View source for Biology:Intestinal mucosal barrier

[[File:Bischoff fig 2 adapted 01.png|thumb|500px|Physical, biochemical, and immune elements of the intestinal mucosal barrier.]]
The '''intestinal mucosal barrier''', also referred to as '''intestinal barrier''', refers to the property of the intestinal mucosa that ensures adequate containment of undesirable [[Biology:Lumen (anatomy)|luminal]] contents within the intestine while preserving the ability to absorb [[Earth:Nutrient|nutrient]]s. 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 [[Biology:Circulatory system|circulatory system]] from exposure to [[Medicine:Inflammation|pro-inflammatory molecules]], such as [[Biology:Microorganism|microorganism]]s, [[Biology:Toxin|toxin]]s, and [[Biology:Antigen|antigen]]s is vital for the maintenance of health and well-being.<ref name="Turner1">{{Cite journal|last=Turner|first=JR|date=November 2009|title=Intestinal mucosal barrier function in health and disease.|journal=Nat Rev Immunol|doi=10.1038/nri2653|pmid=19855405|volume=9|issue=11|pages=799–809|s2cid=205490916 }}</ref><ref name="Lee1">{{Cite journal|last=Lee|first=Sung Hee|date=2015-01-01|title=Intestinal Permeability Regulation by Tight Junction: Implication on Inflammatory Bowel Diseases|journal=Intestinal Research|volume=13|issue=1|pages=11–18|doi=10.5217/ir.2015.13.1.11|issn=1598-9100|pmc=4316216|pmid=25691839}}</ref><ref name="Sánchez1">{{Cite journal|last1=Sánchez de Medina|first1=Fermín|last2=Romero-Calvo|first2=Isabel|last3=Mascaraque|first3=Cristina|last4=Martínez-Augustin|first4=Olga|date=2014-12-01|title=Intestinal inflammation and mucosal barrier function|journal=Inflammatory Bowel Diseases|volume=20|issue=12|pages=2394–2404|doi=10.1097/MIB.0000000000000204|issn=1536-4844|pmid=25222662|s2cid=11434730 |doi-access=free}}</ref> Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: [[Medicine:Food allergy|food allergies]], [[Medicine:Infection|microbial infections]], [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]], [[Medicine:Inflammatory bowel disease|inflammatory bowel disease]], [[Medicine:Coeliac disease|celiac disease]], [[Medicine:Metabolic syndrome|metabolic syndrome]], [[Medicine:Non-alcoholic fatty liver disease|non-alcoholic fatty liver disease]], [[Medicine:Diabetes mellitus|diabetes]], and [[Medicine:Septic shock|septic shock]].<ref name="Sánchez1" /><ref name="Groschwitz1" /><ref name="Yan1">{{Cite journal|last1=Yan|first1=Lei|last2=Yang|first2=Chunhui|last3=Tang|first3=Jianguo|date=2013-08-25|title=Disruption of the intestinal mucosal barrier in Candida albicans infections|journal=Microbiological Research|volume=168|issue=7|pages=389–395|doi=10.1016/j.micres.2013.02.008|issn=1618-0623|pmid=23545353|doi-access=free}}</ref>

== Composition ==
The intestinal mucosal barrier is a heterogeneous entity composed of physical, biochemical, and immune elements elaborated by the intestinal mucosa. The central component is the intestinal epithelial layer, which provides physical separation between the lumen and the body. The secretion of various molecules into the lumen reinforces the barrier function on the extra-epithelial side, while a variety of immune cells provide additional protection below the epithelial layer.<ref name="Sánchez1"/><ref name="Yan1" /><ref name="De Santis1">{{Cite journal|last1=De Santis|first1=Stefania|last2=Cavalcanti|first2=Elisabetta|last3=Mastronardi|first3=Mauro|last4=Jirillo|first4=Emilio|last5=Chieppa|first5=Marcello|date=2015-12-07|title=Nutritional Keys for Intestinal Barrier Modulation|journal=Frontiers in Immunology|volume=6|pages=612|doi=10.3389/fimmu.2015.00612|issn=1664-3224|pmc=4670985|pmid=26697008|doi-access=free }}</ref>

