Leaky gut

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Leaky gut is a name used to describe intestinal or bowel hyperpermeability. Tight junctions (TJs) represent the major barrier within the pathway between intestinal epithelial cells that line the digestion tract. Disruption of TJs leads to intestinal hyperpermeability (the so-called "leaky gut") which has been proposed by some researchers to involve a relationship with acute and chronic diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, type 1 diabetes, allergies, asthma, and autism.[1]

Leaky gut syndrome, or increased intestinal permeability,[2] is a proposed condition of an altered or damaged bowel lining. It is hypothesized to be caused by increased permeability of the gut wall resulting from toxins, poor diet, parasites, infection, or medications.[3] The leaky gut then allows substances such as toxins, microbes, undigested food, waste, or larger than normal macromolecules to leak through an abnormally permeable gut wall. Proponents suggest that these out-of-place substances affect the body directly or initiate an immune reaction.[4]

While physicians, medical researchers, holistic practitioners, and others generally agree that increased permeability of the intestinal lining is a real phenomenon, there is disagreement over whether this "leakiness", in and of itself, is capable of causing or worsening the diseases in question.[5]

Contents

Hypotheses [edit]

A trio of factors including an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness are hypothesised to play a role in the failure to form tolerance, resulting in the autoimmunity that underlies type 1 diabetes. [6]

A lack of mucosal integrity (leaky gut) with consecutive local and systemic inflammation and dysfunction of transport proteins may worsen the clinical symptoms of chronic heart failure. A 'leaky' bowel wall may lead to translocation of bacteria and/or endotoxin, which may be an important stimulus for inflammatory cytokine activation. Although it remains unclear whether increased adherent bacteria in patients with chronic heart failure are a primary or secondary event and whether they contribute to systemic inflammation. Further studies are needed to address the pathophysiology of the intestinal barrier whose reactivity seems to be crucial for heart function.[7][8]

Primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are enigmatic chronic inflammatory diseases of the liver, which can be associated with chronic inflammatory bowel diseases. Cross-recognition between microbial antigens in the gut and host components by the immune system along with stimulation of pattern recognition receptors might give rise to chronic hepatic inflammatory disorders with features of autoimmunity.[9]

Health care practitioners who diagnose "leaky gut syndrome" explain that intestinal inflammation which may originate from intestinal dysbiosis or other sources of irritation, widens the junctions between the cells of the intestinal lining, allowing endotoxins and incompletely digested particles to be partially absorbed. These are targeted by antibodies, forming immune complexes which cause a semi-infectious state and can be carried by the bloodstream to distant sites where they may stimulate the release of cytokines. Low grade fever, transient gut pain, and a sense of inability to absorb nutrients are some reported symptoms in otherwise undiagnosed patients.[10][11]

Pathophysiology [edit]

Defects in the intestinal epithelial barrier function have been observed in a number of bowel disorders such as inflammatory bowel disease (IBD). It is now becoming evident that an aberrant epithelial barrier function plays a central role in the pathophysiology of IBD, gastrointestinal diseases, cardiovascular disease, acute and chronic pediatric and other recognised diseases. [12][13][1][8] Intestinal permeability is also increased in skin conditions such as psoriasis and atopic eczema.[14][15] Researchers have recently investigated increased intestinal permeability in the context of Chronic Urticaria, with an emphasis on possible treatment through an oglioantegenic diet (similar to a restricted Paleo Diet).[16][17]

Laboratory tests [edit]

There are several research and clinical diagnostic tests that actually measure permeability of the gut wall. Practitioners who most often diagnose "leaky gut syndrome" usually do not use these and instead rely on symptoms.[citation needed] Probes of intermediate (MW 150-400) molecular size (Cr EDTA, PEG 400, lactulose, mannitol, rhamnose), have been used to measure intestinal permeability by looking at urinary recovery.[18] Changes in gut permeability have been associated with bowel disorders. Another test used by researchers quantitatively assesses the translocation of lipopolysaccharide (LPS) molecules across the gut wall.[19] LPS is a component of the gram-negative bacterial cell wall. Elevated LPS levels have been found in HIV, graft-versus-host disease, inflammatory bowel disease and people who have had gastrointestinal surgery.[20]

Mechanisms [edit]

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more recent analysis of the functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. [13]

