Gut microbiota, diet may hold clues to RA treatment, management
It was 2013 when data from the Human Microbiome Project first demonstrated that the presence of Prevotella bacteria in the gut strongly correlated with disease in patients with new-onset untreated rheumatoid arthritis.
Since then, new data from the NIH initiative continue to detail the potentially significant influences of the microbiome on rheumatic diseases such as RA, leading researchers to ask bigger questions. In addition to promoting disease activity, the gut microbiota might also influence the response to treatment in patients with RA, making specific microbiota potential therapeutic targets. Furthermore, researchers have begun to explore the effects of dietary interventions to restore the microbiome in patients with RA, as well as dietary approaches to the treatment of RA.
“Right now, people are trying to study the interaction between the microbiome in RA with drugs,” Roxana Coras MD, PhD, a postdoctoral researcher in the division of rheumatology, allergy and immunology at the University of California San Diego, told Healio. “There are a few studies which found a patient’s baseline microbiome was related to response to treatment, but baseline microbiome can also be related to response to diet.”
Healio spoke with Coras about the role of the microbiome in RA, how gut bacteria may affect response to diet and how diet can combat inflammation.
Before disease onset: microbiome’s role
In RA, genetic susceptibility is important, though typically there are environmental factors that will trigger the onset of the disease.
“We do have a few already known environmental factors that can be triggers for disease — smoking tobacco, periodontal disease and recently, there are data that components from the diet can also play a role,” Coras said.
More recent data show the mucosal microbiota can be involved in different ways in the development of RA, Coras said.
“The microbiome is important in the development of immunity, beginning at birth,” Coras said. “The interaction between different immune cells and these bacteria are important for the development of the immune system. If something happens, it can favor development of autoimmune diseases.”
Considerable interest exists in Prevotella copri as a potential mediator of RA pathology, Coras said.
“We have some studies that have shown Prevotella copri is increased in patients with RA compared with healthy controls; however, it can also be related to disease activity,” Coras said. “Patients with more inflammation or higher disease activity can have a higher abundance of these bacteria. It also seems to decrease after treatment in some studies.”
In 2017, Allen C. Steere, MD, professor of medicine at Harvard Medical School and director of translational research in rheumatology at Massachusetts General Hospital, and colleagues published two data sets that provided initial evidence for the immune relevance of Prevotella copri in a subgroup of patients with RA. In one study, researchers identified a T-cell epitope of a 27-kD protein of P. copri based on the identification of HLA-DR–presented peptides directly from patients’ peripheral blood mononuclear cells. In a separate study, the group showed 42% of patients with new-onset RA had Th1 responses to this P. copri protein.
In a study published in The Lancet Rheumatology in July 2020, researchers aimed to assess whether known RA risk alleles were associated with the gut microbiota in a large population without RA. In a cross-sectional study, researchers conducted genotyping and analyzed microbiota data from stool samples, using data from the TwinsUK cohort, excluding participants with an RA diagnosis along with their unaffected co-twins.
The researchers found presence of Prevotella spp were positively associated with the RA polygenic risk score among TwinsUK participants; the finding was also validated in SCREEN-RA participants (n=133) carrying established shared epitope risk alleles. Data also demonstrated an association between Prevotella spp and presence of preclinical RA phases.
“They found that study participants with those genetic markers — meaning just having the genetic susceptibility — had a higher abundance in Prevotella,” Coras said. “This is interesting and is the first study telling us that the microbiome seems to be altered even before disease onset.”
Diet ‘not a replacement’ for treatment
Research suggests positive effects of food and food components on clinical outcomes in RA, but there is currently insufficient evidence to provide specific dietary advice. Food components may interact, but studies evaluating combined effects are lacking, Coras said.
Additionally, modern Western diets, characterized by high consumption of refined carbohydrates, added sugars, red and processed meats and salty foods, can induce a pro-inflammatory state promoting the onset of autoimmune diseases such as RA.
“When it comes to recommending an ideal diet for RA, I don’t think we have that yet,” Coras said. “Research in this field is complicated. There have been several trials looking at the efficacy of diet in RA. If you look at the data, the most compelling evidence suggests that the Mediterranean diet is the only one that can be beneficial for these patients. It offers a moderate improvement in disease activity. It is not a replacement for treatment; it should be used in conjunction with treatment.”
In an open-label, pilot trial, Coras and colleagues evaluated the feasibility and efficacy of a 2-week anti-inflammatory diet (ITIS) in 17 patients with active RA, with fecal and blood samples collected at each visit for microbiome and metabolomics analyses. Using a 50% improvement in pain score, patients were categorized as responders (n = 11) or non-responders (n = 6). The results, presented at the American College of Rheumatology Annual Meeting in 2020, showed the ITIS diet induced changes in both metabolome and microbiome that correlated with clinical outcome measures. Additionally, responders had a smaller change in alpha diversity after the diet intervention compared with nonresponders, suggesting that an already high alpha diversity with relatively limited capacity for further change may be necessary for response with this dietary intervention.
“We saw that patients who responded had a different microbiome vs. nonresponders — a microbiome that seemed healthier because it was more diverse,” Coras said. “If this hypothesis is true, we can start to talk about personalized medicine. We would know which patients will not respond to a diet or drug treatment, based on their microbiome characteristics or if certain species are not present in the gut. First, we would need to modulate the microbiome, which would then help the patient have a good response. This is one way that we can use microbiome to help patients achieve decreased levels of inflammation.”
More to learn
Coras said more studies are needed to provide insight into specific long-term dietary interventions or supplements as a complementary treatment in RA, and to establish the scientific basis for using diet to adjust the gut microbiome to improve RA management.
In the meantime, Coras said clinicians can safely recommend patients make some dietary changes that align with the Mediterranean diet, such as enriching the diet with more polyunsaturated fatty acids — fatty fish, seeds, nuts and avocados. Data also show decreasing consumption of red meat and salt, shown to increase the secretion of proinflammatory cytokines, can be helpful, Coras noted.
“Diet and diet counseling should be part of the standard of care for all rheumatic diseases,” Coras said. “We need more dieticians with a background in inflammatory arthritis. It would be nice to be able to refer patients to such dieticians, even if it is through a virtual visit.”
Coras also said more studies are needed that assess how the diet affects the microbiome.
“There are similar studies in other diseases, like irritable bowel syndrome, diabetes and cardiovascular disease, but no one has really looked at what happens with a dietary intervention and the microbiome in RA,” Coras said. “That will help us explain how and why the diet works. What gets in the way of progress is we do not know the mechanisms behind why diet can work.”
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