Tight Junctions: Defective Intestinal Barrier and Pathological Conditions

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Our main interaction with food, pathogens, and inflammatory signals is made through our intestinal barrier. Indeed, our gut epithelium is where the absorption, digestion, transportation starts, but it also plays the role of protection against pathogens. Therefore, the is a close interaction between the signals provided by our dietary intake or pathogens and the reaction to them by our immune system. Studies have shown that tight junctions (TJ) have a vital function in modulating inflammatory responses and assisting the immune reaction.

 

Tight Junctions

 

Our small intestine offers us two essential functions; it protects us because it is a physical barrier and absorbs our diet’s nutrients. Furthermore, our intestine is lined with intestinal epithelium, comprised of a brush border, villi, crypt, and basolateral plasma membrane structure. The tight junctions (TJ) are placed between each neighboring epithelial cell on the basolateral membrane. Consequently, TJs play an assistant role in the barrier function of our intestinal epithelium.

 

TJs can regulate the paracellular movement of ions, water, and solutes across the intestinal epithelium in-depth. Meanwhile, the detoxification system inhibits the crossing of xenobiotics.

 

Tight junction proteins:

 

Tight junctions are assembled by multiple proteins, which are located between neighboring cells on the apical membrane. Furthermore, TJ is comprised of two functional proteins that interact with actin to provide integrity to the gut barrier:

1.- Integral transmembrane proteins: They provide a network between adjacent cell membranes.
  • Occludin
  • Claudins
  • Junction adhesion molecule (JAM)
  • Tricellulin

 

 

2.- Peripheral membrane or plaque proteins: These proteins function as bridges that bind actin cytoskeleton to the integral transmembrane proteins.
  • Zonula occuldens 1 (ZO-1): Plays an essential role in the formation, function, and integrity of TJs.
  • Zonula occuldens 2 (ZO-2)
  • Zonula occuldens 3 (ZO-3)

 

 

Loss of TJ integrity

 

The function and integrity of TJ play a fundamental role in the protection against pathogen-related stress. Indeed, the integrity of these proteins may prevent infectious disease and modulates inflammation. Nevertheless, the loss of TJ integrity is multifactorial, in which elevated levels of proinflammatory cytokines, lipopolysaccharides (LPS) of pathogenic bacterial and pathological conditions play a crucial role.

 

Proinflammatory cytokines TNF-a, IL-1b, and IFN-y may suppress TJ integrity.

TNF-a activates NF-kB, which upregulates pro-inflammatory cytokine release, and negatively affects the function of ZO-1. Conversely, IL-1b activates NF-kB translocation, which in turn affects TJ permeability.

LPS The LPS in the outer wall of gram-negative bacteria such as E. coli and S. Typhimurium can alter the TJ permeability by inducing systemic inflammation. Consequently, this inflammation modifies the expression and localization of ZO-1 and occludin. Ultimately, this factor combination leads to leaky epithelial and elevated inflammatory signaling.
Pathological conditions Multiple pathological conditions are related to TJ disruption. Conditions like inflammatory bowel disease (IBD), obesity, non-alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD) are linked to a defective intestinal barrier.

 

Pathological conditions

Inflammatory bowel disease (IBD): IBD encompasses conditions like Crohn’s disease and ulcerative colitis. Also, these conditions commonly involve high levels of inflammation and TJ dysregulation. Therefore, this allows the crossing of solutes through the epithelial barrier, resulting in elevated antigen translocation and diarrhea. Furthermore, the antigen translocation promotes inflammatory signaling that triggers the resident and circulating immune cells contributing to the disruption of TJ integrity.

 

On the other hand, Chron’s disease and ulcerative colitis are associated with epithelial apoptosis. Meanwhile, the remaining enterocytes redistribute their TJ resulting in an epithelium contraction. These conditions are associated with decreased expression of different types of occludins and claudins, contributing to gut leakiness.

 

Obesity: The observations of obese and diabetic mouse models conclude that there is an altered TJ assembly. Also, high-fat-induced obesity in mouse models shows that TJ proteins like occluding and claudin are affected by the high levels of proinflammatory cytokines. They also reported an important change in microbiota and increased TNF-a levels, followed by elevated LPS absorption. Consequently, metabolic changes were made present, and ultimately metabolic syndrome was diagnosed in these mice. Lastly, the final observation of these studies concluded that obesity induces inflammation resulting in gut microbiota and TJ disruption changes.

Non-alcoholic steatohepatitis and non-alcoholic fatty liver disease: More information is needed to confirm TJ dysfunction and liver diseases’ molecular mechanisms. Nevertheless, the interaction between the gut-liver axis and obesity plays an essential role in developing these conditions. Conversely, some of the mechanisms associated with these diseases are:

  • Changes in the microbiota composition.
  • Increased circulating LPS.
  • Elevated inflammatory levels.
  • Abnormal crypt and villi morphologies.
  • Elevated levels of metabolic markers.

 

Overall, the integrity and structure of TJ are vital for gut barrier maintenance. Indeed, the paracellular translocation of ions, water, and molecules is the main protective factor against inflammatory diseases. Also, the morphology of TJ’s structural proteins is essential for the protection and prevention of several diseases.

Keto-induced microbiota:

Diet-induced ketosis can produce beneficial bacteria that may boost TJ structure. Nowadays, we can monitor and assess ketone bodies with the use of LEVL devices, with a simple breath test. At El Paso Functional Medicine we follow Covid-19 safety practices.

 

 

The crosstalk between our gut barrier and pathogenic bacterial or food allergens is key to prevent serious conditions. Indeed, our gut barrier is the first line of protection between our immune system and environmental factors. Consequently, the maintenance of an anti-inflammatory diet can boost TJ integrity. Besides, phytonutrients and antioxidants provided by our diet can inhibit NF-kB inflammatory pathway. Remember, food first! – Ana Paola Rodríguez Arciniega, MS.

 

References

 

Lee, Bonggi et al. “Tight Junction in the Intestinal Epithelium: Its Association with Diseases and Regulation by Phytochemicals.” Journal of immunology research vol. 2018 2645465. 16 Dec. 2018, doi:10.1155/2018/2645465

 

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Disclaimer

 

The information herein is not intended to replace a one-on-one relationship with a qualified healthcare professional, licensed physician, and not medical advice. We encourage you to make your own health care decisions based on your research and partnership with a qualified health care professional. Our information scope is limited to chiropractic, musculoskeletal, physical medicines, wellness, sensitive health issues, functional medicine articles, topics, and discussions. We provide and present clinical collaboration with specialists from a wide array of disciplines.

Each specialist is governed by their professional scope of practice and their jurisdiction of licensure. We use functional health & wellness protocols to treat and support care for the musculoskeletal system’s injuries or disorders. Our videos, posts, topics, subjects, and insights cover clinical matters, issues, and topics that relate to and support, directly or indirectly, our clinical scope of practice.* Our office has made a reasonable attempt to provide supportive citations and has identified the relevant research study or studies supporting our posts. We provide copies of supporting research studies available to regulatory boards and the public upon request. We understand that we cover matters that require an additional explanation of how it may assist in a particular care plan or treatment protocol; therefore, to further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us 915-850-0900 Read More…

Dr. Alex Jimenez DC, MSACP, CCST, IFMCP*, CIFM*, CTG*

email: coach@elpasofunctionalmedicine.com
phone: 915-850-0900
Licensed in Texas & New Mexico

 

 

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