Does the Gut Microbiome Affect RA?

Originally published by our sister publication Infectious Disease Special Edition

By Marie Rosenthal, MS

Changes in the gut microbiome before rheumatoid arthritis develops could provide an opportunity to prevent RA, but more research is needed to determine how that might be done.

\

Higher amounts of Prevotella bacteria are found in the gut roughly 10 months before patients develop clinical signs and symptoms of RA, a longitudinal study has found (Ann Rheum Dis 2024 Nov 8. doi:10.1136/ard-2024-226362). However, it is unclear whether this is a cause or consequence of disease development, according to the researchers from the University of Leeds, in England. 

“Concluding cause and effect requires more evidence, and ideally [showing] that by removing or inhibiting the cause, we can prevent the effect—this is the holy grail!” Mark Wilcox, MD, told Infectious Disease Special Edition. 

Previous research linked RA to the gut microbiome (Rheumatology (Oxford) 2021;60:3380–3387), but this new study reveals a potential intervention point, the researchers said. The study initially took data from 124 people who had high levels of cyclic citrullinated peptide (CCP+), an antibody that attacks healthy cells in the blood, which indicates the risk for developing RA. They compared their samples with 22 healthy people and seven who were recently diagnosed with RA by assessing their stool and blood samples at five points during the 15-month study.

Those at risk were identified by the presence of precursor anti-CCP antibodies, which are specific for RA, and by whether patients experienced joint pain in the preceding three months.

The diets among the three groups were similar, although alcohol intake and the amount of regular moderate to vigorous exercise differed.

During the study period, 30 of the 124 in the at-risk group progressed to RA, and their microbial diversity was notably reduced compared with that of the healthy comparison group, particularly within specific areas. This alpha diversity was also reduced in those who progressed compared with those who did not, and was linked to higher anti-CCP antibody levels. In those with low anti-CCP antibody levels, microbial diversity was similar to 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.

The findings from this larger group showed that the gut microbiome was less diverse in the at-risk group, compared with the healthy control group. The longitudinal study, which took samples from 19 patients over 15 months, revealed the changes in bacteria at 10 months before progression to RA.

“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,” said lead author Christopher Rooney, the National Institute for Health Research (NIHR) Academic Clinical Lecturer at the University of Leeds and Leeds Teaching Hospitals NHS Trust. “This new research might give us a major opportunity to act sooner to prevent rheumatoid arthritis.”

Potential treatments that the researchers want to test at the 10-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.
Although they cannot prove cause and effect, higher numbers of Prevotella could someday be used as a biomarker for RA. However, the disease is complex, according to Prof. Wilcox, so one biomarker probably will not be diagnostic.

“This could be a possibility,” said Prof. Wilcox, the consultant and head of Microbiology Research and Development, and the infection lead of the Leeds NIHR Diagnostic Technologies Medical Technology and In Vitro Diagnostic Co-operative at Leeds Teaching Hospitals NHS Trust; and a professor of medical microbiology and the Sir Edward Brotherton Chair of Bacteriology at the University of Leeds.

“However, it is likely that there are multiple factors responsible for the initiation of RA.  So, a prediction tool or set of biomarkers will probably be needed to be most accurate at predicting RA,” Prof. Wilcox said.

Because antibiotics affect gut bacteria, their role should also be considered. “We are gradually learning more about the downsides to taking antibiotics, including their effects on the microbiome, particularly the ‘good’ bacteria in the gut,” Prof. Wilcox said.  “As we learn more about these effects, then we will be better equipped to weigh up the risks versus the benefits of taking an antibiotic.  

“People should not avoid antibiotics because of a concern of RA specifically. However, everyone should be aware that antibiotics are valuable medicines that need to be used carefully and not as cure-alls,” said Dr. Wilcox, who is also the lead on Clostridioides difficile infection for the U.K. Health Security Agency and the national clinical director of Antimicrobial Resistance & Infection Prevention and Control for NHS England.   

The researchers collaborated with the NIHR Leeds Biomedical Research Centre. Leeds Teaching Hospitals NHS Trust, Versus Arthritis and Leeds Hospitals Charity were also partners on the project. Patients at Chapel Allerton Hospital helped to design the research to make stool sampling easier for participants.