Understanding Leaky Gut and Autoimmunity: The Zonulin Connection

Short Summary (if you don't want to read the whole thing)

But we really encourage you to read the full article below - understanding how your gut works is crucial for long-term health. Our role is to help you understand it.

To understand what's coming next, you need to understand that your gastrointestinal tract (GIT) is a long tube starting in your mouth and ending at your anus. This tube actually separates your body from the outer world. Whatever enters this tube stays there unless your body deliberately decides what to let in and what to keep out. When you digest food that's good for you, your body opens specialised gates to let those beneficial particles in whilst keeping others out.

A healthy body, if you eat something harmful (or if bacteria get in), will keep its internal gates on this tube locked and will force that object, creature, or molecule to exit as soon as possible from the other end.

And here we touch on a main problem. A healthy body will do that. But an unhealthy body, or a body that's being forced to unlock the gates, must surrender.

Your gut barrier is like a sophisticated security system. Dr Alessio Fasano and his team identified a compound named 'zonulin' and characterised its crucial role in intestinal permeability - also know as 'leaky gut' (a breach in your security gates system). When this system malfunctions, it can lead to various autoimmune conditions. Here's why this matters for your health::

• Your gut has a complex security system (tight junctions)

• Zonulin can create "holes" in this barrier

• Common triggers include gluten, stress, and certain toxins

• When the barrier is open, different unwanted molecules can enter your body and trigger the immune response (LPS, bacteria, and even undigested food particles).

• This process is linked to multiple autoimmune diseases, where your immune cells attack your own body (see also a blogpost on molecular mimicry)

• Understanding this helps develop effective treatments

The Full Story

The Gut Barrier: Your Sophisticated Security System

Your intestinal wall is lined with a single layer of cells connected by tight junctions - microscopic "security gates" between cells. Think of it as an intelligent border control system:

• Tight junctions are protein complexes located at the very top (apical) side of intestinal cells

• They form a selective barrier controlling what passes between cells (through a kind of sophisticated gates)

• In healthy conditions, they allow nutrients through while blocking harmful substances

• When compromised, this security system fails, allowing unwanted substances to enter

Understanding Gluten and Its Impact

Gluten is a protein found in several grains:

• Wheat (including varieties like spelt, kamut, farro)

• Rye

• Barley

• Most oats (due to cross-contamination)

Common sources include:

• Bread, pasta, cereals

• Processed foods

• Sauces and condiments

• Many prepared meals

• Beer and some alcoholic beverages

When consumed, gluten breaks down into tiny molecules called glutenins and gliadins, with the latter one triggering zonulin release within 30-60 minutes, loosening tight junctions in EVERYONE, not just those with coeliac disease.

Other Triggers That Compromise Your Gut Barrier

1. Medications:

• NSAIDs (ibuprofen, aspirin)

• Antibiotics

• Chemotherapy drugs

• Antacids and proton pump inhibitors

• Some antidepressants

2. Food Additives:

• Emulsifiers (carboxymethylcellulose, polysorbate-80, etc)

• Artificial sweeteners

• Microbial transglutaminase ("meat glue")

• Nanoparticles in food packaging

• Synthetic food dyes (colours in your beautiful sweets)

3. Other Factors:

• Chronic stress (increases cortisol, directly impacts barrier function - see blogpost on cortisol and visceral fat)

• Environmental toxins

• EMF exposure

• Sleep disruption (yes!)

• Excessive exercise

Chromosome 16: The Genetic Connection

Chromosome 16 plays a crucial role in your immune system functioning, containing genes that control immune responses, including the HP gene that produces zonulin. While this helps us understand potential health risks, your genes aren't your destiny.

Through epigenetics - how your lifestyle and environment influence gene expression - you can significantly impact your health outcomes despite genetic predispositions. Diet, stress, physical activity, sleep, and toxin exposure all affect whether genetic risks become real health issues.

Remember, as someone smart said: Your genes might load the gun, but your lifestyle choices and environment pull the trigger.

Chromosome 16 is particularly important because multiple  conditions are linked to this chromosome:

• Autoimmune

  • Adult Polycystic kidney disease

  • IBD (NOD2 Locus)

  • SLE

  • T1DM

  • Rheumatoid arthritis

• Cancers

  • Acute nonlymphocytic leukaemia

  • Breast cancer

  • Fanconi's anaemia

  • Myeloid Leukaemia

  • Prostate cancers

• In the Nervous System

  • Batten's disease

  • Lou Gerhig's

  • Multiple Sclerosis

  • Autism

Understanding Autoimmune Diseases

Autoimmune diseases occur when your immune system attacks healthy cells. Think of it as your body's defence system misidentifying "friend" as "foe." Common characteristics:

• Body attacks its own tissues

• Often runs in families

• Can affect multiple organs

• Usually chronic conditions

• Often triggered by environmental factors

Common Autoimmune Conditions

1. Coeliac Disease

Characteristics:

