Intestinal permeability is a term describing the control of material passing from inside the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

through the cells lining the

gut wall The gastrointestinal wall of the gastrointestinal tract is made up of four layers of specialised tissue. From the inner cavity of the gut (the lumen) outwards, these are: # Mucosa # Submucosa # Muscular layer # Serosa or adventitia The mucosa is ...

, 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 (such as

antigens In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

) from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles (< 4 Å in radius) can migrate through

tight junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...

claudin Claudins are a family of proteins which, along with occludin, are the most important components of the tight junctions ( zonulae occludentes). Tight junctions establish the paracellular barrier that controls the flow of molecules in the interce ...

pore pathways, and particles up to 10–15 Å (3.5

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

) 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 Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barl ...

Physiology

Selective permeability routes in epithelium

The barrier formed by the

intestinal epithelium 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 functi ...

separates the external environment (the contents of the intestinal lumen) from the body and is the most extensive and important mucosal surface of body. However, the intestinal mucin can also be barriers for the host antimicrobial peptides, thus plays a bidirectional barrier for host-microbial interaction. The intestinal epithelium is composed of a single layer of cells and serves two crucial functions. First, it acts as a barrier, preventing the entry of harmful substances such as foreign

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

s and

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s. Second, it acts as a selective filter which facilitates the uptake of dietary

nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...

electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...

s, water and various other beneficial substances from the intestinal lumen. Selective permeability is mediated via two major routes: *Transepithelial or transcellular permeability. This consists of specific transport of

solutes In chemistry, a solution is a special type of homogeneous mixture composed of two or more substances. In such a mixture, a solute is a substance dissolved in another substance, known as a solvent. If the attractive forces between the solvent ...

across the epithelial cells. It is predominantly regulated by the activities of specialised transporters that translocate specific electrolytes, amino acids, sugars, short chain fatty acids and other molecules into or out of the cell. *Paracellular permeability. It depends on transport through the spaces that exist between epithelial cells. It is regulated by cellular junctions that are localized in the laminal membranes of the cells. This is the main route of passive flow of water and solutes across the intestinal epithelium. Regulation depends on the intercellular tight junctions which have the most influence on paracellular transport. Disruption of the tight junction barrier can be a trigger for the development of intestinal diseases.

Modulation

One way in which intestinal permeability is modulated is via

CXCR3 Chemokine receptor CXCR3 is a Gαi protein-coupled receptor in the CXC chemokine receptor family. Other names for CXCR3 are G protein-coupled receptor 9 (GPR9) and CD183. There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokin ...

receptors in cells in the

, which respond to

zonulin Zonulin (haptoglobin 2 precursor) is a protein that increases the permeability of tight junctions between cells of the wall of the digestive tract. It was discovered in 2000 by Alessio Fasano and his team at the University of Maryland School of ...

Gliadin Gliadin (a type of prolamin) is a class of proteins present in wheat and several other cereals within the grass genus ''Triticum''. Gliadins, which are a component of gluten, are essential for giving bread the ability to rise properly during baki ...

(a glycoprotein present in wheat) activates

signaling in all people who eat

gluten Gluten is a structural protein naturally found in certain cereal grains. Although "gluten" often only refers to wheat proteins, in medical literature it refers to the combination of prolamin and glutelin proteins naturally occurring in all grain ...

, irrespective of the genetic expression of

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

. This leads to increased intestinal permeability to macromolecules. Bacterial infections such as

cholera Cholera is an infection of the small intestine by some strains of the bacterium ''Vibrio cholerae''. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and ...

, select enteric viruses, parasites, and stress can all modulate intestinal tight junction structure and function, and these effects may contribute to the development of chronic intestinal disorders. So called absorption modifying excipients, investigated for the possibility of increasing intestinal drug absorption, can increase the gut permeability.

Clinical significance

Most people do not experience adverse symptoms, but the opening of intercellular tight junctions (increased intestinal permeability) can act as a trigger for diseases that can affect any organ or tissue depending on genetic predisposition. Increased intestinal permeability is a factor in several diseases, such as

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...

type 1 diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

spondyloarthropathies Spondyloarthropathy or spondyloarthrosis refers to any joint disease of the vertebral column. As such, it is a class or category of diseases rather than a single, specific entity. It differs from spondylopathy, which is a disease of the vertebra ...

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

, certain types of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

fatty liver Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complicat ...

atopy Atopy is the tendency to produce an exaggerated immunoglobulin E (IgE) immune response to otherwise harmless substances in the environment. Allergic diseases are clinical manifestations of such inappropriate, atopic responses. Atopy may have a ...

and

allergic Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

diseases, among others. In the majority of cases, increased permeability develops prior to disease, but the cause–effect relationship between increased intestinal permeability in most of these diseases is not clear. A well studied model is

, in which increased intestinal permeability appears secondary to the abnormal immune reaction induced by

and allows fragments of gliadin protein to get past the intestinal epithelium, triggering an immune response at the intestinal submucosa level that leads to diverse gastrointestinal or extra-gastrointestinal symptoms. Other environmental triggers may contribute to alter permeability in celiac disease, including intestinal infections and iron deficiency. Once established, this increase of permeability might self-sustain the inflammatory immune responses and perpetuate a vicious cycle. Eliminating gluten from the diet leads to normalization of intestinal permeability and the autoimmune process shuts off.

