Leaky gut has become a buzzword over the past few years, so much so that most gastroenterologists scoff when the word is uttered. Many blogs are released by mainstream sources attempting to debunk the “myth” of having a leaky gut. Many research studies prove that leaky gut is a real medical condition known as inappropriately increased gut permeability. Our intestinal junctions are quite tight when they are healthy and, when signaled, only open to our bloodstream what our body needs to thrive. For example, we adsorb through our intestinal lining nutrients, water, supplements, and medications. However, suppose our intestinal junctions open more extensive or more frequently than they should (inappropriately increased gut permeability). In that case, other things might enter our bloodstream, making us ill, including microorganisms, toxins, and toxicants. So, what is leaky gut, what are its causes, and what might be done to make your gut lining bulletproof hopefully?

What is Leaky Gut?

The innermost layer of the digestive tract is your mucosa layer, and it is what encounters whatever you swallow. The mucosa layer surrounds the open space within your “digestive tube” known as the lumen. Your mucosa layer is produced from an oligomeric mucus gel-forming glycoprotein known as mucin two by our goblet cells, encoded by the MUC2 gene; the intestinal mucosa layer is comprised of an outer layer and an inner layer of mucus. The unattached outer layer of mucus is where most of your intestinal microbiome resides when you are healthy. When your intestinal tract is healthy, microorganisms should not penetrate the mucus’s inner layer (which is renewed every hour) and enter your intestinal epithelial layer. If intestinal mucus production is hindered, gastrointestinal inflammation, dysbiosis, and infection can occur. 1

Your intestinal mucosa layer also contains the lamina propria, an unusually cellular layer of connective tissue, and muscularis mucosae, a thin layer of smooth muscle that helps maintain intestinal peristalsis. Within the mucosa layer of your intestinal tract is a single layer of columnar epithelial cells, meaning the thin layer of cells making up the intestinal epithelium is longer than they are wider. At least seven known types of intestinal epithelial cells include enterocytes, goblet cells, Paneth cells (colon crypts do not contain these cells), microfold cells, enteroendocrine cells, and cups cells, and tuft cells. Enterocytes are most of the cells that comprise the intestinal epithelium and are absorptive cells that facilitate nutrient uptake. The enterocytes within the small intestine produce the enzymes peptidase, sucrase, maltase, lactase, lipase. These enzymes help us digest and assimilate our food.2 3 4

Your intestinal epithelium also contains many immune cells, including dendritic cells, T cells, B cells, and macrophages, which with a healthy microbiome, help maintain intestinal homeostasis. The intestinal microbiome is also a crucial component of your mucosa layer, living on your intestinal mucus’s outer layer. Your microbiome helps to further breakdown nutrients for absorption by our enterocytes. Our microbiome also produces short-chain fatty acids, including butyrate from our food’s fermentation, to fuel intestinal cells. These include colonocytes (enterocytes found in the colon).5 6

Villi are small, finger-like projections that extend into the lumen from our intestinal epithelium. Villi increase the surface area of the intestinal walls allowing for more absorption of nutrients. Microvilli (brush border) are very similar to villi, and they cover the intestinal singular columnar epithelial layer (mainly enterocytes). Microvilli-like villi contain enterocytes that produce enzymes that facilitate absorption of nutrients (for example, the microvilli are the final location of intestinal carbohydrate digestion and absorption) into our bloodstream. Intestinal crypts are found between intestinal villi and stem cells produced in the gastrointestinal tract to mature and form new epithelium. Intestinal crypts also secrete intestinal juice, which aids in proper digestion and contains enterocytes to help absorb nutrients.7 8 9

