A study headed by researchers at the University of Leeds has found that changes in the makeup of the gut microbiome are linked to the onset of clinically evident rheumatoid arthritis (RA) in those at risk of the disease because of genetic, environmental, or immunological factors. The cross-sectional and longitudinal observational study found alterations to the abundance of Prevotellaceae bacteria in the gut before individuals developed clinical rheumatoid arthritis.
The study initially took data from 124 individuals with high levels of CCP+, an antibody that attacks healthy cells in the blood, indicating risk of developing rheumatoid arthritis. The researchers compared their samples to 22 healthy individuals and seven individuals with a new rheumatoid arthritis diagnosis.
The findings from this larger group showed that the gut microbiome was less diverse in the at-risk group, compared to the healthy control group. The longitudinal study, which took samples from 19 patients over 15 months, revealed the changes in bacteria at ten months before progression to rheumatoid arthritis.
While previous research has linked rheumatoid arthritis to the gut microbiome, the newly reported study could point to a potential intervention point. While the researchers noted that it’s not clear if this instability is a cause or consequence of disease development, the findings might help identify those at risk and pave the way for preventive and personalized treatment strategies, they suggest.
Lead researcher Christopher Rooney, PhD, NIHR academic clinical lecturer at the University of Leeds and Leeds Teaching Hospitals NHS Trust, said: “Patients at risk of rheumatoid arthritis are already experiencing symptoms such as fatigue and joint pain, and they may know someone in their family who has developed the disease. As there is no known cure, at-risk patients often feel a sense of hopelessness, or even avoid getting tested. This new research might give us a major opportunity to act sooner to prevent rheumatoid arthritis.”
Rooney and colleagues reported on their study findings in Annals of the Rheumatic Diseases, in a paper titled, “Dynamics of the gut microbiome in individuals at risk of rheumatoid arthritis: a cross-sectional and longitudinal observational study.” The research was carried out in collaboration with the National Institute for Health Research Leeds Biomedical Research Centre, under the research themes of antimicrobial resistance and infection and musculoskeletal disease. Leeds Teaching Hospitals NHS Trust, Versus Arthritis, and Leeds Hospitals Charity were also partners on the project.
Affecting more than half a million people in the U.K., rheumatoid arthritis is a chronic disease that causes swelling, pain, and stiffness in the joints because the immune system is mistakenly attacking the body’s healthy cells. “Understanding the RA disease spectrum with recognition of at-risk individuals has propelled RA research into prevention strategies,” the authors wrote.
Previously published research consistently shows an unfavorable imbalance in the gut microbiomes of those at risk as well as those diagnosed with rheumatoid arthritis compared with the gut microbiomes of those without the disease. But it’s not clear exactly which microbes might be involved. “… there remains little consensus on the bacterial constituent members of an RA-related dysbiosis,” the team continued. “Subsequently, a variety of gut bacteria have been implicated as a potential impetus in the development of RA, none more so than Prevotella copri.” Prevotellaceae, and particularly Prevotella copri, have been inconsistently associated with RA development, the investigators pointed out, but while early studies showed an overabundance, there have been more recent studies that question these observations. “This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional, and temporal changes in the gut microbiome in RA progressors versus non-progressors.”
For their study, the team tracked changes in the gut microbiome profiles of 124 people at risk of developing rheumatoid arthritis, in seven people with newly diagnosed people (new onset RA; NORA) and in 22 healthy people over a period of 15 months, by assessing their stool and blood samples at five different time points.
Those at risk were identified by the presence of precursor anti-cyclic citrullinated protein (anti-CCP) antibodies, which attack healthy cells and are specific for rheumatoid arthritis, and by the experience of joint pain in the preceding three months.
During the study period, 30 of the 124 individuals in the at-risk group progressed to rheumatoid arthritis, and their microbial diversity was notably reduced compared with that of the healthy comparison group, particularly within specific areas—known as alpha diversity.
Alpha diversity was also reduced in both those who progressed and those who didn’t, and linked to anti-CCP antibody levels. In those with low anti-CCP antibody levels, microbial diversity was comparable with that of the healthy comparison group.
Recognized genetic, blood, and imaging risk factors for arthritis development were also significantly linked to lower microbial diversity, as was steroid use.
A specific strain of Prevotellaceae sp.—(ASV2058) most likely P. copri—was abundant in the microbiomes of those who progressed as well as in those of the newly diagnosed, but not in the microbiomes of those in the healthy comparison group. Another strain (ASV1867) of P. copri was also increased at the start of the study in those who progressed, possibly suggesting that different strains of P. copri might have different roles in rheumatoid arthritis progression, the investigators suggested.
Further analysis indicated that both enrichment (three) and depletion (five) of Prevotellaceae-specific strains were associated with progression. “Strain-specific phenomena are noted with both enrichment (three strains) and depletion (five strains) of Prevotellaceae-specific strains associated with progression,” the team wrote. “ASV2058 is included as one of those five depleted strains.”
While P. copri strains were most strongly associated with clinical risk factors for rheumatoid arthritis, other Prevotellaceae strains were also implicated, including Alloprevotella, Paraprevotella clara, Prevotella stercorea, Prevotellamassilia timonensis, and Prevotella shahii.
The authors acknowledged that as an observational study, the findings don’t allow any firm conclusions to be drawn about causal factors. They acknowledged various study limitations, including the small number of participants, the relatively short monitoring period, and the lack of direct one-on-one comparison between the at-risk and healthy participants.
Nevertheless, they stated, “Individuals at risk of RA harbor a distinctive gut microbial composition, including but not limited to an overabundance of Prevotellaceae species.” This microbial signature is consistent and correlates with traditional risk factors, they pointed out. “Longitudinal examination shows a dynamic microbial environment preceding RA onset. Further research into this late phase of disease development is merited, especially given the potential of the gut microbiome as a target for prevention, including in high-risk individuals with imminent arthritis.”
The Leeds research team will now carry out an analysis of treatments that have already been trialed, to inform future testing of treatments at this potential ten-month intervention point. Potential treatments that the researchers want to test at the ten-month window include changes to diet like eating more fiber, taking prebiotics or probiotics, and improving dental hygiene to keep harmful bacteria from periodontal disease away from the gut.
