Epithelial Permeability: Causes and Strategies to Minimize It

Epithelial Barrier Integrity, the Central Role of Peptidoglycan (PGN) and potential role in two thirds of non-injury deaths in the United States for people under 80

Epithelial tissues—including the intestinal lining, oral mucosa, and skin—form the body’s primary physical and immunological barriers. These surfaces are continuously exposed to dense microbial ecosystems whose cell wall components interact with host immune pathways. Among all pathogen-associated molecular patterns (PAMPs), peptidoglycan (PGN) stands out as the most universal: it is found in every bacterium, both Gram-positive and Gram-negative, and fragments of PGN are constantly released during bacterial growth, division, shedding, and death. Because epithelial barriers are not completely sealed systems, PGN is a persistent biological signal capable of crossing into subepithelial tissues when barrier integrity is compromised. Its interaction with innate immune receptors—especially TLR2, NOD1, and NOD2—can drive sustained inflammation and contribute to multi-system disease.

Intestinal Permeability and PGN Translocation

The gastrointestinal tract contains the largest microbial biomass in the body, making it the primary source of circulating PGN. Under healthy conditions, tight junctions and mucus restrict PGN fragments from entering the bloodstream. However, intestinal permeability increases when:

  • Dysbiosis reduces production of barrier-supporting metabolites like butyrate.

  • Inflammation activates TLR2/NOD pathways, which disrupt tight junction proteins and epithelial turnover.

  • Dietary stressors—ultra-processed foods, emulsifiers, alcohol, low fiber—damage the mucus layer and epithelial cells.

  • Stress, infections, NSAIDs, and metabolic disease further weaken epithelial cohesion.

Because bacteria continuously shed PGN fragments, even subtle increases in permeability can create a chronic low-grade influx of PGN into circulation. This persistent exposure may drive systemic inflammation, insulin resistance, neuroimmune activation, and other chronic disease pathways.

PGN Exposure from the Oral Cavity

The oral microbiome is another major source of PGN due to constant bacterial turnover on teeth, gingiva, and the tongue. Periodontal inflammation, smoking, alcohol use, high-sugar diets, and poor hygiene widen intercellular spaces and weaken epithelial barriers, allowing PGN fragments to enter gingival tissue and the bloodstream.

Notably, PGN from oral bacteria has been linked to:

  • Cardiovascular inflammation

  • Neuroinflammation and microglial activation

  • Worsening metabolic diseases

  • Exacerbation of autoimmune conditions

The oral cavity can therefore act as a significant “portal of entry” for PGN into systemic circulation, especially in individuals with chronic gum disease.

Skin Barrier Permeability and PGN

Although the skin is a robust barrier, its microbiome also produces continuous PGN shedding. When the stratum corneum or lipid matrix is disrupted—by detergents, UV exposure, low humidity, eczema, stress, infection, or microbiome imbalance—PGN can penetrate deeper layers and activate TLR2 on keratinocytes and resident immune cells.

This contributes to chronic skin inflammation seen in conditions like:

  • Atopic dermatitis

  • Psoriasis

  • Rosacea

  • Chronic wound inflammation

Damaged skin barriers may also elevate systemic PGN load, adding to overall inflammatory burden.

Strategies to Minimize PGN-Mediated Barrier Stress

1. Strengthen the Gut Barrier

  • Prioritize fiber, resistant starch, and prebiotics to promote butyrate production and tighten epithelial junctions.

  • Reduce processed foods, emulsifiers, sugar, and alcohol.

  • Use probiotics that reinforce barrier function and beneficial microbial balance.

  • Consider L-glutamine, zinc-carnosine, vitamin D, and polyphenols to support epithelial repair.

2. Reduce Oral PGN Entry

  • Maintain meticulous oral hygiene (brushing, flossing, tongue cleaning).

  • Treat periodontal inflammation promptly.

  • Avoid smoking and excessive alcohol, which increase epithelial permeability.

  • Support a balanced oral microbiome by minimizing overuse of antiseptic mouthwashes.

3. Support Skin Barrier Integrity

  • Protect against UV damage, avoid harsh detergents, and use moisturizers that restore lipid layers.

  • Address eczema or dermatitis early to prevent PGN infiltration.

  • Minimize exposure to environmental irritants and pollutants.

4. Reduce Systemic Inflammation

  • Omega-3 fatty acids, curcumin, and other anti-inflammatory compounds modulate TLR2/NOD signaling.

  • Manage stress, improve sleep, and engage in moderate exercise.

5. Develop new pharmaceutical agents to clear translocated PGN

  • High Dose IgM for acute infection

  • Low Dose Extended Half-life IgG for chronic removal