=== Physical elements ===

==== Mucus layer(s) ====
[[Biology:Mucus|Mucus]] forms a layer (or layers, in the case of the [[Biology:Large intestine|colon]]) that separates the bulk of the luminal contents from the intestinal epithelium. The mucus consists of a highly [[Biology:Glycosylation|glycosylated]] [[Chemistry:Hydrate|hydrated gel]] formed by mucin molecules that are secreted by [[Biology:Goblet cell|goblet cell]]s. The mucus prevents large particles from contacting the epithelial cell layer while allowing small molecules to pass. The mucus also facilitates passage of the luminal contents along the length of the intestines, protects the epithelial cells from [[Biology:Digestive enzyme|digestive enzyme]]s, and prevents the direct contact of microorganisms with the epithelial layer.<ref name="Turner1"/><ref name="Yan1" /><ref name="De Santis1"/><ref name="Márquez">{{Cite journal|title=Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity. | pmid=26819512 | doi=10.3748/wjg.v22.i4.1433 | volume=22 | issue=4 | pmc=4721978 | year=2016 | journal=World J. Gastroenterol. | pages=1433–48 | last1 = Márquez | first1 = M | last2 = Fernández Gutiérrez | first2 = Del Álamo C | last3 = Girón-González | first3 = JA | doi-access=free }}</ref>

==== The intestinal epithelium ====
The intestinal epithelium is the foremost component of the intestinal mucosal barrier. It consists of the layer of epithelial cells lining the intestine. Crucial for forming an effective barrier is the precise control of the [[Biology:Paracellular transport|paracellular pathway]] (a route for translocation of molecules between cells). Sealing of the space between adjacent cells is mediated by [[Biology:Cell junction|junctional complexes]] formed by protein connections elaborated by each individual cell.<ref name="Turner1"/> In addition to its protective function, the intestinal epithelium controls the selective uptake of beneficial ions, nutrients, and other substances from the lumen into the body.<ref name="Sánchez1"/>

==== Microbiota ====
The [[Biology:Commensalism|commensal microbial species]] that inhabit the gut are considered by some to be part of the intestinal mucosal barrier. The [[Biology:Gut microbiota|gut microbiota]] can influence barrier function both directly, by stimulating epithelial cell proliferation and secretion of [[Biology:Interleukin 8|IL-8]], and indirectly by producing [[Chemistry:Short-chain fatty acid|short-chain fatty acid]]s, which are an important energy source for colonic epithelial cells (colonocytes).<ref name="Sánchez1" />

=== Biochemical elements ===

==== Bile and gastric acid ====
The [[Biology:Bile|bile]] produced by the [[Biology:Liver|liver]] to aid in the digestion of [[Chemistry:Lipid|lipid]]s has bactericidal properties.<ref name="Márquez"/> The [[Biology:Gastric acid|gastric acid]] produced by the stomach can also kill microorganisms.<ref>{{Cite journal|last=Schubert|first=ML|date=November 2014|title=Gastric secretion|journal=Curr Opin Gastroenterol|doi=10.1097/MOG.0000000000000125|pmid=25211241|volume=30|issue=6|pages=578–82|s2cid=8267813 }}</ref> Both contribute to intestinal barrier function although they are not produced by the intestinal mucosa.

