Gut Dysbiosis, Increased Permeability, and the Development of Autoimmune Conditions

The human body contains many protective barriers, including those in the gut, airways, skin, oral cavity, vagina, and placenta. Here, we focus on the barrier within the gut. Under ideal digestive conditions, only small, fully broken‑down nutrients should enter the bloodstream. This process is disrupted when intestinal permeability increases, often referred to as ‘leaky gut.’

Stop Wasting Money on Probiotics. Here’s What Actually Improves Gut Health (YouTube link)

Bricks and Mortar Model

The gastrointestinal tract covers roughly 300–400 sq. m., with only a single epithelial layer separating the body from large amounts of dietary and microbial antigens.^[25]

These epithelial cells are connected by a “brick‑and‑mortar” system known as tight junctions.^[14,23] In this model:

• Bricks: intestinal epithelial cells
• Mortar: the tight junctions that seal the spaces between them

Researchers at the University of Maryland School of Medicine and Harvard Medical School identified zonulin as a molecule that can disrupt this “mortar.” ^[1,9]

• Zonulin is a human analogue of the Vibrio cholerae zonula occludens toxin.
• It can trigger tight junction disassembly and increase intestinal permeability in non‑human primate epithelium.
• Zonulin levels rise during the acute phase of celiac disease, when tight junctions open and permeability increases.

Figure 1.  Prevention of gut-barrier dysfunction in arthritis ameliorates joint inflammation^[30]

Leaky Gut 

The lining of the intestines is a delicate environment essential to overall health. A protective mucus layer sits on top of the epithelial cells and forms an important part of this barrier.^[13] Its role is to regulate what passes between the intestinal lumen and the rest of the body. Working together with immune cells in the gut, this barrier helps determine how the immune system responds to foreign substances. When the barrier becomes weakened or compromised, the condition is often referred to as “leaky gut.”

Video 1.  Gut Dysbiosis - Starving Our Microbial Self (YouTube link)

Increased Intestinal Permeability and Its Association with Autoimmune Diseases

Recent studies indicate that increased intestinal permeability (often called 'leaky gut') is commonly observed in many individuals with autoimmune diseases, though prevalence varies by condition and is not universal.^[32-37]

Increased intestinal permeability can allow luminal contents (such as undigested food particles, bacterial components, or antigens) to cross the gut barrier more readily, potentially exposing the underlying immune system to these substances. In susceptible individuals, prolonged exposure may contribute to immune dysregulation and heightened risk for autoimmune conditions, though this is often part of a complex interplay involving genetics, dysbiosis (gut microbiota changes), and inflammation.

In cases of compromised intestinal barrier function, partially digested food particles, bacterial antigens, or other luminal substances may translocate across the epithelium into gut-associated lymphoid tissue and, in some instances, the systemic circulation. This can activate immune responses, including proliferation of T helper cells that promote effector responses (e.g., cytotoxic T cells and antibody production) against perceived threats. If regulatory T cells fail to adequately suppress or balance this activation, it may contribute to inappropriate immune responses, chronic inflammation, and—in genetically predisposed individuals—autoimmunity

Symptoms Linked to Gut Dysbiosis and Increased Intestinal Permeability

Gut dysbiosis and increased permeability are associated with both digestive and systemic symptoms, often through chronic low-grade inflammation and immune activation.

Common digestive symptoms include:

• Bloating, gas, constipation, diarrhea, or abdominal discomfort after meals.

Many people have few or no gut symptoms and instead experience systemic effects, such as:

• Swelling in hands/feet after eating
• Morning muscle stiffness
• Brain fog, poor concentration, or fatigue
• Headaches
• Anxiety, irritability, or mood changes
• Allergies, skin rashes, or food sensitivities
• Frequent infections or weakened immunity

These arise when luminal contents (e.g., bacterial fragments, food particles) cross a compromised gut barrier, triggering inflammation and immune dysregulation. In genetically susceptible individuals, this may contribute to autoimmune disease progression (e.g., RA, T1D, SLE, MS), though symptoms vary widely and are not universal. Identifying specific triggers can be difficult due to overlapping or delayed reactions.

Factors Contributing to Gut Dysbiosis and Increased Intestinal Permeability

Gut dysbiosis and increased permeability often result from factors that damage the epithelial barrier or shift the microbiome, potentially leading to antigen translocation, inflammation, and immune dysregulation in autoimmune-prone individuals.

Key contributors include:

• Dysbiosis from pathogens (e.g., Candida, parasites, harmful bacteria) or exposures like glyphosate (linked in some studies to celiac-like patterns, though debated).^[20]
• Pathogenic enzymes that degrade tight junctions.
• Chronic/severe stress, acute trauma (e.g., surgery, food poisoning), or unresolved infections.
• Alcohol overuse.
• Medications: antibiotics, NSAIDs (e.g., ibuprofen), chemotherapy.
• Viral infections or chronic toxins.
• Vitamin D deficiency, which weakens mucosal integrity and raises IBD risk.^[23]

These can trigger or worsen food sensitivities, even in adulthood, as increased permeability allows dietary antigens to reach the immune system more easily, potentially contributing to sensitization and ongoing inflammation in autoimmune contexts.

Symptoms and effects vary widely; professional assessment is advised for individual cases.

Conclusion

A resilient gut barrier is the cornerstone of immune balance. When dysbiosis and "leaky gut" trigger chronic inflammation and autoimmunity, a food-first approach offers a powerful remedy.

As advocated by Dr. Will Bulsiewicz, you can restore your gut ecosystem by prioritizing:

• Diversity: Aim for 30+ different plant foods weekly to maximize prebiotic fiber
• Fermentation: Incorporate kimchi, kefir, or sauerkraut to introduce beneficial microbes.

