Intestinal Permeability: Mechanisms and Causes that Lead to Leaky Gut

What causes leaky gut?  What are the mechanisms involved in the development of leaky gut?  Diet, medication, infections, stress, hormonal imbalances, neurologic and metabolic issues and autoimmunity can all promote leaky gut.

This is part 4 of a 5-part series on Intestinal Permeability (Leaky Gut)

Main points of this issue:

  • Mechanisms leading to leaky gut
  • There are multiple factors that contribute to leaky gut
  • Diet can promote leaky gut
  • Medication can promote leaky gut
  • Infections can promote leaky gut
  • Stress can promote leaky gut
  • Hormonal imbalances can promote leaky gut
  • Neurologic issues can promote leaky gut
  • Metabolic issues can promote leaky gut
  • Autoimmunity can promote leaky gut

Mechanisms Leading to Leaky Gut

Think of the cells of your intestinal lining, where absorption of micromolecules takes place, as bricks which sit side by side along the basement membrane. These “bricks” are held together by proteins that form tight junctions, which can be considered the “mortar” between the bricks. Micronutrients are absorbed into the epithelial cells and transported through the cells and basement membrane where they enter the bloodstream. If the mortar starts to break down, you get penetration of foreign molecules through the intestinal barrier which can then enter the bloodstream (hence the term “leaky gut”). These foreign molecules may include undigested food molecules, toxins or bacteria.

These large molecules are reacted against by the underlying intestinal immune system. This reaction then promotes exaggerated immune responsiveness leading to systemic inflammation (inflammation throughout the bloodstream). This creates a vicious cycle of further intestinal inflammation, damage to the intestinal lining, and increased intestinal permeability. This leads to intestinal disorders and autoimmune disease:

“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. When the finely-tuned trafficking of macromolecules is dysregulated in individuals, both intestinal and extraintestinal autoimmune disorders can occur.”1

What are the Causes of Leaky Gut?

  • Diet
  • Medication
  • Infection
  • Stress
  • Hormonal Imbalances
  • Neurologic Issues
  • Metabolic Issues
  • Autoimmunity

Diet Can Promote Leaky Gut

  • Gluten (wheat)
  • Casein (milk)
  • Processed food
  • Excess sugar
  • Fast food
  • Alcohol

The standard American diet (SAD) alone is sufficient to cause leaky gut. If someone is eating transfats, fried foods, deamidated gliadin (from wheat), processed casein (from milk) and other processed foods every single day, they will probably end up with leaky gut. How does food cause inflammation? Food causes an inflammatory response which activates T cells which release cytokines which then activate their joint swelling and inflammation. Alcohol consumption can cause leaky gut. Someone who drinks alcohol and eats the standard American diet is at risk for developing leaky gut.2

Medications Can Promote Leaky Gut

  • Corticosteroids
  • Antibiotics
  • Antacids
  • Xenobiotics

Medications can cause leaky gut, especially prednisone and antibiotics.

Infections Can Promote Leaky Gut

  • H. pylori
  • Bacterial overgrowth
  • Yeast overgrowth
  • Intestinal viruses
  • Parasitic infection

Any type of pathogenic infection can cause leaky gut.

Stress Can Promote Leaky Gut

Stress alone can cause leaky gut. Stress causes increased blood flow to skeletal muscles and decreased blood flow to the gut. You immediately get decreased blood flow to the gut when under stress. We know that stress responses have major influences on leaky gut.

“Increased exposure to life events determines a defective jejunal epithelial response to incoming stimuli. This abnormal response may represent an initial step in the development of prolonged mucosal dysfunction.”3

“Prolonged exposure to stress can induce low-grade inflammation, cause ultra structural epithelial abnormalities, and alter bacterial-host interactions, allowing greater microbial translocation.4”

Hormonal Imbalances Can Promote Leaky Gut

Deficiency of the following hormones leads to leaky gut:

  • Thyroid hormone
  • Estrogen
  • Progesterone
  • Testosterone

Thyroid Hormone and Leaky Gut

“Lack of thyroid hormone stimulation of gastric and intestinal cells leads to ulcerations and intestinal permeability known as “leaky gut syndrome”. Additionally, endoscopic examination of gastric ulcers found low T3, low T4, and abnormal levels of reverse T3 on gastric ulcerative tissues.”5