==== Defensins ====
Specialised secretory epithelial cells called [[Biology:Paneth cell|Paneth cell]]s secrete abundant quantities [[Biology:Alpha defensin|human α-defensins]] into the intestinal lumen of healthy individuals.<ref>{{Cite journal|last1=Jäger|first1=S|last2=Stange|first2=EF|last3=Wehkamp|first3=J|date=January 2013|title=Inflammatory bowel disease: an impaired barrier disease|journal=Langenbecks Arch Surg|doi=10.1007/s00423-012-1030-9|pmid=23160753|volume=398|issue=1|pages=1–12|s2cid=23568811}}</ref>

==== Lysozyme ====
[[Biology:Lysozyme|Lysozyme]] is another defensive molecule secreted by Paneth cells into the lumen.<ref name="Ouellett1">{{Cite journal|last=Ouellette|first=AJ|date=July 2011|title=Paneth Cell α-Defensins in Enteric Innate Immunity|journal=Cell Mol Life Sci|doi=10.1007/s00018-011-0714-6|pmc=4073591|pmid=21560070|volume=68|issue=13|pages=2215–29}}</ref>

==== Regenerating islet-derived protein 3 gamma (Reg3γ) ====

Reg3γ is an antibacterial [[Biology:Lectin|lectin]] secreted by Paneth cells that serves to prevent microorganisms from coming into contact with the epithelial layer.<ref name="Sánchez1" /><ref name="Ouellett1" />

=== Immunological elements ===

==== Antimicrobial peptides ====

[[Biology:Antimicrobial peptides|Antimicrobial peptides (AMPs)]], which are a diverse array of molecules that kill bacteria and fungi, are secreted by Paneth cells into the lumen.<ref name="De Santis1"/><ref name="Márquez"/>

==== Secretory immunoglobulin A (sIgA )====

[[Biology:Immunoglobulin A|Secretory immunoglobulin A (sIgA)]] is produced by [[Biology:Plasma cell|plasma cell]]s in the lamina propria and transported into the lumen by intestinal epithelial cells.<ref name="Márquez"/> SIgA blocks epithelial-specific [[Biology:Receptor (biochemistry)|receptors]] on pathogens, thereby preventing their attachment to epithelial cells.

==== Cellular immunity ====

A variety of immune cells reside in the [[Biology:Lamina propria|lamina propria]] which underlies the intestinal epithelium. These include [[Biology:Dendritic cell|dendritic cells (DCs)]], [[Biology:Macrophage|macrophage]]s, [[Biology:Intraepithelial lymphocyte|intraepithelial lymphocyte]]s (IEL), [[Biology:Regulatory T cell|T regulatory cells (T Regs)]], [[Biology:T helper cell|TCD4+ lymphocytes]], [[Biology:B cell|B lymphocytes]], and [[Biology:Plasma cell|plasma cell]]s.<ref name="De Santis1"/> This population provides immune protection that is characterised by the rapid detection and killing of microorganisms that penetrate the intestinal epithelium.<ref name="Márquez"/>

== Physiology ==

Intestinal barrier integrity is malleable and multiple mechanisms have been shown to be capable of modulating intestinal permeability (a measure of intestinal barrier function).<ref name="Groschwitz1">{{Cite journal|last1=Groschwitz|first1=Katherine R.|last2=Hogan|first2=Simon P.|date=2009-07-01|title=Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis|journal=The Journal of Allergy and Clinical Immunology|volume=124|issue=1|pages=3–22|doi=10.1016/j.jaci.2009.05.038|issn=0091-6749|pmc=4266989|pmid=19560575}}</ref> Modulating factors include [[Biology:Cytokine|cytokine]]s, [[Biology:White blood cell|immune cells]], and exogenous factors.<ref name="Groschwitz1"/>