These habits foster the production of anti-inflammatory compounds like butyrate, repairing the barrier more effectively than most supplements. By centering your diet on diverse, whole plants, you can calm your immune system and build lasting resilience from the inside out.

References

1. A. Fasano. Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol 2012 Feb; 42(1):71-78.
2. The Immune System Recovery Plan by Susan Blum, M.D. M.P.H.
3. Linda Chia-Hui Yu et al. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J Gastrointest Pathophysiol 2012 Feb 15; 3(1):27-43.
4. Katherine R. Groschwitz and Simon P. Hogan. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009; 124:3-20.
5. Leaky Gut (Core One Health)
6. Fasano A, Not T., Wang W. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet. 2000;355:1518–1519.
7. David Seaman: Inflammation From Our Diet Is Killing Us Slowly
8. Body mass index and musculoskeletal pain: is there a connection?
9. New Research Shows Poorly Understood “Leaky Gut Syndrome” Is Real, May Be the Cause of Several Diseases
• In the 1980s, the UCLA researchers found that leaky gut preceded inflammation, implying that the leakiness plays a key role in Crohn's disease development.
• Harvard celiac researcher, Alessio Fasano, MD found that our bodies make a protein (with the nifty name, “Zonulin”) that essentially unzips the tight junctions that seal the intestinal lining.
10. Researchers Find Increased Zonulin Levels Among Celiac Disease Patients
11. Dr. M's Seven-X Plan for Digestive Health: Acid Reflux, Ulcers, Hiatal Hernia, Probiotics, Leaky Gut, Gluten-free Gastroparesis, Constipation, Colitis, Irritable Bowel, Gas, Colon Cleanse/Detox & more
12. Ulcerative colitis flare-ups: 5 tips to manage them
• Ulcerative colitis, like its sister condition Crohn's disease, is treated as an autoimmune disease.
13. Mucus is Retained in Cystic Fibrosis Patients’ Cells, Leads to Potentially Deadly Infections
• This is what happens when your mucus malfunctions:
• Cystic fibrosis is that mucus lining the lungs, pancreas and other organs is too sticky, which makes it difficult for the organs to work properly and, in the lungs, attracts bacteria and viruses resulting in chronic infections.
14. Physiology Of The Small Intestine
15. Sarah Ballantyne on The Paleo Approach and the Autoimmune Protocol
• Leaky gut could be influencing the immune response
• Eating to promote intestinal health is the same as eating to support immune health
16. Can you outgrow your allergies?
17. Gut permeability and food allergies
18. The Epithelial Gatekeeper Against Food Allergy (good)
• Intestinal epithelial barriers play a crucial role in the maintenance of gut homeostasis by limiting penetration of luminal bacteria and dietary allergens, yet allowing antigen sampling via the follicle-associated epithelium for generation of tolerance.
19. Early Studies Linking Gut Bacteria to Atherosclerosis, Offer Tantalizing Glimpse at New Drug Target
20. Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance (31 citations)
21. Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota
22. Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease
23. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier
24. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005 Mar 25;307(5717):1920-5.
• The Gut Epithelial Barrier – The primary cellular barrier of the bug in preventing antigens encountering the immune system is the single layer of gut epithelium
25. D M Saulnier, S Kolida, G R Gibson. Microbiology of the human intestinal tract and approaches for its dietary modulation. Curr Pharm Des. 2009;15(13):1403-14.
26. Broccoli improved digestive issues similar to symptoms of leaky gut and colitis in animals
• Same for other vegetables, like brussels sprouts and cauliflower 
27. Gut microbes could help trigger multiple sclerosis
28. Putting a stop to leaky gut (Harvard Medical School)
29. The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics
30. Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease
31. Extra Virgin Olive Oil Reduces Gut Permeability and Metabolic Endotoxemia in Diabetic Patients
• Addition of Extra virgin olive oil to a Mediterranean diet or chocolate improves gut permeability and low-grade endotoxemia.
32. Christovich, A., & Luo, X. M. (2022). Gut microbiota, leaky gut, and autoimmune diseases. Frontiers in Immunology, 13, Article 946248. 
33. Mu, Q., Kirby, J., Reilly, C. M., & Luo, X. M. (2017). Leaky gut as a danger signal for autoimmune diseases. Frontiers in Immunology, 8, Article 598.
34. Kharrazian, D., Herbert, M., Lambert, J., & Vojdani, A. (2023). The relationships between intestinal permeability and target antibodies for a spectrum of autoimmune diseases. International Journal of Molecular Sciences, 24(22), Article 16352. 
35. Vineesh, A., et al. (2025). Exploring the relationship between gut health and autoimmune diseases: A systematic review and meta-analysis. Cureus, 17(8), Article e89300. 
36. Kinashi, Y., & Hase, K. (2021). Partners in leaky gut syndrome: Intestinal dysbiosis and autoimmunity. Frontiers in Immunology, 12, Article 673708. 
37. Tomov, D. G., Levterova, B. A., Mihailova, V. N., Troev, D. M., Miteva, M. Z., Uzunova, Y. I., & Orbetzova, M. M. (2024). Influence of the increase in intestinal permeability and microbiota change in the development of Hashimoto's thyroiditis - Systematic review. Endocrine and Metabolic Science, 16(Suppl. C), Article 100195. 
• This 2024 review strengthens evidence for a gut–thyroid link, suggesting that dysbiosis and increased intestinal permeability may fuel inflammation and autoimmunity in Hashimoto’s. Lifestyle measures such as diet and probiotics appear promising adjuncts, though more clinical trials are still needed.