Gut microbiome changes linked to onset of clinically evident rheumatoid arthritis

Changes in the make-up of the gut microbiome are linked to the onset of clinically evident rheumatoid arthritis in those at risk of the disease because of genetic, environmental, or immunological factors, suggests research published online in the Annals of the Rheumatic Diseases.

It’s not clear if this instability is a cause or consequence of disease development, emphasise the researchers, but the findings might nevertheless help to identify those at risk as well as paving the way for preventive and personalised treatment strategies, they suggest.

Previously published research consistently shows an unfavourable 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.

To explore this further, the researchers tracked changes in the gut microbiome profiles of 124 people at risk of developing rheumatoid arthritis; in 7 newly diagnosed people; and in 22 healthy people over a period of 15 months, by assessing their stool and blood samples at 5 different time points.

Those at risk were identified by the presence of precursor anticyclic citrullinated protein (anti-CCP) antibodies, which attack healthy cells and are specific for rheumatoid arthritis, and by experience of joint pain in the preceding 3 months.

Weekly dietary intake was similar among all three groups, although alcohol intake and the amount of regular moderate to vigorous exercise taken differed.

During the study period, 30 of the 124 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. 

Recognised 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, say the researchers.

Further analysis indicated that both enrichment (three) and depletion (five) of Prevotellaceae-specific strains were associated with progression.

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 greatest instability in gut microbiome profile was seen among those who developed arthritis up to 10 months before diagnosis. But this profile was relatively stable in those diagnosed after this time—10-15 months before the development of rheumatoid arthritis. This suggests that changes in the gut microbiome are a late stage phenomenon, say the researchers.

This is an observational study, precluding any firm conclusions to be drawn about causal factors. And the researchers acknowledge 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.

But they conclude: "Individuals at risk of [rheumatoid arthritis] harbour 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. 

“Longitudinal examination shows a dynamic microbial environment preceding [rheumatoid arthritis] 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.”