Intestinal Permeability and Disease

Increased intestinal permeability is the gateway to autoimmune diseases. It has become well-known that intestinal permeability is the third element leading to autoimmune pathogenesis along with genetic factors and environmental triggers.

Table of Contents Toggle Environmental triggers that lead to autoimmune disease.

Infection

Toxic molecules

Allergenic foods (or diet, for example, wheat.)

Nevertheless, these factors interplay with the neuroendocrine network, gut-associated lymphoid tissue, intestinal barrier, and eventually, the integrity of tight junctions between the epithelial cells. Eventually, the correct function of these factors will control and promote a balanced immune response.

Did you know most common chronic diseases are associated with an autoimmune response? Chronic inflammatory diseases like diabetes mellitus type II, inflammatory bowel disease, multiple sclerosis, gestational diabetes, and hyperlipidemia, to name a few. Therefore, if we are going to deal with autoimmune diseases, then why not treat the predecessor of this mechanism? Treat the gut, improve intestinal permeability = healthy patient.

Why treat the gut if the patient came in with a metabolic disease? The intestinal barrier has a crucial function; it regulates macromolecules’ traffic from food to protect the host. Inflammation is the first stage of every disease, and increased intestinal permeability is liked to higher measurements of inflammation markers.

What happens in the gut never stays in the gut…

Learn more on how inflammation, gut permeability, and an exaggerated immune response can lead to disease.

There are 2 possible ways that macromolecules are entering our bloodstream:

1.- Paracellular entry: between out epithelial cells, we have something called tight junctions. Actually, the name says it all; the tight junctions are involved in holding together our epithelial cells with the help of proteins like claudin and occludin. These proteins are a band-like structure that allows a narrow space between each cell and controls molecules’ passage.

Hence, when an environmental injury breaks these bands, large molecules pass between the epithelial cells and enter the submucosa.

2.- Transcellular entry: This happens when the antigen passes through the epithelial cell, rupturing it, and then enters the submucosa.

How gut permeability leads to autoimmunity and disease:

1.     Environmental triggers.

2.     Breakdown in oral tolerance.

3.     Change in gut microbiota.

4.     Enhanced gut permeability.

5.     Large macromolecules pass through the compromised gut barrier.

6.     Immune reactivity.

7.     Autoimmunity.

 

Newest breakthrough: Zonulin

Did you know that gliadin, a protein found in gluten-containing grains, upregulates zonulin?

What is zonulin? Is a newly recognized intestinal peptide that is associated with tight junction regulation. It is found to be responsible for the gut permeability found in celiac disease patients. In recent studies, zonulin has been used as a marker for intestinal permeability.

Zonulin, along with proinflammatory molecules like TNF-a and INF-y, promote the upregulation of lipid draft, which consists of a pathogen carried by lipid and crossing the intestinal barrier in a transcellular way. Nevertheless, new studies have shown that paracellular entry always precedes the transcellular pathway. This means that whenever our inflammation markers increase and zonulin signaling is activated, the potential of an autoimmune response grows higher. Also, research shows that zonulin can be upregulated regardless of the genetic expression of autoimmunity.

Paracellular entry always precedes the transcellular pathway.

We have to consider the size of the molecule that is crossing the epithelial barrier. For example, if a patient has good intestinal permeability, only small molecules will cross the epithelial barrier. Smaller molecules do not cause an immune response. On the other hand, when microvilli get compromised, tight junctions are open, and actin filaments are diminished. Large molecules like gluten peptides and lipopolysaccharides can easily enter the submucosa, inevitably cause an immune reaction.

 

Gut permeability:

1.     Antigens delivered through an easy access permeable lining.

2.     Activation on the innate immune response.

§  IFN-y

§  TNF-a

§  Il-1B

3.     Antibody production that affects barrier permeability.

4.     Transcellular and paracellular translocation via intestinal permeability.

5.     Dysregulated immune response.

6.     Autoimmune mechanism initiated.

In conclusion, we must treat intestinal permeability. Despite the patient’s genetic predisposition, the environmental triggers and gut permeability are the main factors that we can change to control an exacerbated immune response. Also, autoimmune diseases can affect every tissue in our body, indicating that what happens in the gut spreads through our body.

Drago, Sandro, et al. “Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines.” Scandinavian journal of gastroenterology 41.4 (2006): 408-419.

Fasano, Alessio. “All disease begins in the (leaky) gut: Role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases.” F1000Research 9 (2020).

Vibrant Educational Series. 2018. Intestinal Permeability. [Video] www.youtube.com/watch?v=VYIj5PE_F0o

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