• Strong immune reaction to gluten

• Requires HLA DQ2/DQ8 genes

• Damage to intestinal villi with symptoms including:

  • Digestive issues

  • Fatigue

  • Nutrient deficiencies

  • Skin problems

  • Neurological symptoms

  • Joint pain

2. Type 1 and Type 2 Diabetes

• Type 1: Autoimmune attack on pancreatic cells

• Type 2: While not traditionally considered autoimmune, shows inflammatory and autoimmune components

• Both types show increased intestinal permeability

The Role of Nutrition: "All Disease Begins in the Gut" - Hippocrates

This ancient wisdom has found strong support in modern science of autoimmunity. Your gut, often called your "second brain," houses over 70% of your immune system and produces most of your body's neurotransmitters (yes, more than the brain!)

As you've learned so far, when gut health is compromised, it can trigger a cascade of problems throughout your body. Poor nutrition doesn't just mean inadequate vitamins and minerals - it can disrupt your gut barrier, alter your microbiome, and trigger systemic inflammation. This inflammation then becomes the root cause of many chronic diseases, from autoimmune conditions to mental health issues.

Research shows that dietary choices directly impact gut barrier function, immune system regulation, and even gene expression. By prioritising gut health through proper nutrition, we can often address health issues at their source rather than just managing symptoms.

( 1) Under physiological circumstances there is a tightly control of mucosal antigen trafficking (antigen sampling) that, in concert with specific immune cells and chemokine and cytokine mediators lead to anergy and therefore to mucosal tolerance. ( 2) Gut dysbiosis causes inappropriate production of increased amount of zonulin with subsequent functional loss of gut barrier function, followed by microbiota-derived antigen and endotoxin trafficking from the lumen to the lamina propria triggering innate and immunoregulatory responses causing a pro-inflammatory micromilieu. ( 3) If this process continues, an adaptive immune response is mounted, causing production of pro-inflammatory cytokines, including interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) that cause further opening of the paracellular pathway to the passage of antigens, creating a vicious cycle. ( 4) Ultimately, these processes lead to break of tolerance with subsequent onset of chronic inflammatory disease whose nature is influenced by the specific host genetic background that dictates which organ or tissue will be targeted by the inflammatory process. DC, dendritic cell; IL-10, interleukin 10; TGF-β, transforming growth factor beta; Tregs, regulatory T cells. This figure was re-used from Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. Source: doi:10.1080/21688370.2016.1251384 with permissions.

Gut-Healing Nutrients - Example:

1. Essential nutrients:

2. Zinc

3. Glutamine

4. Vitamin D

5. Vitamin A

6. Omega-3 fatty acids

7. Beneficial compounds:

   1. Quercetin

   2. Curcumin

   3. Collagen

   4. Bone broth

   5. N-acetyl glucosamine

Exercise Guidelines

Beneficial:

• Moderate intensity exercise (30-45 minutes)

• Walking

• Swimming

• Yoga

• Light resistance training

Contraindicated:

• Excessive endurance training

• High-intensity training while healing

• Overtraining in any form

• Exercise during acute flares

Comprehensive Treatment Approach

1. Primary Focus: Nutrition

• Remove trigger foods! - STOP EATING GLUTEN NOW!

• Emphasise whole, unprocessed foods

• Avoid added sugar, sweeteners and limit carbohydrates as they feed bad bacteria

• Support gut healing with specific nutrients

• Time meals appropriately

2. Lifestyle Modifications:

• Stress management (crucial) - breathing exercises help significantly

• Sleep optimisation (crucial)

• Appropriate exercise

• Environmental toxin reduction

3. Medical Support:

• Regular monitoring

• Appropriate supplementation

• Professional guidance

• Treatment of underlying conditions

References

• Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A. Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408-419. doi:10.1080/00365520500235334

• Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4(4):e1251384. doi:10.1080/21688370.2016.1251384 

• Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020;9:F1000 Faculty Rev-69. doi:10.12688/f1000research.20510.1

• Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151-175. doi:10.1152/physrev.00003.2008

• Fasano A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012;10(10):1096-1100. doi:10.1016/j.cgh.2012.08.012

• Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. doi:10.1136/gutjnl-2019-318427

• Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut As a Danger Signal for Autoimmune Diseases. Front Immunol. 2017;8:598. doi:10.3389/fimmu.2017.00598

• Sander LE, Lorentz A, Sellge G, et al. Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut. 2021;55(4):498-504. doi:10.1136/gut.2004.061762

  
  

Important Note: While this article presents current scientific understanding of gut health and autoimmunity, each person's situation is unique. At SelfUP and Veek Health, we specialise in creating personalised protocols that consider your individual genetic, environmental, and lifestyle factors. Let us help you develop a targeted approach to optimise your gut health and overall wellbeing.