Sunday, June 10, 2012

Intestinal Permeability

Even with a dysregulated immune system it’s unlikely that in real life conditions (as opposed to experimentally depleting Treg cells) one infection will produce lifelong autoimmune disease.  A healthy person may only sustain autoimmune damage while infected, whereas a person with a dysregulated immune system may have some autoimmune attacks for some time have the infection has cleared.  A lifelong autoimmune disease probably requires a dysregulated immune system and the continuous exposure to the triggering antigen, made possible by intestinal permeability [1]. 

The intestinal mucosal barrier is made up of structures to connect cells together called tight junctions to separate our body from the outside world (technically the interior of the digestive tract is not inside the body) to prevent bacteria, pathogens and toxins from entering the body.  There are a number of proteins that make up the tight junctions and keep them closed, but only one that opens them, zonulin* [2]. 

Zonulin is active in the small intestine but not the large intestine.  The function of zonulin is to open up the tight junctions to move fluid, macromolecules (proteins, lipids, carbohydrates and anything larger) and leukocytes (white blood cells) between the body and small intestine.  In addition bacteria (commensal or pathogenic) and pathogens inherently stimulate the zonulin pathway so our body is protected against infection in the small intestine (which is usually sterile) [3].  When the tight junctions open, water is released into the small intestine and bacteria/pathogens/etc are flushed out of the body, causing diarrhoea* [1].

The first few steps happen to everyone

The prolamines in wheat (gliadin***), rye (secalinin) and barley (hordein) activate the zonulin pathway thereby increasing intestinal permeability and also are the trigger for coeliac disease [4].  Gluten is resistant to digestion in the stomach (acid) and small intestine (peptidases – protein digestion enzymes), increases inflammation and the reactivity of the immune system similar to LPS and promotes dysbiosis [5].  A zonulin inhibitor drug blocks increases in intestinal permeability and GI symptoms when coeliacs have gluten [6] 

Other things that can compromise barrier function and increase intestinal permeability include: small intestinal bacterial overgrowth (SIBO) [3] pro-inflammatory cytokines [7] [8], glucocorticoids, oxidative stress, NSAIDs, psychological stress and acute infections [9] [10]For a longer list on things that are either helpful or harmful for intestinal permeability see this post on Suppversity (highly recommended)

Evidence supporting the role of intestinal permeability in autoimmune disease: 

  • People with ankolosing spondylitis, asthma, coeliac disease, crohn’s disease, dermatitis herpetiformis, lupus, MS, RA and T1D tend to have elevated intestinal permeability or zonulin levels (depending on which was measured) [1] [11] [12] [13]
  • An increase in intestinal permeability following elevated zonulin levels precedes the onset of T1D by 2-3 weeks in an animal model.  Later a zonulin inhibitor drug blocked autoantibodies [1].  Also GI symptoms and elevated zonulin levels precede T1D in humans [14]
  • Intestinal permeability precedes relapse in Crohn’s disease by as much as a year, zonulin is higher in the acute phase of IBD and zonulin levels are associated with the severity of symptoms in Crohn’s disease [1]
  • In an animal model of IBD (IL-10 deficiency) intestinal permeability precedes IBD and a zonulin inhibitor reduces inflammation [15]
  • Immune activity correlates with intestinal permeability [7]
  • Healthy relatives of people with Crohn’s disease [7] and T1D [16] have elevated zonulin levels or intestinal permeability, which suggests intestinal permeability is necessary but not sufficient for autoimmunity

* V. cholerae (cholera) secretes a toxin called zonula occludens toxin (Zot), which has the same effect as zonulin 

** The appendix stores a culture of beneficial bacteria so when bacteria are flushed out of the body the colon can be repopulated. 

*** Gluten is made up of gliadin and glutenin 

Further Reading:
(1) Intestinal Zonulin: Open Sesame
(2) Leaky Gut Research

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