s12970-016-0155-6 . PMC   5121944 . PMID   5121944. Open Access logo PLoS transparent.svg
  35. ↑ Keirns, Bryant H.; Koemel, Nicholas A.; Sciarrillo, Christina M.; Anderson, Kendall L.; Emerson, Sam R. (1 October 2020). "Exercise and intestinal permeability: another form of exercise-induced hormesis?". American Journal of Physiology. Gastrointestinal and Liver Physiology. 319 (4): G512–G518. doi:10.1152/ajpgi.00232.2020. PMID   32845171. S2CID   221328089.
  36. ↑ Van Wijck, Kim; Lenaerts, Kaatje; Van Bijnen, Annemarie A.; Boonen, Bas; Van Loon, Luc J. C.; Dejong, Cornelis H. C.; Buurman, Wim A. (December 2012). "Aggravation of Exercise-Induced Intestinal Injury by Ibuprofen in Athletes". Medicine & Science in Sports & Exercise. 44 (12): 2257–2262. doi: 10.1249/mss.0b013e318265dd3d . PMID   22776871. S2CID   9982820.
  37. ↑ Dziewiecka, Hanna; Buttar, Harpal S.; Kasperska, Anna; Ostapiuk–Karolczuk, Joanna; Domagalska, Małgorzata; Cichoń, Justyna; Skarpańska-Stejnborn, Anna (7 July 2022). "Physical activity induced alterations of gut microbiota in humans: a systematic review". BMC Sports Science, Medicine and Rehabilitation. 14 (1): 122. doi: 10.1186/s13102-022-00513-2 . PMC   9264679 . PMID   35799284. Open Access logo PLoS transparent.svg
  38. ↑ 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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