“Both thyroxine and triiodothyronine have been shown to protect the intestinal mucosal lining from stress-induced intestinal lining injury.”6

Estradiol and Leaky Gut

“Estradiol modulates paracellular permeability and tight junction (TJ) function in the intestinal epithelium.”7

Progesterone and Leaky Gut

“Treatment with progesterone protected intestinal lining macroscopic injury and albumin extravasation.”8

Testosterone and Leaky Gut

We propose that lack of testosterone delays intestinal healing.”9

Neurologic Conditions Can Promote Leaky Gut

Brain integrity is critical in intestinal permeability. 90% of the brain’s output goes into the lower brainstem. When the brain isn’t able to fire into the enteric nervous system, you don’t have gut motility and you don’t have parasympathetic effect. When people have decreased parasympathetic activation, they get leaky gut.

“Traumatic brain injury causes GI dysfunction and increased intestinal permeability. Regulation of the gut barrier may involve the central nervous system.”10

“Traumatic brain injury (TBI) can lead to several physiologic complications, including gastrointestinal dysfunction. Specifically, TBI can induce an increase in intestinal permeability.”11

“At the intestinal level, traumatic brain injury (TBI) induces profound effects, including gastrointestinal mucosa ischemia and motility dysfunction.”12

Metabolic Imbalances Can Promote Leaky Gut

Then you have metabolic issues such as diabetes. Diabetes causes glycosylated-end products which causes leaky gut.

Autoimmunity Leads to Leaky Gut

Most people learn about leaky gut and autoimmunity in the following way: intestinal permeability allows peptides to cross, making the immune system overzealous which then triggers autoimmune expression and increased cytokine activity. In other words, leaky gut leads to autoimmunity. But we now know autoimmunity also leads to leaky gut. Cytokine explosions from autoimmunity activate iNOS which immediately destroys the tight junctions of the intestinal barrier. As the autoimmunity flares up, they will get increased permeability.

Leaky Gut Vicious Cycle

Loss of tight intestinal junctions leads to entry of antigens and peptides and multiple food sensitivities, which leads to intestinal inflammation and promotes further leaky gut.

Content provided by Datis Kharrazian, D.C., Breaking the Complex Web of Leaky Gut Syndrome, 2/10/11

In part 5 of this 5-part series, we answer the following questions:

  • How do we address the treatment of intestinal permeability?
  • Clinical unwinding of leaky gut.
  • Is diet important in the treatment of leaky gut?
  • Vitamin D and Leaky Gut

Continue to part 5 of series

References
1. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9): 416-22

2. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium Alcohol. 2008 Aug 42(5):349-61. Epub 2008 May 27

3. Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation. Gastroenterology. 2008 Jul;135(1):163-172.e1. Epub 2008 Mar 22

4. Pathophysiological mechanisms of stress-induced intestinal damage. Curr Mol Med. 2008 Jun;8(4):274-81

5. The effects of stress on gastric ulceration, T3, T4, reverse T3 and cortisol in neonatal foals. Equine Vet J. 1992; 24(1):37-40

6. The effects of thyroid hormones on stress ulcer formation. Anz J Surg. 2002; 72(9):672-5

7. Estradiol decreases colonic permeability through estrogen receptor beta-mediated up-regulation of occluding and junctional adhesion molecule-A in epithelial cells. J Physiol. 2009 Jul 1;587(Pt 13):3317-28. Epub 2009 May 11

8. Dual effect of female sex steroids on drug-induced gastroduodenal ulcers in the rat Life Sci. 1999;64(25):2341-50

9. Gastric secretion, proinflammatory cytokines and epidermal growth factor (EGF) in the delayed healing of lingual and gastric ulcerations by testosterone. Inflammapharmacology; 2008 Feb; 16(1):40-7

10. Stimulating the central nervous system to prevent intestinal dysfunction after traumatic brain injury. J Trauma. 2010 May;68(5):1059-64

11. Traumatic brain injury and intestinal dysfunction: uncovering the neuro-entericaxis. J Neurotrauma. 2009 Aug;26(8):1353-9

12. Permeability to glucose after experimental traumatic brain injury: effect of gadopentetate dimeglumine administration. Basic Clin Pharmacol. 2008 Sep;103(3):247-54. Epub 2008 Jul 8