What Are Tight Junctions And How Do They Function?

Malfunctioning tight junctions affect your gut health and may be associated with numerous metabolic and inflammatory diseases.
What are tight junctions? How do tight junctions function?

Although it is inside your body, your gastrointestinal (GI) tract — your mouth, stomach, intestines and anus — is actually exposed to the outside environment. Foods we eat and other things from the outside environment (such as viruses and other microbes) make their way into our bodies (and hopefully back out again) through the GI tract. The cells lining our intestinal tract have a big job protecting us from potentially harmful substances in the environment. These cells employ several protective mechanisms, including the formation of tight junctions (TJs) — tight links between cells that keep molecules from crossing over. Several things can compromise the strength of these junctions, however, which can contribute to a number of diseases. Read on to learn more, such as what are tight junctions — and a few tips on how you can keep your own TJs, well, tight.

What are tight junctions?

Tight junctions (TJs) are branches of protein strands that come out from the surface of cells — called the membrane — and link with each other throughout the membrane surface. Think of the junctions as tight spiderwebs, or perhaps a tangle of silly string. There are a lot of different proteins — over 50 — that make up tight junctions, and they can be grouped into four different categories:

  • Transmembrane proteins are wedged in the middle of the cell membrane and facilitate adhesion and permeability (while some things shouldn’t cross, other molecules do need to be let through). Examples include claudin, occludin, tricellulin, and junctional adhesion molecules (JAMs).

  • Scaffold proteins bind to transmembrane proteins and localize underneath tight junctions. Zonula occludens (ZO) proteins are some of the most prominent and most well characterized scaffold proteins. Cingulin is another scaffold protein.

  • Signaling proteins recruit proteins together to form the tight junction, and help ensure the barrier stays strong. Examples include actin, afadin and atypical protein kinase C.

  • Regulation proteins regulate which proteins travel to the cell membrane inside of cellular compartments called vesicles. While such proteins don’t form the tight junction per se, by impacting the proteins that do make it to the tight junction, when, and in what amounts, they can indirectly impact tight junction composition and integrity.

Why are tight junctions important?

As mentioned above, TJs keep harmful substances from the environment from crossing over your intestinal (or brain, heart, and lung) cells and into your bloodstream and tissues. However, TJs also let certain molecules that are important for our health cross and get to where they need to go. 

So, how does it work? In the GI tract, the epithelium creates a selectively permeable barrier that facilitates nutrient absorption and waste secretion while preventing luminal materials — food particles, pathogenic bacteria, etc. — from entering cells and crossing the barrier. The GI tract is also lined with mucus, which is home to numerous immune cells — so there is a very intimate interaction between the intestinal epithelium and the mucosal immune system. 

TJs play a critical role in this relationship, and TJ dysfunction has been linked to several local and systemic diseases. This dysfunction has been called “leaky gut” by scientists — although leaky gut is not a clinically recognized condition — because it results in exactly what it sounds like: the inappropriate “leaking” of luminal contents across the epithelial barrier. This in turn leads to inappropriate immune responses to non-threatening molecules, such as members of the gut microbiome or molecules present in the foods we eat. In severe cases, compromised TJs may be associated with pulmonary edema (lung epithelium), gut bacteria translocation and multiple organ failure.

Tight junction dysfunction and disease

The relationship between tight junction dysfunction and disease appears to be a two-way street. Not only can tight junction dysfunction contribute to the development of several diseases, several disease conditions can also cause tight junction dysfunction — and, therefore, worsening symptoms. Several important factors have been reported to lead to damaged TJs:

  • Cytokines are signaling proteins secreted by immune cells, and they either promote inflammation or calm it down. Proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interferon γ (IFNγ) can alter tight junctions through a phenomenon called claudin switching, which causes changes in the normal levels of claudin proteins. Because some claudins promote barrier permeability and some promote tighter junctions, disrupting the balance prevents the appropriate formation of TJs and further increases inflammation and susceptibility to disease.