The tight junction does not form a completely impermeant seal, because that would prevent paracellular absorption of essential nutrients and ions; intestinal tight junctions are "leaky" and allow solutes to be transported according to size and charge. Abundant data are available to demonstrate that barrier properties of tight junctions can be modulated in response to physiological, pharmacological, and pathophysiological stimuli. [21] Select enteric viruses, bacterial pathogens and parasites modulate intestinal tight junction structure and function and these effects may contribute to the development of chronic intestinal disorders.[22] Enteric pathogens have devised several ways to disrupt tight junctions function of epithelial cells. Generally, this is achieved by either altering the cellular cytoskeleton or by affecting specific tight junction proteins.[23] The actin cytoskeleton is the primary target of immune mediated epithelial barrier dysfunction, pathological disruption occurs in response to infectious and inflammatory stimuli, which include the barrier dysfunction induced by E. coli, Giardia, and TNF. [21]

Alcohol consumption induces a state of "leaky gut" increasing plasma and liver endotoxin levels, leading (in excess) to liver diseases. Via Kupffer cells which when become activated, interact with a complex of proteins located on the extracellular membrane signaling to produce a wide array of soluble factors, including cytokines, chemokines, growth factors, cyclooxygenase and lipoxygenase metabolites, and reactive oxygen species such as superoxide anion, hydrogen peroxide, and nitric oxide. [24]

Treatment [edit]

Researchers propose intake of natural anti-inflammatory and anti-oxidative substances, such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet, prebiotics and the use of probiotics.[13][25][26] Berberine is a constituent of several herbs which have been traditionally used to treat gastrointestinal disorders. According to a 2010 study, berberine ameliorated damage to the tight junctions of intestinal epithelial cells induced by pro-inflammatory cytokines (in vitro). Berberine may thus serve as a targeted therapeutic agent for restoring barrier function in intestinal disease states.[27]

Leaky gut syndrome theories inspired several dietary treatments, including gluten-free diets, casein-free diets, antifungal diets, low-sugar diets, as well as supplements that include nystatin, B12, and probiotics.

Leaky gut syndrome [edit]

While many practitioners maintain that "leaky gut syndrome" is a bona fide pathological condition, the area of "gut problems" lies between conventional and alternative medicine, and can include other diagnoses such as small bowel bacterial overgrowth syndrome or small intestine bacterial overgrowth (SIBO), and yeast syndrome or systemic candidiasis. As of 2005 the syndrome was often considered controversial and scientifically unsettled.[28]

Some alternative practitioners believe that "leaky gut syndrome" is a possible starting point or connection with many disorders such as asthma, diabetes, autoimmune diseases like lupus, diseases like scleroderma, internal colitis, long term disorders like rheumatoid arthritis, severe illnesses like multiple sclerosis and chronic fatigue syndrome and Crohn's disease.[29]

Research [edit]

Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of research that encompasses many fields and is currently receiving attention.[13][21]

See also [edit]

References [edit]