The epithelial layer of cells that comprise the intestinal mucosa layer are joined together by tight junctions (zonula occludens), which form an impermeable membrane unless they are either signaled to open or are unhealthy. The integrity of your tight junctions is controlled by the arrangement of epithelial actin (a family of proteins that form contractile filaments of muscle cells) controlled by integral transmembrane proteins and other proteins, including zonulin. A few of the integral transmembrane proteins include occludin, claudin, and the junction adhesion molecule. Occludin has a looped structure that holds together the extracellular and intracellular space of cells, enhancing tight junction stability and function. Occludin also oxidizes reduced nicotinamide adenine dinucleotide, which influences glucose uptake, mitochondrial adenosine triphosphate production, and gene expression. Claudin also contains a looped structure and establishes a paracellular barrier that controls molecules’ flow within the intercellular space epithelial cells. Claudin is known as “the backbone” of the tight junctions and grants the tight junction’s ability to seal the paracellular space between cells. The junction adhesion molecule (JAM) structure differs from the other integral membrane proteins in that they only have one transmembrane protein instead of four. JAM regulates the paracellular pathway function of the tight junctions and helps maintain the polarity of cells.10 11 12 13 14 15

Zonulin (prehaptoglobin-2 is human-produced zonulin, produced within our liver and intestinal cells) is a protein that helps regulate the movement of water, large molecules, and immune cells between epithelial junctions by decoupling integral transmembrane proteins of the tight junctions. Zonulin needs to be tightly regulated by our body. If too much is released by our cells or is ingested, inappropriately increased gut permeability occurs. Zonulin was discovered as an enterotoxin produced by the Gram-negative Proteobacteria Vibrio cholerae known as the zonula occludends toxin (ZOT). The zonula occludends toxin opens the intestinal epithelial junctions. The junctions become “leaky” and allow too much water and electrolytes to enter the gastrointestinal tract (possibly to prevent Vibrio cholerae from adhering to the outer mucosal layer and becoming part of your microbiome by flushing it out of the intestinal tract). This then causes severe diarrhea, which is seen in the medical condition cholera. A person usually develops cholera when they ingest enough Vibro cholerae contaminated food or water where either the bacteria colonize their intestinal tract and produces ZOT. The contaminated food or water contains ZOT, which makes them ill.16 17 18 19

The Numerous Causes of “Leaky Gut” (Increased Gut Permeability)

There are many known causes of “leaky gut” which include:

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3758667/
  2. http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/bbenzymes.html
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311762/#:~:text=Adjacent%20intestinal%20epithelia%20form%20tight,water%20across%20the%20intestinal%20epithelium
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  6. https://www.cell.com/trends/immunology/pdf/S1471-4906(18)30068-1.pdf
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040026/
  8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965634/
  9. https://www.slideshare.net/nileshkate79/intestinal-glands-and-secretions
  10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311762/#:~:text=Adjacent%20intestinal%20epithelia%20form%20tight,water%20across%20the%20intestinal%20epithelium
  11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255790/
  12. http://pdfs.semanticscholar.org/f6ec/d2ba531c4913d68485748ac650a510cb45e1.pdf
  13. https://journals.physiology.org/doi/full/10.1152/physrev.00004.2017
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311762/
  15. https://pubmed.ncbi.nlm.nih.gov/32224152/
  16. https://www.pnas.org/content/106/39/16799
  17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943850/
  18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570116/
  19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384703/
  20. https://pubmed.ncbi.nlm.nih.gov/28504710/
  21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
  22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581431/
  23. https://www.frontiersin.org/articles/10.3389/fcimb.2019.00099/full
  24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513683/
  25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
  27. https://www.nature.com/articles/s41380-020-0778-5
  28. https://pubmed.ncbi.nlm.nih.gov/16000642/
  29. https://pubmed.ncbi.nlm.nih.gov/16000642/
  30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
  32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
  34. https://www.researchgate.net/publication/51722940_H2_blockers_decrease_gut_mucus_production_and_lead_to_barrier_dysfunction_in_vitro
  35. https://www.sciencedirect.com/science/article/abs/pii/S0048969720339516
  36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/’
  37. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440529/
  38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790068/
  39. https://pubmed.ncbi.nlm.nih.gov/9482766/