  • Pathogenic bacteria, such as Salmonella and some strains of E. coli (as well as others), can disrupt tight junctions by reorganizing or degrading tight junction proteins, altering the structure of the epithelial cell itself, or disrupting signals that dictate appropriate barrier construction and maintenance. They do this via molecules they produce called toxins.

  • Lipopolysaccharides (LPS) are components of the cell wall of Gram-negative bacteria (bacteria that have a very thin cell wall) and can act as toxins. Studies have shown that LPS increases tight junction permeability by altering the levels of different proteins, including claudin-1.

  • Epithelial injury in the gut can result from and/or cause malnutrition or disease — including intestinal ischemia/reperfusion (I/R), sepsis, inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). These diseases will be discussed in more detail in a later section.

When TJs are damaged, some of the proteins comprising them end up traveling throughout the body and can be detected in blood or urine. Multiple tight junction proteins, including claudins 2, 3, and 4 and the scaffold protein zonulin, are common biomarkers of epithelial injury and compromised TJs.

Tight junction dysfunction has been associated with several different diseases impacting multiple areas of the human body. We’ll break them down by body site:

Gastrointestinal diseases

Gastrointestinal diseases are some of the most widely studied diseases associated with tight junction dysfunction. Disruptions in this important barrier have been associated with:

  • Obesity. Obese individuals commonly suffer from a leaky, hyperpermeable gut. Studies show that this is due to claudin switching. In obesity specifically, claudin-2, which is only expressed by leaky tissue, is upregulated. This upregulation has been directly linked to consumption of a high fat diet and is modulated by TNFα/NF-kB/JUN MAP Kinase signaling
  • Inflammatory bowel disease (IBD). Patients with IBD suffer from decreased tight junction barrier function, increased pro-inflammatory cytokine production and immune dysregulation. In an attempt to further elucidate the complex relationship, research revealed that TNFα and an inflammatory cytokine called interleukin-13 (IL-13) induce barrier loss in epithelial cell models of IBD in the laboratory.
  • Non-alcoholic fatty liver disease (NAFLD). Researchers are still trying to elucidate the role of the gut in NAFLD, but an increasing number of studies suggest bacterial endotoxin (aka LPS) plays a role. Intestinal biopsies from NAFLD patients revealed increased intestinal permeability that appeared to be due to disrupted TJs, which would facilitate the passage of LPS across the intestinal barrier.
  • Celiac disease. Compromised TJs can contribute to celiac disease, an inappropriate immune response to the gluten present in some foods (breads, pasta, cereal, etc.) that causes diarrhea, abdominal pain, tiredness, anemia, and even infertility in some cases.

Neurological disorders

While TJs are typically thought of in the context of the GI tract, the blood-brain barrier (BBB) — the physical barrier that protects your brain from dangerous molecules, including bacteria and viruses, circulating in your bloodstream — also contains TJs. Given the relationship between tight junction damage and GI disease, many scientists wonder whether dysfunctional TJs can impact the brain. When it comes to neurological disorders, the evidence, though still in its infancy, is building. A recent review summarized the research connecting the BBB, TJs and several diseases, including:

  • Stroke
  • Multiple sclerosis
  • Brain tumors
  • Parkinson’s disease
  • Alzheimer’s disease

The review authors emphasize the importance of this work given that a huge struggle treating such conditions is the inability of most drugs to transit across the BBB. Perhaps a better understanding of TJs and how to leverage them in a positive way could enable drugs to be delivered to the brain and nervous system without allowing harmful substances to pass through. However, at this early stage of research, this is only conjecture.

Cardiorespiratory failure/disease

Lung and cardiac tissue also contain TJs, and several studies have connected tight junction dysfunction with cardiac and pulmonary failure. More recently, scientists have examined the relationship between COVID-19 and TJs, finding that COVID-19 causes a large increase in tight junction permeability in the lungs, resulting in the passage of bacterial and fungal materials into the circulatory system. This in turn leads to increased systemic inflammation and higher mortality. Many other pathogenic bacteria and viruses recognize tight junction proteins and bind specifically to them, in effect hi-jacking the tight junction system and using it against itself to gain entry into our cells.

