Intestinal permeability

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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 (such as antigens) from leaving the intestine
and migrating to the body more widely. [1] In a healthy human intestine, small
particles (< 4 Å in radius) can migrate through tight junction claudin pore
pathways,[2] and particles up to 10–15 Å (3.5 kDa) can transit through the
paracellular space uptake route.[3]

Contents

 1Physiology
 2Modulation
 3Clinical significance
 4Research directions
 5Leaky gut syndrome
 6See also
 7References

Physiology[edit]

Scheme of selective permeability routes of epithelial cells (red arrows). The transcellular (through the
cells) and paracellular (between the cells) routes control the passage of substances between the
intestinal lumen and blood.
The barrier formed by the intestinal epithelium separates the external
environment (the contents of the intestinal lumen) from the body[4] and is the most
extensive and important mucosal surface of body.[5] 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 antigens, toxins and microorganisms.[4][6] Second, it acts as a selective
filter which facilitates the uptake of dietary nutrients, electrolytes, water and
various other beneficial substances from the intestinal lumen. [4] Selective
permeability is mediated via two major routes:[4]

Transepithelial or transcellular permeability. This consists of specific
transport of solutes 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.[4]

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. [4] 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.[7] Disruption of the tight junction barrier can be a trigger
for the development of intestinal diseases.

Modulation[edit]
One way in which intestinal permeability is modulated is via CXCR3 receptors in
cells in the intestinal epithelium, which respond to zonulin.[8]
Gliadin (a glycoprotein present in wheat) activates zonulin signaling in all people
who eat gluten, irrespective of the genetic expression of autoimmunity. This
leads to increased intestinal permeability to macromolecules. [8][9][10] Bacterial
pathogens such as cholera, select enteric viruses, and parasites modulate
intestinal tight junction structure and function, and these effects may contribute to
the development of chronic intestinal disorders. [8][11] So called absorption modifying
excepients, investigated for the possibility of increasing intestinal drug
absorption, can increase the gut permeability. [12] Stress and infections also seem
to cause perturbations in intestinal permeability. [9]

Clinical significance[edit]
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.[8][10][13]
Increased intestinal permeability is a factor in several diseases, such as Crohn's
disease, celiac disease,[14] type 1 diabetes,[15] type 2 diabetes,[14] rheumatoid
arthritis, spondyloarthropathies,[16] inflammatory bowel disease,[8][17] irritable bowel
syndrome,[9] schizophrenia,[18][19] certain types of cancer,[8] obesity,[20] fatty liver,
[21]
 atopy and allergic diseases,[15] among others. In the majority of cases,
increased permeability develops prior to disease, [8] but the cause–effect
relationship between increased intestinal permeability in most of these diseases
is not clear.[17][22]
A relationship with autism has been hypothesized but the data supporting this
theory are limited and contradictory, since both increased intestinal permeability
and normal permeability have been documented in people with autism. It is
important to note that almost all studies use cohorts of children who have already
developed autism, beyond the age of onset (it is not determined if increased
permeability could be a cause that resolves itself later in childhood). Studies with
mice provide some support to this hypothesis.[23]
A well studied model is celiac disease, in which increased intestinal permeability
appears secondary to the abnormal immune reaction induced by gluten 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. [24][25] Other environmental
triggers may contribute to alter permeability in celiac disease, including intestinal
infections and iron deficiency.[24] Once established, this increase of permeability
might self-sustain the inflammatory immune responses and perpetuate a vicious
circle.[24] Eliminating gluten from the diet leads to normalization of intestinal
permeability and the autoimmune process shuts off. [26]

Research directions[edit]
In normal physiology, glutamine plays a key role in signalling in enterocytes 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.
[27]

Prebiotics and certain probiotics such as Escherichia coli Nissle 1917 have been

found to reduce increased intestinal permeability. [9] Lactobacillus rhamnosus,
[28]
 Lactobacillus reuteri,[28] and Faecalibacterium prausnitzii[29] have also been
shown to significantly reduce increased intestinal permeability.
Larazotide acetate (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 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.[25][30]

Leaky gut syndrome[edit]

Main article: Leaky gut syndrome
A proposed medical condition called leaky gut syndrome has been popularized
by some health practitioners, mainly of alternative medicine and nutritionists, with
claims that restoring normal functioning of the gut wall can cure many systemic
health conditions. Insufficient evidence has been found to support this claim, or
the claim that purported treatments for "leaky gut syndrome"—nutritional
supplements, probiotics,[9] herbal remedies, gluten-free foods, or low FODMAP,
low sugar, or antifungal diets—have any beneficial effect for most of the
conditions they are claimed to help.[17]

See also[edit]
 Environmental enteropathy
 Intestinal mucosal barrier

References[edit]
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