Research directions

In normal physiology,

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral, ...

plays a key role in signalling in

enterocytes Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its s ...

that are part of the intestinal barrier, but it is not clear if supplementing the diet with glutamine is helpful in conditions where there is increased intestinal permeability.

Prebiotics Prebiotics are compounds in food that induce the growth or activity of beneficial microorganisms such as bacteria and fungi. The most common example is in the gastrointestinal tract, where prebiotics can alter the composition of organisms in the ...

and certain

probiotics Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria-host i ...

such as ''E.Coli'' strain Nissle 1917 have been found to reduce increased intestinal permeability. ''

Lactobacillus rhamnosus ''Lacticaseibacillus rhamnosus'' (previously ''Lactobacillus rhamnosus'') is a bacterium that originally was considered to be a subspecies of '' L. casei'', but genetic research found it to be a separate species in the ''L. casei'' clade, which ...

'', '' Lactobacillus reuteri'', and ''

Faecalibacterium prausnitzii ''Faecalibacterium'' is a genus of bacteria. Its sole known species, ''Faecalibacterium prausnitzii'' is gram-positive, mesophilic, rod-shaped, anaerobic and is one of the most abundant and important commensal bacteria of the human gut microbiot ...

'' have also been shown to significantly reduce increased intestinal permeability.

Larazotide acetate Larazotide (INN; also known as AT-1001; formulated as the salt with acetic acid, larazotide acetate) is a synthetic eight amino acid peptide that functions as a tight junction regulator and reverses leaky junctions to their normally closed state ...

(previously known as AT-1001) is a zonulin receptor antagonist that has been probed in clinical trials. It seems to be a drug candidate for use in conjunction with a

gluten-free diet A gluten-free diet (GFD) is a nutritional plan that strictly excludes gluten, which is a mixture of proteins found in wheat (and all of its species and hybrids, such as spelt, kamut, and triticale), as well as barley, rye, and oats. The incl ...

in people with celiac disease, with the aim to reduce the intestinal permeability caused by gluten and its passage through the epithelium, and therefore mitigating the resulting cascade of immune reactions. Decreasing intestinal barrier function with aging can cause increased translocation of microbial products, such as

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

, into the systemic blood circulation that subsequently causes systemic inflammation (

inflammaging Inflammaging (also known as inflamm-aging or inflamm-ageing) is a chronic, sterile low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related patho ...

) and significant clinical outcomes: metabolic syndrome, decreased physical function, and mortality. It has been shown that the loss of intestinal barrier function is associated with an increased formation of

Nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...

(NO) and lower activity of

arginase Arginase (, ''arginine amidinase'', ''canavanase'', ''L-arginase'', ''arginine transamidinase'') is a manganese-containing enzyme. The reaction catalyzed by this enzyme is: : arginine + H2O → ornithine + urea It is the final enzyme of the ure ...

.Brandt, A., Baumann, A., Hernández-Arriaga, A., Jung, F., Nier, A., Staltner, R., ... & Bergheim, I. (2022). Impairments of intestinal arginine and NO metabolisms trigger aging-associated intestinal barrier dysfunction and inflammaging´. Redox Biology, 102528. Genetic disruption of arginase-2 in mouse attenuates the onset of senescence and extends lifespan.Xiong, Y., Yepuri, G., Montani, J. P., Ming, X. F., & Yang, Z. (2017). Arginase-II deficiency extends lifespan in mice. Frontiers in physiology, 8, 682. Arginase inhibitors have been developed to reduce the effect of NO on intestinal permeability.

Leaky gut syndrome

Leaky gut syndrome Leaky gut syndrome is a hypothetical, medically unrecognized condition. Unlike the scientific phenomenon of increased intestinal permeability ("leaky gut"), claims for the existence of "leaky gut syndrome" as a distinct medical condition come m ...

" is a hypothetical, medically unrecognized condition. It has been popularized by some

nutritionist A nutritionist is a person who advises others on matters of food and nutrition and their impacts on health. Some people specialize in particular areas, such as sports nutrition, public health, or animal nutrition, among other disciplines. In many c ...

s and practitioners of

alternative medicine Alternative medicine is any practice that aims to achieve the healing effects of medicine despite lacking biological plausibility, testability, repeatability, or evidence from clinical trials. Complementary medicine (CM), complementary and alt ...

who claim that ''restoring normal functioning'' of the

can cure many systemic health conditions. However, reliable source evidence to support this claim has not been published. Nor has there been published any reliable evidence that the treatments promoted for so-called "leaky gut syndrome"—including nutritional supplements,

probiotic Probiotics are live microorganisms promoted with claims that they provide health benefits when consumed, generally by improving or restoring the gut microbiota. Probiotics are considered generally safe to consume, but may cause bacteria-host i ...

s, herbal remedies, (or low- FODMAP ''diets''; low-sugar, antifungal, or

-free ''diets'')—have any beneficial effect for most of the conditions they are claimed to help.

References