Rheumatoid arthritis is a chronic inflammatory disease affecting the lives of 2.3 million Europeans, and represents a heavy economic burden estimated at more than EUR 240 billion every year. Treatment options are limited and carry the potential for severe side effects such as immunosuppression. Recent work has suggested that a gum disease-causing bacterium, as well as microbes living in the intestine, may contribute to arthritis. The MaRiA project set out to characterise the role of these microbiota in patients with chronic inflammation.
“Inflammation is a process that protects us during infection and injury, however it must be switched off once no longer required. The switch is regulated by so-called specialised pro-resolving mediators,” explains project officer Magdalena Flak. In chronic inflammatory diseases such as arthritis, the biological pathway that controls inflammation becomes stuck in an ‘on’ position. Patients with rheumatoid arthritis are more likely to have gum disease. After treatment for gum disease, they often see improvements to their rheumatism symptoms. The connection may lie with Porphyromonas gingivalis, a bacterium naturally present in the mouth. Flak says it is a pathobiont, a microbe that is typically benign but sometimes causes disease. When Flak and her colleagues at Queen Mary University of London inoculated arthritic mice with P. gingivalis, they observed the defence mechanisms of the gut wall breaking down.
When they looked more closely, they discovered that during arthritis, levels of the anti-inflammatory molecule n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA) were decreased in the intestine, which rendered the gut susceptible to the detrimental behaviour of the bacterium. Mice without arthritis did not experience the same effects when inoculated with the bacteria. “It’s not that P. gingivalis makes it through the gut barrier. The low levels of RvD5n-3 DPA combined with the pathogenic behaviour of P. gingivalis make the gut more permissive to invasion by gut-resident bacteria. This is likely to induce increases in systemic inflammation,” says Flak. When Flak treated the arthritic mice with RvD5n-3 DPA, the breakdown of the gut barrier stopped and prevented the worsening of joint disease by P. gingivalis. “Although we did not reverse arthritis altogether, we could improve it significantly,” she adds. How P. gingivalis is able to downregulate the activity of RvD5n-3 DPA is still unclear.
“Funding facilitated collaboration within our institution and also outside of it. It enabled me to spread knowledge from these findings to the research community at conferences, and to the general public,” notes Flak, who carried out her research with support from the Marie Skłodowska-Curie Actions programme. “Ultimately it allowed me to develop my own line of research.” This, she says, includes questions such as how host and microbiota interact, how lipid mediators affect the behaviour of disease-causing bacteria, and what facilitates the switch of bacteria from a benign to a pathogenic state. Flak adds that the work will help pave the way for a new class of chronic inflammation disease treatments based on specialised pro-resolving lipid mediators.
MaRiA, rheumatoid, arthritis, gum, bacteria, Porphyromonas, gingivalis, inflammation, resolvins, lipid, mediators