Do Specific Gut Bacteria Have A Role In The Development Of Celiac Disease?

Celiac disease is an auto-immune disease in which a person reacts to gluten - a protein found in grains including rye, wheat, barley and also oats. It is estimated that about 1% of the American population has celiac disease. Around 80% of Americans with celiac disease are undiagnosed or misdiagnosed with other conditions.

When a person with celiac disease eats gluten, their immune system produces antibodies against gluten which can also causing damage to the small intestine. This leads to the symptoms of celiac disease including abdominal pain, diarrhea, bloating, malnutrition and fatigue. The only existing treatment for celiac disease is a gluten-free diet.

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 A large proportion on people with celiac disease have a specific gene which pre-disposes them to celiac disease. Around 5-25% of people with celiac disease have a first-degree relative with the condition. But why is it that only a small proportion of individuals who are genetically susceptible to celiac disease actually develop the disorder?  Certain gene mutations are known to trigger celiac disease, yet, only 2-3% of people who possess such mutations actually develop the condition.

The answer to this has been uncertain, but recent study suggests it may be explained by how specific gut bacteria respond to gluten. Some researchers have proposed that the presence of specific gut bacteria may have a role in the development of celiac disease.

Dr. Elena F. Verdu, of the Digestive Health Research Institute at McMaster University in Canada, and her colleagues have investigated how the immune responses to gluten varies with different populations of gut bacteria in mouse models with gluten intolerance. Their findings were published in The American Journal of Pathology.

The team assessed three groups of mice that expressed a gene called DQ8, which is also found in humans and makes them genetically susceptible to gluten intolerance. Each group of mice had different gut bacteria compositions, or gut microbiomes. The researchers exposed each group of mice to the same amount of gluten.

•  Group 1 mice were germ free
• Group 2 mice had specific, pathogen-free flora which possessed a wide range of normal gut bacteria; their gut microbiomes were free of Proteobacteria; and did not have any opportunistic pathogens present
•  Group 3 mice, also had specific, pathogen-free flora (as for group 2), but it also included Proteobacteria such as Escherichia coli and Helicobacter; and also included other opportunistic pathogens such as Staphylococcus and Streptococcus

Note:

1.  The Proteobacteria are a major group of gram negative bacteria. They include a wide variety of pathogens, such as Escherichia, Salmonella, Vibrio, Helicobacter, and many other notable genera
2. Opportunistic pathogens are bacteria which live normally on/in the body and cause disease in people with a compromised immune system or other pre-existing disease.

Gram negative bacilli

.           Results: Group 1 – The Germ Free Mice

The germ- free mice exhibited signs of celiac disease. The germ-free mice showed increased levels of intraepithelial lymphocytes in the gut. The proliferation and activation of intraepithelial lymphocytes is an early indicator of celiac disease. The germ-free mice also experienced increased death of cells called enterocytes that line the gastrointestinal tract, as well as anatomical alterations of the villi, the small, finger-like projections that line the small intestine.

The researchers also identified that the germ free mice in group 1 developed antibodies in response to gliadin, a component of gluten. These mice also demonstrated T-cell responses specific to this component.

Results: Groups 1 mice with specific, pathogen-free flora

Increased intraepithelial lymphocytes levels were not seen in group 2, the mice with specific, pathogen-free flora only

 Results: Groups 2 mice with specific, pathogen-free flora, Proteobacteria and opportunistic pathogens

The group 3 mice demonstrated greater gluten-induced pathology than the group 2 mice, according to the researchers, so the team set out to investigate whether the presence of Proteobacteria, such as Escherichia and Helicobacter, plays a role.

The team found that development of gluten-induced pathology was NOT halted if the mice were also inoculated with entero-adherent Escherichia coli isolated from a patient with celiac disease.

They found that the presence of Proteobacteria worsened gluten-induced pathology. On increasing the presence of Proteobacteria in new born mice, the researchers found that gluten-induced pathology got worse. Specifically, the team identified an increase in levels of intraepithelial lymphocytes.

Conclusions

"These studies demonstrate that perturbation of early microbial colonization in life and induction of dysbiosis (microbial imbalance inside the body), characterized by increased Proteobacteria, enhances the severity of gluten-induced responses in mice genetically predisposed to gluten sensitivity," says Dr. Verdu. "Importantly, our data argue that the recognized increase in celiac disease prevalence in the general population over the last 50 years could be driven, at least in part, by perturbations in intestinal microbial ecology. Specific microbiota-based therapies may aid in the prevention or treatment of celiac disease in subjects with moderate genetic risk."

In an editorial linked to the study, Dr. Robin G. Lorenz, of the University of Alabama at Birmingham, notes that while these findings suggest the presence of Proteobacteria may play an important role in celiac disease pathology, they do not mean that Proteobacteria causes the condition. An alternative, he suggests, is that Proteobacteria somehow boost the immune response to gluten or gliadin.