The microbiome affects celiac severity in mice

In non-celiac people, gluten is broken down into its constituent proteins and does not elicit any immune response.  In celiac disease, however, the gluten proteins cause inflammation, which can result in a number of GI issues.  The microbiome has long been thought to play a role in this disease, because of its importance to immune mediation, and its role in gluten breakdown.  An international group of scientists recently tested the role of various different characteristic microbiome communities on the immune reaction in mice with celiac disease.  They published their results last week in the American Journal of Pathology.

The scientists used a mouse model for celiac disease that involved genetically modified mice that had an immune response to gluten.  They split the mice into three groups, one group had a typical healthy microbiome, the next had a healthy microbiome but without proteobacteria, and the final group was germ free (i.e. completely lacking a microbiome).  When the germ free mice were challenged with gluten they had the highest inflammatory response.  This included increases in immune cells, and breakdown of the intestinal villi.  Unsurprisingly, when the germ free mice were colonized with normal microbiota, their inflammatory response was attenuated.   The scientists then discovered an important relationship between celiac’s and Proteobacteria.  The mice that harbored this phylum had more severe responses to gluten, suggesting that these bacteria somehow worsen the inflammatory response to gluten.  Antibiotic treatment that increased the amounts Proteobacteria, and the relative abundances of Escherichia, Helicobacter, Pasteurella, and Lactobacillus, also increased the inflammatory response.

The exact mechanisms by which the microbiome are mediating the immune response are unclear.  Bacteria are known to induce various immune cells and also break down gluten, and these mechanisms may be involved.  In either case gluten sensitivity and celiac disease are clearly affected by the microbiome.

Can hookworms fight against celiac disease?

Helminths, or gut worms, are native inhabitants of our microbiome that are known to have substantial immunosuppressive effects.  Some scientists believe they are a keystone species in the microbiome and that their absence in people following a Western lifestyle may be contributing to the rise in autoimmune diseases, such as celiac disease.  In fact, scientists have recently shown that hookworm infection leads to higher gluten tolerance in individuals with celiac disease.  The cause of hookworm’s broad immunosuppression is unknown, but those same scientists investigated the possibility that it may be caused by the worms’ ability to modulate the bacteria in the gut.  The researchers recently tested this hypothesis and published their results in Nature Scientific Reports.

First, the researchers measured the fecal microbiota of eight human subjects with celiac disease, all of whom had followed a gluten free diet for at least five years prior to the trial.  Compared to a control group that hadn’t followed a gluten free diet, the trial subjects had a greater abundance of Bacteroidetes, while the control group showed greater abundance of Firmicutes.  Next, the subjects were successfully infected with hookworm and gluten was slowly reintroduced into their diets over a period of 44 weeks. The scientists measured the subjects gut microbiota at different time points and discovered that the hookworms, in conjunction with the gluten introduction, restored levels of Firmicutes in the celiac disease patients.  By the end of the study all of the remaining participants had rich abundances of both Bacteroidetes and Firmicutes.

It should be noted, and the authors admit, that the study is limited by its small sample size.  Still though, the results lead one to believe that helminths are modulating the microbiome, and that this may contribute to the overall immunosuppressive effects of these worms.  People have been known to practice helminth therapy to achieve immunosuppression in the gut, however this is dangerous for a number of reasons.  Instead researchers, such as the ones that performed this study, are in search of the mechanism for this immunosuppression.  There is certainly some very interesting biology that occurs during a helminth infection, and hopefully sometime soon scientists can turn these helminths into therapies.

Common yeast may trigger celiac disease onset

Candida albicans growing in petri dish

Celiac disease is a serious autoimmune disorder in which gluten, found in wheat, rye, and barley, triggers an immune response that damages the absorption capabilities of the intestines. The AMI has covered this topic in a few previous blogs (click celiac disease tag below) in relation to autoimmune disorders and possible bacterial triggers. One contributing factor to the celiac disease response is due to the protein gliadin, which is found in gluten. Gliadin, along with transglutaminase (which is a human protein that binds to, and deaminates gliadin), trigger a T Cell response that leads to the inflammation and tissue damage.

The yeast Candida albicans is a common gut commensal that is linked to inflammatory bowel diseases and vaginal infections.  This yeast also binds with transglutaminase, using a protein called Hwp1, in an identical fashion as gliadin.  This results in the bacteria’s strong binding to the intestinal wall, where it triggers an autoimmune response to destroy the yeast.  

Researchers in France hypothesized that the similarity between gliadin's and C. albicans' binding to transglutaminase may result in a similarity in the body's response to these two things.  In essence, they suggested that gluten ‘tricks’ the body into an immune response because it 'looks' similar to C. albicans.  

In the study, recently published by Plos One, blood cultures from 87 adult patients with celiac disease and 41 patients with C. albicans infection were collected.  The scientists then isolated the body's natural antibody for Hwp1 and measured its response to both gliadin and Hwp1.  They discovered that gliadin also binds to Hwp1's antibody, meaning that it should elicit the same immune response as Hwp1.  Therefore, the body should mount an immune response for gluten that is characteristic of C. albicans infection, and this response could manifest itself as celiac disease.

The significance of this study is that it comes closer to finding a cause and prevention of celiac disease. The T cell immune response that results from transglutaminase binding to gliadin could initially be triggered by a C. albicans yeast infection. This may explain why some people only become gluten sensitive later in life - perhaps it only occurs after they have a C. albicans infection and the body builds up antibodies for this yeast. This is another example of how microbes found in healthy individuals can be harmful when homeostasis is not controlled. 

Treating celiac disease with bacteria?

Celiac disease is a condition that results in an individual's immune system attacking it’s own small intestine as a result of gluten consumption. Researchers at the University of Nebraska and the University of Alberta published a study in the Journal of Applied Microbiology that aimed to identify gastrointestinal bacteria that are able to break down gluten proteins, possibly opening the door for therapeutic interventions. To do this, they studied the gastrointestinal tract of pigs, as they are physiologically similar to humans.

The scientists found four strains from the Lactobacillus species that had the greatest ability to degrade gluten, L. amylovorus, L. johnsonii, L.ruminis, and L. salivarius. Pigs were fed a diet supplemented with 20% gluten for at least 16 weeks and samples of their gastrointestinal bacteria were collected. They found that the four bacterial strains were enriched, and these strains were capable of degrading specific molecules that have been linked to the immune response in celiac disease.

This study identified specific bacteria that could potentially be used to treat celiac disease. Other studies have also identified L. ruminis and L. amylovorous as bacteria that are primary degraders of gluten, making them prime candidates for therapeutic use. Currently, the only way for an individual with celiac disease to remain healthy is to avoid any product containing gluten. In the future, it may be possible for bacterial strains, possibly those identified in this study, to be introduced into the gut of a celiac disease patient through a probiotic or other method to allow for the digestion of gluten.