Intestinal mucosal barrier

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Physical, biochemical, and immune elements of the intestinal mucosal barrier. Bischoff fig 2 adapted 01.png
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 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. [1] [2] [3] 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. [3] [4] [5]

Contents

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. [3] [5] [6]

Physical elements

Mucus layer(s)

Mucus forms a layer (or layers, in the case of the colon) that separates the bulk of the luminal contents from the intestinal epithelium. The mucus consists of a highly glycosylated hydrated gel formed by mucin molecules that are secreted by goblet cells. 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 digestive enzymes, and prevents the direct contact of microorganisms with the epithelial layer. [1] [5] [6] [7]

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 paracellular pathway (a route for translocation of molecules between cells). Sealing of the space between adjacent cells is mediated by junctional complexes formed by protein connections elaborated by each individual cell. [1] 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. [3]

Microbiota

The commensal microbial species that inhabit the gut are considered by some to be part of the intestinal mucosal barrier. The gut microbiota can influence barrier function both directly, by stimulating epithelial cell proliferation and secretion of IL-8, and indirectly by producing short-chain fatty acids, which are an important energy source for colonic epithelial cells (colonocytes). [3]

Biochemical elements

Bile and gastric acid

The bile produced by the liver to aid in the digestion of lipids has bactericidal properties. [7] The gastric acid produced by the stomach can also kill microorganisms. [8] Both contribute to intestinal barrier function although they are not produced by the intestinal mucosa.

Defensins

Specialised secretory epithelial cells called Paneth cells secrete abundant quantities human α-defensins into the intestinal lumen of healthy individuals. [9]

Lysozyme

Lysozyme is another defensive molecule secreted by Paneth cells into the lumen. [10]

Regenerating islet-derived protein 3 gamma (Reg3γ)

Reg3γ is an antibacterial lectin secreted by Paneth cells that serves to prevent microorganisms from coming into contact with the epithelial layer. [3] [10]

Immunological elements

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. [6] [7]

Secretory immunoglobulin A (sIgA )

Secretory immunoglobulin A (sIgA) is produced by plasma cells in the lamina propria and transported into the lumen by intestinal epithelial cells. [7] SIgA blocks epithelial-specific receptors on pathogens, thereby preventing their attachment to epithelial cells.

Cellular immunity

A variety of immune cells reside in the lamina propria which underlies the intestinal epithelium. These include dendritic cells (DCs), macrophages, intraepithelial lymphocytes (IEL), T regulatory cells (T Regs), TCD4+ lymphocytes, B lymphocytes, and plasma cells. [6] This population provides immune protection that is characterised by the rapid detection and killing of microorganisms that penetrate the intestinal epithelium. [7]

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). [4] Modulating factors include cytokines, immune cells, and exogenous factors. [4]

Measurement

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 passive diffusion." [11] 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. [12] [13] For example, in vivo testing using lactulose / 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. [14]

Endogenous regulators

Cytokines

Immune cells

Exogenous regulators

Pathogens

Clinical significance

A disrupted intestinal mucosal barrier can allow passage of microbes, microbial products, and foreign antigens into the mucosa and the body proper. This can result in activation of the immune system and secretion of inflammatory mediators. Certain immune responses might, in turn, cause cellular damage that could result in further barrier dysfunction. [7] Defects in intestinal mucosal barrier function with the accompanying translocation of microbes and their products have been linked with a variety of conditions, [3] some of which are thought to additionally require a genetic predisposition. [15] Both intestinal and extra-intestinal autoimmune disorders can result. [15] Intestinal barrier dysfunction is thought to be precondition for and exacerbating factor of numerous autoimmune and inflammatory conditions, including food allergies, inflammatory bowel diseases, celiac disease and diabetes. [4]

Food allergies

Intestinal barrier dysfunction may be a critical factor for antigen sensitisations and the IgE/mast cell-mediated 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+ 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. [4]

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). [4]

Inflammatory bowel disease

An emerging model of inflammatory bowel disease (IBD) 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. [4]

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. [4]

Type 1 diabetes

A combination of genetics, dysregulated intestinal barrier function, and inappropriate immune responses has been hypothesised to play a role in type 1 diabetes. Elevated intestinal permeability has been reported observed in patients at disease onset. The resulting increase in exposure to antigens can trigger autoimmune destruction of beta cells in the pancreas. [4]

Other conditions

Defects in intestinal mucosal barrier function have also been implicated in irritable bowel syndrome, metabolic syndrome, non-alcoholic fatty liver disease, and septic shock. [3] [13]

Stress

Psychological and physical stress can induce a variety of alterations in intestinal function. These include changes in gut motility, intestinal permeability, ion flux, fluid balance and mucus secretion. Furthermore, acute and chronic stress in animal models has shown that stress can cause degradation of intestinal barrier function. [4] Psychological stress can influence the clinical outcome of inflammatory bowel disease and irritable bowel syndrome. Long-term stress has been shown to be positively associated with an increased propensity for relapse of ulcerative colitis. [4]

History

Cummings adopted the term mucosal barrier in 2004 to describe the "complex structure that separates the internal milieu from the luminal environment." [16] 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. [6]

See also

Related Research Articles

<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.

Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the gastrointestinal tract and involve visceral hypersensitivity and motility disturbances.

<span class="mw-page-title-main">Enterochromaffin cell</span> Cell type

Enterochromaffin (EC) cells are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. They were discovered by Nikolai Kulchitsky.

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">Paneth cell</span> Anti-microbial epithelial cell of the small intestine

Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands and the large eosinophilic refractile granules that occupy most of their cytoplasm.

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 from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles can migrate through tight junction claudin pore pathways, and particles up to 10–15 Å can transit through the paracellular space uptake route. There is some evidence abnormally increased intestinal permeability may play a role in some chronic diseases and inflammatory conditions. The most well understood condition with observed increased intestinal permeability is celiac disease.

<span class="mw-page-title-main">Intestinal gland</span> Gland between the intestinal villi that produces new cells

In histology, an intestinal gland is a gland found in between villi in the intestinal epithelium lining of the small intestine and large intestine. The glands and intestinal villi are covered by epithelium, which contains multiple types of cells: enterocytes, goblet cells, enteroendocrine cells, cup cells, tuft cells, and at the base of the gland, Paneth cells and stem cells.

<span class="mw-page-title-main">Respiratory epithelium</span> Mucosa that serves to moisten and protect the airways

Respiratory epithelium, or airway epithelium, is a type of ciliated columnar epithelium found lining most of the respiratory tract as respiratory mucosa, where it serves to moisten and protect the airways. It is not present in the vocal cords of the larynx, or the oropharynx and laryngopharynx, where instead the epithelium is stratified squamous. It also functions as a barrier to potential pathogens and foreign particles, preventing infection and tissue injury by the secretion of mucus and the action of mucociliary clearance.

Microfold cells are found in the gut-associated lymphoid tissue (GALT) of the Peyer's patches in the small intestine, and in the mucosa-associated lymphoid tissue (MALT) of other parts of the gastrointestinal tract. These cells are known to initiate mucosal immunity responses on the apical membrane of the M cells and allow for transport of microbes and particles across the epithelial cell layer from the gut lumen to the lamina propria where interactions with immune cells can take place.

<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).

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Interleukin-22 receptor subunit alpha-2 (IL-22RA2), also known as interleukin-22 binding protein (IL-22BP) is a naturally secreted monomeric protein acting as an interleukin-22 (IL-22) antagonist with inhibitory effects on IL-22 activity in vivo. IL-22BP is in humans encoded by the IL22RA2 gene located on chromosome 6, and in mice is encoded by the il22ra2 gene located on chromosome 10. IL-22BP belongs to the class II cytokine receptor family and it is a soluble receptor homolog of IL-22R.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that form the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelial cells, it serves two main functions: absorbing useful substances into the body and restricting the entry of harmful substances. As part of its protective role, the intestinal epithelium forms an important component of the intestinal mucosal barrier. Certain diseases and conditions are caused by functional defects in the intestinal epithelium. On the other hand, various diseases and conditions can lead to its dysfunction which, in turn, can lead to further complications.

<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.

<span class="mw-page-title-main">Mucosal immunology</span> Field of study

Mucosal immunology is the study of immune system responses that occur at mucosal membranes of the intestines, the urogenital tract, and the respiratory system. The mucous membranes are in constant contact with microorganisms, food, and inhaled antigens. In healthy states, the mucosal immune system protects the organism against infectious pathogens and maintains a tolerance towards non-harmful commensal microbes and benign environmental substances. Disruption of this balance between tolerance and deprivation of pathogens can lead to pathological conditions such as food allergies, irritable bowel syndrome, susceptibility to infections, and more.

Mucosal-associated invariant T cells make up a subset of T cells in the immune system that display innate, effector-like qualities. In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B2 and B9 metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.

Limosilactobacillus mucosae is a rod shaped species of lactic acid bacteria first isolated from pig intestines. It has mucus-binding activity. The species is an obligate anaerobe, catalase-negative, doesn't form spores and is non-motile. Its type strain is S32T, and has been found to be most closely related to Limosilactobacillus reuteri.

<span class="mw-page-title-main">Tuft cell</span>

Tuft cells are chemosensory cells in the epithelial lining of the intestines. Similar tufted cells are found in the respiratory epithelium where they are known as brush cells. The name "tuft" refers to the brush-like microvilli projecting from the cells. Ordinarily there are very few tuft cells present but they have been shown to greatly increase at times of a parasitic infection. Several studies have proposed a role for tuft cells in defense against parasitic infection. In the intestine, tuft cells are the sole source of secreted interleukin 25 (IL-25).

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 is being studied in people with celiac disease.

<span class="mw-page-title-main">Type 3 innate lymphoid cells</span>

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

References

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