Celiac disease is a common food sensitivity triggered by gluten and its incidence is rising at an alarming rate. The reasons for this are not fully understood but suggestions are that they relate to changes in gut microbial composition or function.
As part of previous research into gluten digestion processes, Dr. Alberto Caminero of McMaster University (Canada) had described a mechanism through which the bacterial protease LasB, from the opportunistic pathogen Pseudomonas aeruginosa, can participate in the digestion of gluten in vivo.
“Digestion of gluten by microbes is not the same as detoxification,” explained Caminero. In other words, while some opportunistic pathogens use gluten avidly, this metabolism is partial and generates peptides that are more immunogenic or inflammatory for celiac disease patients.
In a recent follow-up study published in Nature Communications and led by Dr. Elena Verdu of McMaster’s Farncombe Institute, Dr. Caminero identified additional pathways by which the opportunistic pathogen incites gluten sensitivity, but which are independent of gluten metabolism.
Using small intestinal biopsies from celiacs and healthy controls, the authors first described an increase in small intestinal proteolytic activity towards gluten in the celiac biopsies, which correlated with an increased abundance of bacteria known to degrade gluten. “In other words, biopsies from celiacs had more bacteria that were able to use gluten as an energy source,” said Verdu.
“We then set out to investigate whether this activity directly influenced inflammation in the host,” she continued. To do this, the authors colonized germ-free mice with a single model bacterium—P. aeruginosa—which produces LasB, a protease involved in gluten metabolism. Mice colonized with the protease-producing P. aeruginosa showed higher proteolytic activity, higher numbers of small intestinal innate immune cells—known as intraepithelial lymphocytes—and a more inflammatory molecular signature compared to mice that were colonized with a strain of P. aeruginosa that lacked the protease. This innate immune activation in the mice was independent of exposure to gluten in their diet and required signaling through protease-activated receptor (PAR)-2, a receptor commonly expressed in the gastrointestinal tract. However, the mice that did not express the human celiac risk genes remained healthy.
A different situation emerged when the experiments were repeated in transgenic mice that expressed the human celiac risk genes. When “HLA-DQ8” mice were colonized with the protease-producing P. aeruginosa, the bacterial proteolytic activity synergized with gluten to induce more severe inflammation and intestinal damage.
These findings suggest that enzymes produced by opportunistic pathogens and certain bacteria within the gut can trigger host immune responses that could increase susceptibly to food sensitivities.
Graphical abstract created by Heather Galipeau for a blog post on the Nature Microbiology website:
Caminero A, McCarville JL, Galipeau HJ, et al. Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. Nat Commun. 2019; 10:1198. doi: 10.1038/s41467-019-09037-9.
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