Momentum Builds for Microbiome as RA Trigger

Another study has suggested that a component of the gut microbiome may contribute to development of rheumatoid arthritis (RA) — but now it’s a different bug from those previously implicated in the condition.

In a series of animal experiments and clinical studies, the culprit appeared to be an intestinal organism in the genus Subdoligranulum, according to Kristine A. Kuhn, MD, PhD, of the University of Colorado in Aurora, and colleagues.

As reported in Science Translational Medicine, the researchers confirmed “cross-reactivity between RA-relevant autoantigens and bacterial taxa in the closely related families Lachnospiraceae and Ruminococcaceae.” Both are represented in the typical human microbiome and the latter includes Subdoligranulum.

Moreover, mice born and raised in sterile conditions, then gavaged orally with a Subdoligranulum isolate obtained from a person with early RA, developed paw swelling and other features resembling the human disease. That isolate was one of five that seemed reactive with RA-related antigens in lab experiments.

These results overall suggest that Subdoligranulum bacteria play a role in at least some RA cases, although Kuhn’s group stopped short of asserting that they are the one and only cause of RA.

Indeed, some members of the group also participated in the study MedPage Today reported on a week ago, which pointed to a different intestinal bacterium, Prevotella copri, as an RA trigger.

In the newly reported work, the researchers had also treated the germ-free mice with P. copri, without seeing RA-like symptoms or biomarkers. But Kuhn told MedPage Today in an email that it wasn’t the same P. copri strain used in the earlier study. “We cannot conclude that [P. copri] does not cause RA,” she said; rather, P. copri “may be relevant in a subset of individuals,” while Subdoligranulum plays that role in another. “Or, alternatively, they trigger pathology at different phases of disease development,” she added.

In an earlier interview published by the University of Colorado, following a meeting presentation of some of the Subdoligranulum data, Kuhn said the research indicates “this bacteria might be important, probably not in all patients but in some patients, or that it’s one more layer of what’s needed to get rheumatoid arthritis,” in addition to genetic, environmental, and lifestyle factors.

An accompanying editorial in Science Translational Medicine by two researchers at NYU Langone Health in New York City also expressed caution. “The characterization of the relevant antibodies and of the specificities for autoantigen and microbiota is thorough; however, the scope is somewhat limited because it is confined to studying a single bacterial subvariant within a murine model. It is hence unclear how representative that bacterial strain is of all potentially arthritogenic strains in at-risk individuals and patients with RA,” wrote Rabi Upadhyay, MD, and Dan R. Littman, MD, PhD.

But they were also optimistic that this line of research would eventually pay dividends. Current RA therapies are generally effective at controlling the disease, yet “any semblance of molecular remission or capacity to reestablish immunologic tolerance itself has eluded the field,” Upadhyay and Littman noted.

“By identifying the specific gut microbiota members that may be the provocateurs of the original local immune response, and perhaps by pursuing clinical trials where these bacteria are eliminated in at-risk individuals, rheumatologists may finally stand a chance of reversing or preventing disease,” they concluded.

Kuhn told MedPage Today that, as a next step, her group plans “to perform large population studies to understand in individuals at risk for RA how genetic risk as well as different bacterial strains and other mucosal exposures interact with each other and drive the eventual development of rheumatoid arthritis.”

Limitations to the current study were many. Among them were the use of very special mice in the experimental work, and that the Subdoligranulum isolates used in those studies came from a single, carefully chosen RA patient.