Intestinal barrier function

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Intestinal Barrier - The Gut's Gatekeepers

  • Function: Regulates passage of luminal contents (nutrients, microbes) into circulation. A selective, semi-permeable barrier.

  • Components & Layers of Defense:

    • Physical Barrier: Epithelial cells linked by tight junctions (TJs).
      • TJ Proteins: Claudins, Occludins, & Zonulin-1 (ZO-1) form the seal. 📌 Mnemonic: Come On, Zip-it!
      • Mucus Layer: Produced by goblet cells; traps debris & bacteria.
    • Chemical Barrier: Secretions that neutralize threats.
      • Antimicrobial Peptides (AMPs): Defensins & lysozyme from Paneth cells.
      • Secretory IgA (sIgA): Binds and neutralizes luminal antigens and pathogens.
    • Immunological Barrier: Gut-Associated Lymphoid Tissue (GALT).
      • Peyer's patches, intraepithelial lymphocytes (IELs).

Intestinal barrier: epithelium, junctions, immune cells

Exam Favorite: Increased intestinal permeability ("leaky gut") is linked to elevated levels of zonulin, a protein that reversibly opens tight junctions. This is implicated in autoimmune and inflammatory disorders like Celiac disease and IBD.

Barrier Regulation - Opening the Floodgates

  • Zonulin: The primary physiological modulator of intestinal permeability, acting as a gatekeeper for tight junctions (TJs).
    • Triggers for release include gliadin (from gluten) and bacterial dysbiosis.
  • Mechanism of Increased Permeability:
    • Inflammatory signals (e.g., TNF-α, IFN-γ) or zonulin upregulate Myosin Light Chain Kinase (MLCK).
    • MLCK activation phosphorylates myosin, causing contraction of the perijunctional actin ring.
    • This contraction pulls TJ proteins (claudins, occludin) apart, opening the paracellular pathway.

⭐ Elevated zonulin levels are strongly associated with celiac disease and other autoimmune disorders, serving as a biomarker for compromised barrier function ("leaky gut").

Intestinal Barrier Pathways

Barrier Dysfunction - When the Walls Fall

  • Pathogenesis: Compromise of tight junctions (zonula occludens) & epithelial integrity, leading to ↑ intestinal permeability ("leaky gut").
  • Triggers:
    • Infections: Viral (Norovirus), bacterial (Salmonella, C. difficile).
    • Inflammation: IBD (Crohn's, UC), celiac disease.
    • Ischemia: Shock, sepsis, major trauma/burns.
    • Toxins/Drugs: Alcohol, NSAIDs.
  • Consequences:
    • Translocation of luminal antigens (e.g., LPS) into circulation.
    • Triggers systemic inflammatory response (↑ TNF-α, IL-1, IL-6).
    • Can precipitate Systemic Inflammatory Response Syndrome (SIRS) & Multi-Organ Dysfunction Syndrome (MODS).

Intestinal Barrier: Transcellular vs. Paracellular Pathways

Zonulin, a protein that modulates tight junction permeability, is a key regulator. Its upregulation, triggered by gliadin and bacteria, is implicated in celiac disease and other autoimmune disorders.

High‑Yield Points - ⚡ Biggest Takeaways

  • The intestinal barrier relies on tight junctions (claudins, occludins), a mucus layer, and secretory IgA (sIgA).
  • Barrier dysfunction, or "leaky gut," is a key factor in celiac disease and inflammatory bowel disease (IBD).
  • Zonulin is a key physiological modulator of intestinal permeability, often upregulated in autoimmune conditions.
  • Paneth cells provide innate immunity by secreting antimicrobial peptides (e.g., defensins).
  • Goblet cells produce mucus, forming a protective physical and chemical shield.

Practice Questions: Intestinal barrier function

Test your understanding with these related questions

A 24-year-old woman comes to the physician because of progressively worsening episodes of severe, crampy abdominal pain and nonbloody diarrhea for the past 3 years. Examination of the abdomen shows mild distension and generalized tenderness. There is a fistula draining stool in the perianal region. Immunohistochemistry shows dysfunction of the nucleotide oligomerization binding domain 2 (NOD2) protein. This dysfunction most likely causes overactivity of which of the following immunological proteins in this patient?

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Flashcards: Intestinal barrier function

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Motilin is secreted from the small intestine during _____ states (fed or fasting)

TAP TO REVEAL ANSWER

Motilin is secreted from the small intestine during _____ states (fed or fasting)

fasting

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