  1. ^ a b Liu Z, Li N, Neu J (April 2005). "Tight junctions, leaky intestines, and pediatric diseases". Acta Paediatr. 94 (4): 386–93. doi:10.1111/j.1651-2227.2005.tb01904.x. PMID 16092447. 
  2. ^ Meadows, Susannah (2013-02-01). "The Boy With a Thorn in His Joints". New York Times. Retrieved 2013-02-01. 
  3. ^ Liu Z, Li N, Neu J (April 2005). "Tight junctions, leaky intestines, and pediatric diseases". Acta Paediatr. 94 (4): 386–93. doi:10.1111/j.1651-2227.2005.tb01904.x. PMID 16092447. 
  4. ^ Kiefer D, Ali-Akbarian L (2004). "A brief evidence-based review of two gastrointestinal illnesses: irritable bowel and leaky gut syndromes". Altern Ther Health Med 10 (3): 22–30; quiz 31, 92. PMID 15154150. 
  5. ^ Knight, A (July 8, 2004): Doctors split over leaky gut syndrome. Sidney Morning Health archive. Retrieved April 24, 2013
  6. ^ Vaarala O, Atkinson MA, Neu J (October 2008). "The "perfect storm" for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity". Diabetes 57 (10): 2555–62. doi:10.2337/db08-0331. PMC 2551660. PMID 18820210. 
  7. ^ Sandek A, Rauchhaus M, Anker SD, von Haehling S (September 2008). "The emerging role of the gut in chronic heart failure". Curr Opin Clin Nutr Metab Care 11 (5): 632–9. doi:10.1097/MCO.0b013e32830a4c6e. PMID 18685461. 
  8. ^ a b Krack A, Sharma R, Figulla HR, Anker SD (November 2005). "The importance of the gastrointestinal system in the pathogenesis of heart failure". Eur. Heart J. 26 (22): 2368–74. doi:10.1093/eurheartj/ehi389. PMID 15980032. 
  9. ^ Terjung B, Spengler U (February 2009). "Atypical p-ANCA in PSC and AIH: a hint toward a "leaky gut"?". Clin Rev Allergy Immunol 36 (1): 40–51. doi:10.1007/s12016-008-8088-8. PMID 18626795. 
  10. ^ Leaky Gut Syndromes: Breaking the Vicious Cycles. Galland L. Townsend Letter for Doctors, August/September 1995, p. 63.
  11. ^ http://www.mdheal.org/leakygut.htm Galland 1995 fulltext article
  12. ^ Laukoetter MG, Nava P, Nusrat A (January 2008). "Role of the intestinal barrier in inflammatory bowel disease". World J. Gastroenterol. 14 (3): 401–7. doi:10.3748/wjg.14.401. PMC 2679128. PMID 18200662. 
  13. ^ a b c d Fasano A, Shea-Donohue T (September 2005). "Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases". Nat Clin Pract Gastroenterol Hepatol 2 (9): 416–22. doi:10.1038/ncpgasthep0259. PMID 16265432. 
  14. ^ Humbert, P.; Bidet, A.; Treffel, P.; Drobacheff, C.; Agache, P. (1991). "Intestinal permeability in patients with psoriasis". Journal of dermatological science 2 (4): 324–326. PMID 1911568.  edit
  15. ^ Pike, M. G.; Heddle, R. J.; Boulton, P.; Turner, M. W.; Atherton, D. J. (1986). "Increased Intestinal Permeability in Atopic Eczema". Journal of Investigative Dermatology 86 (2): 101–104. doi:10.1111/1523-1747.ep12284035. PMID 3745938. 
  16. ^ http://www.ncbi.nlm.nih.gov/pubmed/15355472
  17. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856071/
  18. ^ Assessment of the lactulose - mannitol test in Crohn's disease. F ANDRE et al., Gut, 1988, 29, 511-515
  19. ^ Evidence for Translocation of Microbial Products in Patients with Idiopathic CD4+ Lymphocytopenia. Lee et al. J Infect Dis 2009 June 1; 199(11): 1664–1670
  20. ^ Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. Caradonna et al. J Endotoxin Res 2000;6:205–14
  21. ^ a b c Shen L, Turner JR (April 2006). "Role of epithelial cells in initiation and propagation of intestinal inflammation. Eliminating the static: tight junction dynamics exposed". Am. J. Physiol. Gastrointest. Liver Physiol. 290 (4): G577–82. doi:10.1152/ajpgi.00439.2005. PMID 16537969. 
  22. ^ O'Hara JR, Buret AG (2008). "Mechanisms of intestinal tight junctional disruption during infection". Front. Biosci. 13: 7008–21. PMID 18508712. 
  23. ^ Berkes J, Viswanathan VK, Savkovic SD, Hecht G (March 2003). "Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation". Gut 52 (3): 439–51. doi:10.1136/gut.52.3.439. PMC 1773546. PMID 12584232. 
  24. ^ Cubero FJ, Nieto N (June 2006). "Kupffer cells and alcoholic liver disease". Rev Esp Enferm Dig 98 (6): 460–72. PMID 16948545. 
  25. ^ Maes M, Leunis JC (December 2008). "Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria". Neuro Endocrinol. Lett. 29 (6): 902–10. PMID 19112401. 
  26. ^ Sturniolo GC, Di Leo V, Ferronato A, D'Odorico A, D'Incà R (May 2001). "Zinc supplementation tightens "leaky gut" in Crohn's disease". Inflamm. Bowel Dis. 7 (2): 94–8. doi:10.1097/00054725-200105000-00003. PMID 11383597. 
  27. ^ Li N, Gu L, Qu L, et al. (February 2010). "Berberine attenuates pro-inflammatory cytokine-induced tight junction disruption in an in vitro model of intestinal epithelial cells". Eur J Pharm Sci 40 (1): 1–8. doi:10.1016/j.ejps.2010.02.001. PMID 20149867. 
  28. ^ Pizzorno, JE, Murray, MT, (November 2005) Textbook of Natural Medicine, 3rd edition, Churchill Livingstone, pp 167, 584, 1527 ISBN 0-443-07300-7
  29. ^ Leaking Gut Syndrome

External links [edit]

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