Numerous studies have linked the gut microbiota to inflammatory diseases. These studies have shown that immune-mediated inflammatory diseases, such as Crohn’s disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), and rheumatoid arthritis (RA), change the composition of the gut microbiota. Now, a team of researchers led by Éric Boilard, PhD, of Université Laval has uncovered that a protein naturally present in the gut acts on the microbiota and causes the formation of molecules that exacerbate the symptoms of these diseases.

Their findings are published in the Journal of Clinical Investigation in a paper titled, “The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation.”

“Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids,” the researchers wrote. “Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis.”

Boilard, a professor in the Faculty of Medicine at Université Laval and a researcher at CHU de Québec–Université Laval Research Centre, noted that the protein phospholipase A2-IIA, was discovered several years ago in the fluid that surrounds the joints of people with arthritis. The protein was also detected in the gut where it is produced in abundance.

“It took a long time before we realized that it exhibits antibacterial activity,” explained Boilard. “The protein interacts little with the membrane of human cells, but it has high affinity for bacterial membranes. It binds to these membranes and splits them, releasing small molecules such as fatty acids.”

Experiments on mice revealed that phospholipase changes the profile of bacterial lipids that end up in the gut. “By releasing fatty acids from the bacterial membranes, the protein produces proinflammatory lipids that exacerbate chronic inflammation and increase the severity of arthritis symptoms in these mice,” noted Boilard.

In another article, researchers led by Makoto Murakami of the University of Tokyo demonstrated that the action of phospholipase on the gut microbiota of mice also affects psoriasis, another inflammatory disease, as well as skin cancer. “Three years ago, we realized that our respective teams were on the same track,” said Boilard. “We agreed to work together to shed light on this new lead.”

“The work of both teams suggests that local inhibition of phospholipase may alleviate the inflammatory process that exacerbates certain diseases. It also suggests that blocking the bacterial proinflammatory lipids produced in the gut by this protein could reduce symptoms in people with systemic inflammatory diseases. The next step in our work is to test these ideas in patients with arthritis.”

The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

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