Gut microbiota, immune system development, and celiac disease

Genes contribute to the risk of celiac disease (CD), but the role of environmental factors, including perturbations in gut microbiota, is so far unclear. We recently published a review article focusing on the role of the gut microbiota in oral tolerance to food antigens. The article discusses the potential mechanisms by which the microbiota might contribute to CD.

In studies comparing patients with active CD to healthy controls, researchers have observed differences in fecal microbial composition, microbial diversity, and short chain fatty acid content. Direct evidence that these changes give rise to CD, however, is lacking.

CD involves both innate and adaptive immune responses; evidence from animal models shows that the connection between the gut microbiota and CD may have to do with how the microbiota affect the immune system. Modulation of adaptive immune responses by commensals and pathogens have been studied in detail and in particular in the colon. But much less is known about microbial modulation of innate immune parameters that could be of importance in CD.

Epidemiological data show possible environmental factors that might trigger the perturbations of intestinal microbiota that are associated with CD. Some of these factors may include planned c-sections, antibiotics early in life, intestinal infections, and infant feeding practices, although recent clinical trials have not confirmed that the latter play a role in CD risk in high-risk children. (I am referring to the latest studies on early gluten introduction to the diet, which show no increased risk, at least in kids with already “high” risk, i.e. with associated genes PLUS first degree celiac relative.)

The paper concludes that dysbiosis of the microbiota is associated with CD, but more data are needed to clarify the exact role. In particular, more animal research is needed to support a causal connection.

Below, I answer some questions from the GMFH editors:

You mention in the paper that some data supports the potential of probiotics to mediate the immune effects of CD. How close are we to other CD treatments besides a lifelong gluten-free diet?

The data in this respect are emerging, and a couple of studies have shown a promising effect. One was a paper from Julio Bai’s group and an abstract presented at a meeting. They showed that specific probiotics improved symptoms in newly diagnosed patients with CD that were still consuming a controlled gluten containing diet during the trial (see more here). A follow up study presented in abstract form at the DDW [Digestive Disease Week] 2014 suggests this improvement is associated with modulation of innate immunity by the probiotic.

No recommendations can be given at this point on the use of probiotics in CD, and more data are needed, although the picture is promising.

Do you think prevention in genetically susceptible individuals will be the way to go? What are the limits of the prevention model?

Prevention is a very interesting concept, especially because we can identify groups “at risk” to develop CD. So, we could target theoretically these populations with high risk to develop CD. So far we have no evidence that this could be achieved, and it would have to be tested.

Personally I think prevention is easier to achieve than treatment, if for example one makes a parallel with IBD [inflammatory bowel disease]. However, CD is a special case, because if we remove the trigger, gluten, patients enter in remission. This said, a proportion of patients on a gluten free diet remain symptomatic or have residual inflammation. This could relate to inadvertent gluten contamination despite the patient making efforts to avoid gluten. But a recent paper by Katri Kaukinen suggests persistent symptoms despite a gluten free diet is associated with persistent dysbiosis. Thus, improvement of residual inflammation or symptoms in these patients by targeting the persistent dysbiosis could also be important.

Reference:

Galipeau HJ, & Verdu EF. (2015) Gut microbes and adverse food reactions: Focus on gluten related disorders. Gut Microbes DOI:10.4161/19490976.2014.969635

Elena Verdú
Elena Verdú
Dr. Verdu’s research has focused on the pathophysiology of inflammatory and functional gastrointestinal disorders. She undertook clinical research training at the University of Lausanne, Switzerland, where she studied the interaction between chronic infection with Helicobacter pylori and gastritis in humans and the possible therapeutic role of probiotic bacteria. Her PhD studies in the Institute of Microbiology and Gnotobiology at the Czech Academy of Science and University of Lausanne focused on the effect of bacterial antigens in animal models of inflammatory bowel disease. As a post-doctoral fellow at McMaster University she gained experience with animal models of gut functional diseases and investigated the mechanisms of action of probiotic bacteria. As a member of the Farncombe Family Digestive Health Research Institute at McMaster University, Dr. Verdu investigates host-microbial and dietary interactions in the context of celiac disease, irritable bowel syndrome and inflammatory bowel disease. She has been honored with the New Investigator Award (Canadian Celiac Association), the New Investigator Award (Functional Gut-Brain Research Group, USA) and the Campbell Research Award in celiac disease (Canadian Celiac Association). The American Gastroenterology Association and the Canadian Association of Gastroenterology have awarded her the “Master’s in Gastroenterology Award” for basic science and “Young Investigator’s Award”, respectively. She is Associate Professor at the Division of Gastroenterology, Dep. of Medicine at McMaster University and currently directs the Axenic Gnotobiotic Unit at McMaster.