=== Measurement ===
[[Biology:Intestinal permeability|Intestinal permeability]] is a measurement of intestinal mucosal barrier function and is defined as "the facility with which intestinal epithelium allows molecules to pass through by non-mediated [[Biology:Passive transport|passive diffusion]]."<ref>{{Cite journal|last1=Travis|first1=S.|last2=Menzies|first2=I.|s2cid=26314837|date=1992-05-01|title=Intestinal permeability: functional assessment and significance|journal=Clinical Science|volume=82|issue=5|pages=471–488|issn=0143-5221|pmid=1317756|doi=10.1042/cs0820471}}</ref> Permeability in this respect is mostly related to the measurable passage of ions and small inert molecules. Standard methods for measurement include tissue electrical resistance for in vitro testing and passage of ingested inert molecules of specific molecular weights into the urine for in vivo testing.<ref>{{Cite journal|last1=Ménard|first1=S.|last2=Cerf-Bensussan|first2=N.|last3=Heyman|first3=M.|date=2010-05-01|title=Multiple facets of intestinal permeability and epithelial handling of dietary antigens|journal=Mucosal Immunology|volume=3|issue=3|pages=247–259|doi=10.1038/mi.2010.5|issn=1935-3456|pmid=20404811|doi-access=free}}</ref><ref name=":0">{{Cite journal|last1=Bischoff|first1=Stephan C.|last2=Barbara|first2=Giovanni|last3=Buurman|first3=Wim|last4=Ockhuizen|first4=Theo|last5=Schulzke|first5=Jörg-Dieter|last6=Serino|first6=Matteo|last7=Tilg|first7=Herbert|last8=Watson|first8=Alastair|last9=Wells|first9=Jerry M.|date=2014-01-01|title=Intestinal permeability--a new target for disease prevention and therapy|journal=BMC Gastroenterology |volume=14|pages=189|doi=10.1186/s12876-014-0189-7|issn=1471-230X|pmc=4253991|pmid=25407511 |doi-access=free }}</ref> For example, in vivo testing using [[Chemistry:Lactulose|lactulose]] / [[Chemistry:Mannitol|mannitol]] consists of ingesting 5 g lactulose and 2 g mannitol followed by determination of urinary concentrations of lactulose and mannitol 5 hours after ingestion. The percentage lactulose excretion and the lactulose mannitol ratio in the urine are calculated and used as a measure of intestinal permeability.<ref>{{Cite journal|last1=Johnston|first1=S. D.|last2=Smye|first2=M.|last3=Watson|first3=R. G.|last4=McMillan|first4=S. A.|last5=Trimble|first5=E. R.|last6=Love|first6=A. H.|date=2000-07-01|title=Lactulose-mannitol intestinal permeability test: a useful screening test for adult coeliac disease|journal=Annals of Clinical Biochemistry|volume=37|pages=512–519|issn=0004-5632|pmid=10902869|issue=4|doi=10.1177/000456320003700413|s2cid=24741927 }}</ref>

=== Endogenous regulators ===

==== Cytokines ====
*[[Biology:Interferon gamma|Interferon-gamma (IFNγ)]]<ref name="Groschwitz1"/>
*[[Biology:Tumor necrosis factor alpha|Tumor necrosis factor alpha (TNFα)]]<ref name="Groschwitz1"/>
*Th2 helper cell effector cytokines [[Biology:Interleukin 4|interleukin 4 (IL4)]] and interleukin 13 (IL-13)<ref name="Groschwitz1"/>
*Anti-inflammatory cytokine interleukin 10 (IL-10)<ref name="Groschwitz1"/>
*[[Biology:Zonulin|Zonulin]]<ref name="Groschwitz1" />

==== Immune cells ====
*[[Biology:Intraepithelial lymphocyte|Gamma/delta-positive intestinal intraepithelial lymphocytes]] (iIELγδ+)<ref name="Groschwitz1"/>
*[[Biology:Mast cell|Mast cell]]s<ref name="Groschwitz1"/>
*[[Biology:Eosinophil|Eosinophil]]s<ref name="Groschwitz1"/>

=== Exogenous regulators ===
*[[Chemistry:Ethanol#Gastrointestinal disease|Alcohol]]<ref name="Groschwitz1"/> 
*Nonsteroidal anti-inflammatory drugs (NSAIDs)<ref name="Groschwitz1" /> can cause increased [[Biology:Gastric acid|gastric acid]] secretion, diminished [[Chemistry:Bicarbonate|bicarbonate]] secretion, diminished mucus secretion and diminished trophic effects on epithelial mucosa by inhibiting COX-1, COX-2 and prostaglandins.
*[[Chemistry:Tacrolimus|Tacrolimus]]<ref name="Groschwitz1" />

