Leaky gut
Encyclopedia
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
.
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.
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.
(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.
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. 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. 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. 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.
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.
, N-acetyl cysteine and zinc
, in conjunction with a leaky gut diet, prebiotics and the use of probiotics. Berberine
is a traditional herbal medicine, which has been used for patients with gastrointestinal disorders for a long time. According to a new report, berberine can ameliorate pro-inflammatory cytokines induced intestinal epithelia tight junction damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.
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.
Systemic inflammatory response syndrome
Systemic inflammatory response syndrome is an inflammatory state affecting the whole body, frequently a response of the immune system to infection, but not necessarily so...
(SIRS), inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
, type 1 diabetes
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
, allergies, asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, and autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
.
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.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.
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.
Pathophysiology
Defects in the intestinal epithelial barrier function have been observed in a number of bowel disorders such as inflammatory bowel diseaseInflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
(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.
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.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. 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. 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. 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.
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.
Treatment
Researchers propose intake of natural anti-inflammatory and anti-oxidative substances (NAIDS's), such as glutamineGlutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
, N-acetyl cysteine and zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
, in conjunction with a leaky gut diet, prebiotics and the use of probiotics. Berberine
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...
is a traditional herbal medicine, which has been used for patients with gastrointestinal disorders for a long time. According to a new report, berberine can ameliorate pro-inflammatory cytokines induced intestinal epithelia tight junction damage in vitro, and berberine may be one of the targeted therapeutic agents that can restore barrier function in intestinal disease states.
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.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.