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]

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[edit] Hypotheses

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. [2]

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.[3][4]

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.[5]

It is hypothesised that the inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). [6] An increased translocation of LPS from gram-negative bacteria are causally related to depression following external (psychological) and internal (organic) stressors. [7]

In CFS and somatization 'functional' symptoms, may have a genuine organic cause, that is activation of peripheral and central IO&NS pathways and gut-derived inflammation. Inflammatory pathways are detected in both disorders. These IO&NS pathways may be induced by a number of trigger factors, for example psychological stress, strenuous exercise, viral infections and an increased translocation of LPS from gram-negative bacteria (leaky gut).[8][9]

[edit] Pathophysiology

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. [10][11][1][4]

[edit] Mechanisms

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. [11]

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. [12] 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.[13] 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.[14] 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. [12]

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. [15]

[edit] Treatment

Researchers propose intake of natural anti-inflammatory and anti-oxidative substances (NAIDS's), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet, and the use of probiotics. [11][9][16]

[edit] Research

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 a great deal of attention. [11]

The tight junction is a far more dynamic and complex structure than previously recognized. Although significant progress has been made, greater understanding of tight junction maintenance and regulation in health and disease is needed. Ultimately, such knowledge will provide means to selectively and specifically regulate the tight junction that may allow development of targeted therapies for diverse diseases. [12]

[edit] References

  1. ^ a b Liu Z, Li N, Neu J (April 2005). "Tight junctions, leaky intestines, and pediatric diseases". Acta Paediatr. 94 (4): 386–93. PMID 16092447. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0803-5253&date=2005&volume=94&issue=4&spage=386. 
  2. ^ 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. PMID 18820210. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ Maes M, Yirmyia R, Noraberg J, et al (March 2009). "The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression". Metab Brain Dis 24 (1): 27–53. doi:10.1007/s11011-008-9118-1. PMID 19085093. 
  7. ^ Maes M (June 2008). "The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression". Neuro Endocrinol. Lett. 29 (3): 287–91. PMID 18580840. 
  8. ^ Maes M (January 2009). "Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms". Curr Opin Psychiatry 22 (1): 75–83. PMID 19127706. 
  9. ^ a b 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. 
  10. ^ Laukoetter MG, Nava P, Nusrat A (January 2008). "Role of the intestinal barrier in inflammatory bowel disease". World J. Gastroenterol. 14 (3): 401–7. PMID 18200662. http://www.wjgnet.com/1007-9327/14/401.asp. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ O'Hara JR, Buret AG (2008). "Mechanisms of intestinal tight junctional disruption during infection". Front. Biosci. 13: 7008–21. PMID 18508712. http://www.bioscience.org/2008/v13/af/3206/fulltext.htm. 
  14. ^ 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. PMID 12584232. PMC 1773546. http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=12584232. 
  15. ^ Cubero FJ, Nieto N (June 2006). "Kupffer cells and alcoholic liver disease". Rev Esp Enferm Dig 98 (6): 460–72. PMID 16948545. http://www.grupoaran.com/mrmUpdate/lecturaPDFfromXML.asp?IdArt=458120&TO=RVN&Eng=0. 
  16. ^ 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. PMID 11383597. 


[edit] See also

Leaky gut syndrome

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