Intestinal Barrier Dysfunction Caused by Pathogens

Gut flora, gut microbiota or gastrointestinal microbiota, is the complex community of microorganisms that live in the gastrointestinal tract, or GI tract, of humans and other animals, even in insects. The composition of gut microbiota is unique to each individual, much like our fingerprints. The human body’s gastrointestinal microbiota can consist of up to tens of trillions of bacteria, where there can even be more than 3 million different genomes of gut microbiota within a single body.

What is the essential function of the gut microbiota?

The gut flora is as essential for digestion as each important organ of the digestive system, as it can help the body digest certain foods that the stomach and small intestine have not been able to digest, it helps maintain the wholeness of the intestinal mucosa, it helps with the production of some vitamins, and it plays a fundamental role in the immune system by adding a protective effect along the gastrointestinal tract. A healthy and balanced gut microbiota is key to ensuring proper digestive function, however, an imbalance of gut bacteria can affect the function of the digestive system.

Intestinal Barrier Dysfunction Causing Pathogens

The gut is home, both permanently and temporarily, to an exceedingly complex variety of gut flora, or gut microbiota, which also means that it can become an abundant source of potentially pathogenic organisms, toxins and antigens. The interactions involving enteric pathogens and the intestinal epithelium, a layer of cells that forms the luminal surface or lining of both the small and large intestine of the gastrointestinal tract, or GI tract, can often lead to changes in the intestinal barrier, as well as that in fluid and electrolyte transport, and it could also start an inflammatory response in the gastrointestinal tract. Enteric pathogens can affect intestinal barrier function directly, by binding to cell surface molecules and causing changes in tight junction, or TJ, protein expression. Alternatively, pathogens generate toxins and proteases, which can promote cell damage and apoptosis, or programmed cell death, alter epithelial ion transport, including the TJs and the cytoskeleton. Herein, we will provide examples and short descriptions of numerous mechanisms by which pathogens can affect barrier function.

Vibrio Cholera

Vibrio cholera, or V cholera, is a major enteric pathogen which alters intestinal barrier function by interrupting the normal function of TJs, by deregulating intestinal ion and fluid transport and also by causing inflammation in the gastrointestinal tract. A major toxin produced by V cholera is the cytotoxin, hemagglutinin protease (HA/P), a zinc-binding metalloprotease that destroys tight junction proteins and reduces barrier function. Studies of mutant toxin-attenuated strains of Vibrio cholera have identified HA/P as the primary toxin responsible for alterations of TJs and diminished TER in cultured MDCK and T84 cells. In vitro research studies revealed that HA/P breaks the extracellular domain of occludin. This disrupts intracellular occludin-ZO-1 interactions and destabilizes the TJ complex and cytoskeletal structures, resulting in enhanced paracellular permeability.

Another toxin developed by V cholera is zonula occludens toxin, abbreviated as Zot, an enterotoxin that reversibly increases intestinal epithelial permeability, alters the actin cytoskeleton and causes fragmentation of ZO-1 and occludin. Zonula occludens toxin binds into the zonulin receptor on the apical side of the intestinal epithelial cells and triggers phospholipase C, which leads to PKCα-dependent polymerization of the actin cytoskeleton. Actin polymerization is believed to promote cytoskeletal reorganization and the destabilization of TJ complexes. Consistent with this hypothesis, pretreating intestinal epithelial monolayers using PKCα inhibitors averted Zot-induced fluctuations in actin polymerization and permeability. A human homologue for Zot, zonulin, has been identified and found to bind to the same receptor, in order to regulate intestinal permeability. Zonulin is also considered to balance tight junction, or TJ, function and its deregulation has been involved in the development of many inflammatory diseases related to intestinal barrier dysfunction, such as inflammatory bowel disease, or IBD, Type I diabetes and autoimmune diseases.

Enteropathogenic E. Coli (EPEC)

Enteropathogenic E. Coli, or EPEC, is a diarrhea-causing bacteria that affects TJ proteins by adhering directly into the surface of epithelial cells. They form attaching and effacing lesions, characterized by the localized destruction of the adjacent epithelial microvilli and the creation of a pedestal-like structure in the accumulation of cytoskeletal proteins, such as actin, below the site of attachment. EPEC uses a syringe-like type III secretion system to trigger TJ changes in intestinal epithelial ion secretion. Infection of intestinal T84 monolayers with EPEC increased epithelial permeability and has been associated with the destabilization and dissociation of both ZO-1, occludin and claudin-1 tight junction complex from the lateral membrane. The molecular mechanisms related to EPEC-mediated TJ changes are still unknown; however, research studies utilizing pharmacological agents that inhibit MLCK, believe the involvement of the MLCK pathway might be implicated in the procedure.

Clostridium Perfringens

Although several different genomes of gut microbiota have been demonstrated to affect the TJs, the enterotoxin of Clostridium perfringens, or CPE, which is a common cause of food poisoning, directly interacts with and uses TJs as receptors. CPE binds to the extracellular loop of claudins-3 and -4 on the cell surface of enterocytes, forming small protein complexes in the plasma membrane. These complexes promote oligomerization and the formation of larger plasma membranes, which may be connected to increased plasma membrane permeability. Clostridium perfringens also interacts with occludin to promote its removal from the tight junction and redistribution into the cytoplasm. The redistribution of claudins and occludin destabilizes the TJ complex, altering intestinal paracellular permeability. By way of instance, vulnerability of MDCK monolayers to CPE caused a reversible decrease in TER and increase in permeability. Finally, the large CPE and TJ-containing complexes are believed to introduce into the plasma membrane to form a functional pore, which causes Ca2+ influx that triggers host epithelial cell death by apoptosis or oncosis.

In conclusion, gut flora, gut microbiota or gastrointestinal microbiota, are just as essential for digestion as the other important organs of the digestive system. The complex variation of gut microbiota is fundamental towards ensuring proper digestive function, however, some genomes of gut microbiota can cause changes in the TJ complexes, affecting intestinal barrier function and altering intestinal permeability. Understanding which types of bacteria can lead to gastrointestinal disease can help patients and doctors develop a proper treatment plan. Information referenced from the National Center for Biotechnology Information (NCBI) and the National University of Health Sciences. The scope of our information is limited to chiropractic and spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .

By Dr. Alex Jimenez

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