==== Pathogens ====
*[[Biology:Pathogenic Escherichia coli#Virulence properties|Enteropathogenic ''Escherichia coli'' (EPEC)]]<ref name="Groschwitz1" /> 
*''[[Biology:Vibrio cholerae|Vibrio cholerae]]''<ref name="Groschwitz1" /> 
*''[[Biology:Clostridium perfringens|Clostridium perfringens]]''<ref name="Groschwitz1" /> 
*''[[Biology:Candida albicans|Candida albicans]]''<ref name="Yan1" />

== Clinical significance ==

A disrupted intestinal mucosal barrier can allow passage of microbes, microbial products, and [[Biology:Antigen|foreign antigens]] into the mucosa and the body proper. This can result in activation of the [[Biology:Immune system|immune system]] and secretion of [[Medicine:Inflammation|inflammatory mediators]]. Certain immune responses might, in turn, cause cellular damage that could result in further barrier dysfunction.<ref name="Márquez"/> Defects in intestinal mucosal barrier function with the accompanying translocation of microbes and their products have been linked with a variety of conditions,<ref name="Sánchez1"/> some of which are thought to additionally require a [[Biology:Genetic predisposition|genetic predisposition]].<ref name="Fasano1">{{Cite journal|last1=Fasano|first1=Alessio|last2=Shea-Donohue|first2=Terez|date=2005-09-01|title=Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases|journal=Nature Clinical Practice Gastroenterology & Hepatology|volume=2|issue=9|pages=416–422|doi=10.1038/ncpgasthep0259|issn=1743-4378|pmid=16265432|s2cid=7259212 }}</ref> Both intestinal and extra-intestinal autoimmune disorders can result.<ref name="Fasano1"/> Intestinal barrier dysfunction is thought to be precondition for and [[Biology:Irritation|exacerbating factor]] of numerous autoimmune and inflammatory conditions, including [[Medicine:Food allergy|food allergies]], [[Medicine:Inflammatory bowel disease|inflammatory bowel disease]]s, [[Medicine:Coeliac disease|celiac disease]] and [[Medicine:Diabetes mellitus|diabetes]].<ref name="Groschwitz1"/>

=== Food allergies ===

Intestinal barrier dysfunction may be a critical factor for antigen sensitisations and the [[Biology:Immunoglobulin E|IgE]]/[[Biology:Mast cell|mast cell]]-mediated [[Medicine:Anaphylaxis|anaphylactic]] effector phase of food allergies. The development of food allergies depend on the antigen coming into contact with components of the mucosal immune system. This leads to antigen sensitisation and dietary antigen-specific CD4+ [[Biology:T helper cell|Th2 cell]] and IgE production. The hypothesis is that intestinal barrier dysfunction allows dietary antigens to cross the intestinal barrier, come into contact with the mucosal immune system, and trigger an antigen-specific immune response.<ref name="Groschwitz1"/>

Reduced intestinal barrier function correlates with the severity of symptoms experienced by food allergy sufferers. Oral challenge with the implicated allergen results in an increased lactulose/mannitol ratio in the urine (a measure of intestinal permeability).<ref name="Groschwitz1"/>

=== Inflammatory bowel disease ===

An emerging model of inflammatory bowel disease (IBD) [[Medicine:Pathogenesis|pathogenesis]] postulates three prerequisite factors: 1) degradation of intestinal barrier function, 2) translocation of luminal contents into the lamina propria and subsequent exposure to immune cells, and 3) an inappropriate immune response. Although intestinal barrier dysfunction is clearly implicated in the development of inflammatory bowel disease, it is unclear what initiates the self-perpetuating cycle that leads to disease exacerbation. Nevertheless, there is a growing body of evidence that implicates increased intestinal permeability as a primary etiologic factor of inflammatory bowel disease pathogenesis.<ref name="Groschwitz1"/>

