THIS HAPPENS WHEN JUNCTIONS ARE TIGHT

In the recent years, we are hearing more and more about the importance of tight junctions and gut permeability to partly assess gut health. We call tight junction the mechanism that bind intestinal cells to each other to structure the intestinal epithelial barrier. This intestinal barrier is indeed the first line of defense between the organism and the hundreds of trillions of bacteria and viruses that populate the lumen.

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But the intestinal cells need to organize as well the selective absorption of nutrients. The transport of molecules across the epithelial layer occurs through three major pathways: the trans-cellular pathway (passive diffusion across the cell membranes), the carrier-mediated pathway (carrier/receptor-mediated trans-cellular pathway), and the paracellular pathway (passive diffusion between the spaces through adjacent cells). That paracellular pathway is managed by a complex of proteins that will connect the epithelial cells to each other. These junctions are actually made of three different architectures called (1) Tight junctions, (2) Adherens junctions and (3) Desmosomes.


Tight junctions are the most apical intercellular protein complex formed by trans­ membrane proteins, such as claudins, occludins and tri­cellulins, which are connected to the actin cytoskeleton via a cytoplasmic plaque including zona occludens (ZO­1, ZO­2 and ZO­3) – cf diagram below. The name claudin comes from Latin word claudere that means "to close". The transmembrane receptor JAM (junctional adhesion molecule) is also a critical pilar of tight junctions.


Adherens junctions are multiprotein complexes composed of the transmembrane protein E­cadherin and intracellular components such as p120 / catenin, which link the adherens junction to the actin cytoskeleton. Desmosomes is the third groups of proteins. They are junc­tional complexes of transmembrane proteins (desmo­glein and desmocollin) that connect keratin filaments of neighboring intestinal epithelial cells via desmoplakin.

Tight junc­tions are indeed responsible for the sealing of the intercellular space and regulate the paracellular passage of particles, whereas Adherens junctions and Desmosomes are strong adhesive bonds between intestinal epithelial cells that confer mechanical strength to the Intestinal Epithelial Barrier (IEB). In total, we numbered more than 40 different proteins involved in these junctions. Any alteration to one or several of these proteins could affect the gut permeability and be detrimental to the organism.


The physiological properties of the junctional gate are that of a semipermeable diffusion barrier that discriminates solutes on the basis of size and/or charge. Solutes can cross the junctional paracellular pathway along two routes.


The charge-selective permeation pathway is thought to consist of pores allowing diffusion of ions and small uncharged molecules. The estimated diameter of these pores is ~4–8 Å. A second diffusion pathway, the size-selective pathway, allows the diffusion of larger molecules up to a size limit of ~30–60 Å.


The permeability of the intestinal epithelium varies along its tract, and depends upon the composition and abundance of claudins and occludins in the tight junctions. Studies of transepithelial resistance in the rat show that the colon is less permeable than the small bowel. Other publications confirmed that the paracellular spaces between intestinal cells vary in size depending on their position along the villi, with larger openings at the base of the villi (10–15 Å) or the crypts (>20 Å) and smaller openings at the tips of the villi (4–5 Å only). Recent data shows as well that the paracellular spaces vary depending on the nature of the cells whether it is between enterocytes or between enterocytes and other intestinal cells as Paneth cells, goblet cells or stem cells. These structures are very dynamic as they respond to stimuli that may stabilize or destabilize them.

As example, Pro-inflammatory cytokines activate signaling pathways that can disrupt cell junctions by proteolysis of junction molecules and/or depressing Claudins proteins expression. Junctions are consequently disconnected from the actin cytoskeleton, resulting in increased intestinal permeability, translocation of bacteria, toxins and antigen and ultimately further inflammation.


Gut permeability can be modulated as well directly by microbes either positively through the production of short-chain fatty acids or negatively with the release of fungi mycotoxins or bacterial endotoxins. Butyrate, produced by bacteria in the colon, will indeed fuel the intestinal cells in energy and promote the production of proteins as claudins, occludins and JAM proteins. Dietary glutamine could as well beneficial for the tight junctions as source of energy for the enterocytes.



Bacterial endotoxins and mold mycotoxins present in the lumen will have the reverse effect by disrupting the cell homeostasis and negatively affect the assembly of cells junctions’ proteins.


Other ingredients like Zinc oxide or some plant extracts showed some effects in consolidating the tight junctions. Some recent in-vitro study demonstrated the effect of anethole (plant extract) on the transcription of the gene responsible for the production by the intestinal epithelial cells of claudin and JAM that will reinforce their tight junctions. The usage of certain form of Zinc Oxide (I remind you that not all sources of zinc oxide are equivalent) confirmed as well a positive effect on the tight junctions. But for many additives, it is difficult to know whether they act directly on the process of assembly of the tight junctions or whether they affect the bacterial population in the lumen which would result, as consequences, on higher production of butyrate and therefore tighter junctions.


In the coming months and year, we will certainly read more update from the scientific community on the subject of intestinal cell junctions. A better knowledge of their mechanisms could help nutritionists to provide through the feed effective solutions in order to promote better gut health for animals.


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