27 February 2012

Celiac Disease and it's link to your genes and gut microbes...



Celiac disease is an autoimmune disorder triggered by gluten, a protein in wheat, barley, rye and spelt. Currently, the only treatment available is the adoption of a lifelong gluten free diet, which is made particularly challenging due to the prevalence of wheat in western diets. It is an excellent example of environmental challenge meeting gene susceptibility, and is a unique example of how exclusion of an environmental trigger can resolve the symptoms.


“Celiac disease has become much more common in the last 50 years, and we don’t know why,” said Dr Joseph Murray of Mayo Clinic “…Obviously human genes haven’t changed, but something has changed in our environment to make this disease more common....”
 
Celiac disease is an inflammatory disorder with autoimmune features characterized by destruction of the intestinal epithelium and remodelling of the intestinal mucosa following the ingestion of dietary gluten. The human gut is home to trillions of commensal organisms, and we are just beginning to understand how these microorganisms interact with, and influence, the host immune system. This may also include the late onset development of Celiac Disease or gluten intolerance.

Key Ideas:
  • Celiac disease (CD) is an autoimmune disorder triggered by ingestion of gluten, a major protein in wheat, rye, barley and often oats.
  • Research into the root causes indicates that the disorder develops when a person exposed to gluten also has a genetic susceptibility to CD and an unusually permeable intestinal wall.
  • Essentially the same trio—an environmental trigger, a genetic susceptibility and a “leaky gut”—seems to underlie other autoimmune disorders as well. This finding raises the possibility that new treatments for CD may also ameliorate other conditions.
  • CD is an immune mediated pathology that may be managed not simply through exclusion of the antigen – gluten, but also through the improvement of digestion, reduction of gut permeability, support or mucosal IgA (the gut's immune system)
"If people with celiac disease are born with a genetic susceptibility to it. ... why do some individuals show no evidence of the disorder until late in life?  We are finding there is a link to the "bug" population in the gut.  These bugs collectively known as the microbiome, may differ from person to person and from one population to another, even varying in the same individual as life progresses. They can also influence which genes in their hosts are active at any given time. Hence, a person whose immune system has managed to tolerate gluten for many years might suddenly lose tolerance if the microbiome changes in a way that causes formerly quiet susceptibility genes to become active"

CD and gluten intolerance represent distinct situations in which local tissue damage in the gut may manifest a wide range of illnesses elsewhere, supporting the notion that many illnesses have an origination in the GI tract

Why Is Gluten So Tough To Handle?

There are two unique features to gluten that may partly  explain its ability to trigger an immune response.
  1. They have a high content of proline in the gluten proteins, that are hard to break down using our natural proteases in the gut lumen.
  2. The gluten fragments are good substrates for the enzyme TransGlutamase (TG2) converting glutamine residues to glutamate. This increases the ability of the gluten peptides to bind to the genetically inherited molecules HLA-DQ2 or HLA-DQ8.

References

1. Fasano A. Surprise from celiac disease. Scientific American August 2009.
2.  Shan,L Et al. Structural Basis for Gluten Intolerance in Celiac Sprue. Science 297, 2275-2279. 2002

3. Arentz-Hansen H, K├Ârner R, Molberg O, Quarsten H, Vader W, Kooy YM, Lundin KE, Koning F, Roepstorff P, Sollid LM, McAdam SN.The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.J Exp Med. 2000 Feb 21;191(4):603-12.
4. Round JL, Mazmanian SK., The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May;9(5):313-23
5. http://www.nleducation.co.uk

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