The optimal dietary profile for healthy tighter junctions

Given the significant association between tight junction dysfunction and metabolic and inflammatory disease, doctors and pharmacologists are paying more attention to them as potential targets for various therapeutic interventions aimed at treating disease. And while a lot of potential treatments have shown promise when using cells, very few of these therapies are effective when moving into animal models. One area that looks promising: dietary interventions.

The research seems to be clear on one thing: a high-fat diet can damage TJs and increase intestinal permeability. Therefore, it should be no surprise that a high-fiber diet (essentially the antithesis of a high-fat diet) can increase intestinal integrity, mainly due to bacterial production of short chain fatty acids (SCFAs) as a result of fermentation of fiber. SCFAs, such as butyrate, stimulate healthy metabolism by the cells that comprise the intestinal barrier and deplete harmful intracellular oxygen, fortifying TJs and keeping them strong. 

Research in animal models suggests that another group of molecules, polyphenols — micronutrients that also come from plants, also play a role in strengthening TJs. The amino acids glutamine and tryptophan also play a protective role in maintaining a healthy intestinal barrier. 

A recent review expanded on our current knowledge base around nutrients and TJs, summarizing some of the main nutrient categories, how they impact TJs (either directly or indirectly) and which foods they can be obtained from:

  • Quercetin: a polyphenol that protects cells from oxidative and inflammation-associated injuries. Onions, kale, and apples are excellent sources of quercetin.

  • Berberine: a bioactive compound isolated from plants and that has been used as a traditional Chinese medicine to treat GI diseases, diarrhea, and bacterial infections, all of which impact tight junction integrity. Coptis rhizoma (the roots of medicinal herbs/plants) and barberry are the most common natural sources of berberine, which is typically ingested as a supplement in pill form.

  • Genistein: an isoflavone (plant-derived compounds with estrogenic activity) that may impact tight junction integrity by supporting the transfer of signals between cells that play a role in tight junction formation. Soybeans are the main source of genistein.

  • Kaempferol: a flavonol (compounds with antioxidant properties) that has repeatedly shown antioxidant and anti-inflammatory effects (read: good for tight junction integrity) in cells and animal models. Apples, grapes, broccoli, kale, and chives are sources of this compound.

Other compounds that may have a beneficial impact on TJs include curcumin (found in the spice turmeric) and various phytochemicals.

It’s important to note that many of these connections are indirect: these molecules have beneficial impacts on inflammation, and inflammation plays a role in tight junction dysfunction, so the connection is implied rather than directly demonstrated. Additionally, few of these connections have been validated in clinically-relevant research studies performed on humans. Nevertheless, many of these compounds that appear associated with TJ health  — most of which are found in plant-based diets — have numerous other notable beneficial effects on human health, including reduced risk for a number of diseases.

Key takeaways

Tight junctions are critical for maintaining a healthy GI tract and preventing systemic inflammation that can contribute to chronic diseases such as IBD or celiac disease and acute, life-threatening conditions such as sepsis. TJs are our first line of defense between our GI tracts and the outside environment, which is full of potentially harmful molecules — including bacteria, viruses and toxic substances. Scientists are still hard at work trying to unravel the myriad factors that can impact TJs, how dysfunctional ones contribute to disease, and how we can strengthen our own TJs. Many doctors are resorting to dietary interventions based on numerous cell culture and animal models, but results have yet to be replicated clinically. Nevertheless, there are numerous benefits that can be gained from following plant-based diets rich in compounds that may increase the health of tight junctions. We recommend following a diet rich in whole, colorful foods to increase and support your overall health and well-being and reduce your risk for chronic disease.

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