=== Celiac disease ===

Altered intestinal barrier function may play a role in the development of celiac disease. By allowing gliadin, the causative agent of celiac disease, to cross the intestinal barrier, inappropriate activation of the immune system can occur. Celiac disease sufferers have been shown to have elevated intestinal permeability and altered tight junctions. Moreover, these disruptions persist in patients who successfully maintain a gluten-free diet. Data also exist demonstrating that increased intestinal permeability is present prior to onset of celiac disease.<ref name="Groschwitz1"/>

=== Type 1 diabetes ===

A combination of genetics, dysregulated intestinal barrier function, and inappropriate immune responses has been hypothesised to play a role in [[Medicine:Type 1 diabetes#Pathophysiology|type 1 diabetes]]. Elevated intestinal permeability has been reported observed in patients at disease onset. The resulting increase in exposure to antigens can trigger [[Medicine:Autoimmunity|autoimmune]] destruction of beta cells in the pancreas.<ref name="Groschwitz1"/>

=== Other conditions ===
Defects in intestinal mucosal barrier function have also been implicated in [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]], [[Medicine:Metabolic syndrome|metabolic syndrome]], [[Medicine:Non-alcoholic fatty liver disease|non-alcoholic fatty liver disease]], and [[Medicine:Septic shock|septic shock]].<ref name="Sánchez1" /><ref name=":0" />

=== Stress ===

Psychological and [[Medicine:Stress|physical stress]] can induce a variety of alterations in intestinal function. These include changes in [[Biology:Peristalsis|gut motility]], [[Biology:Intestinal permeability|intestinal permeability]], ion flux, [[Chemistry:Fluid balance|fluid balance]] and mucus secretion. Furthermore, acute and chronic stress in animal models has shown that stress can cause degradation of intestinal barrier function.<ref name="Groschwitz1"/> Psychological stress can influence the clinical outcome of [[Medicine:Inflammatory bowel disease|inflammatory bowel disease]] and [[Medicine:Irritable bowel syndrome|irritable bowel syndrome]]. Long-term stress has been shown to be positively associated with an increased propensity for relapse of [[Medicine:Ulcerative colitis|ulcerative colitis]].<ref name="Groschwitz1"/>

== History ==

Cummings adopted the term mucosal barrier in 2004 to describe the "complex structure that separates the internal milieu from the luminal environment."<ref name="Cummings1">{{Cite journal|last1=Cummings|first1=John H.|last2=Antoine|first2=Jean-Michel|last3=Azpiroz|first3=Fernando|last4=Bourdet-Sicard|first4=Raphaelle|last5=Brandtzaeg|first5=Per|last6=Calder|first6=Philip C.|last7=Gibson|first7=Glenn R.|last8=Guarner|first8=Francisco|last9=Isolauri|first9=Erika|date=2004-06-01|title=PASSCLAIM--gut health and immunity|journal=European Journal of Nutrition|volume=43|issue=Suppl 2 |pages=II118–II173|doi=10.1007/s00394-004-1205-4|issn=1436-6207|pmid=15221356|s2cid=2467749 }}</ref> More recently, intestinal barrier has been used by gastroenterologists, immunologists and microbiologists to emphasise the component of the intestine that protects the body from microorganisms and their toxins.<ref name="De Santis1"/>

== See also ==
*[[Biology:Antimicrobial peptides|Antimicrobial peptides]]
*[[Biology:Immunoglobulin A|Immunoglobulin A]]
*Intestinal epithelium
*[[Biology:Intestinal permeability|Intestinal permeability]]
*Human gastrointestinal tract
*[[Biology:Gastric mucosal barrier|Gastric mucosal barrier]]
*Gastrointestinal physiology
*Gut (anatomy)
*Mucosa-associated lymphoid tissue
*Mucin

== References ==
{{Reflist}}

[[Category:Digestive system]]

{{Sourceattribution|Intestinal mucosal barrier}}