According to new research, the number of microbial small RNAs (sRNAs) in a person’s plasma correlates to disease outcomes, including those associated with rheumatoid arthritis.
Michelle Ormseth, M.D., an assistant professor in the Division of Rheumatology and Immunology at Vanderbilt University Medical Center, is one of the first to specifically study sRNAs of microbial origin in the context of rheumatoid arthritis – as opposed to the human tRNA, mRNA, rRNA and yRNA commonly circulating in the body.
“When you look at all the sRNAs circulating in our blood, there’s a large proportion that don’t align to the human genome. About 20 percent map perfectly to bacterial genomes,” said Ormseth, who previously catalogued human sRNAs in rheumatoid arthritis. “It’s possible barrier issues in the gut or mouth during rheumatoid arthritis might influence microbial sRNA levels, such that microbial sRNAs could serve as biomarkers for disease.”
While most microbial sRNAs are unmapped, recent studies find the enigmatic fragments can significantly alter host gene expression and immune function. Ormseth says microbial sRNAs could be beneficial.
“You’d assume bits of genetic material from bacteria would cause inflammation and make things worse, but it seems they may downregulate immune responses. That’s a good thing for people with rheumatoid arthritis.”
Connections to Disease Outcomes
Ormseth’s most recent study, published in the Annals of the Rheumatic Diseases, sought to determine if microbial sRNAs are altered by rheumatoid arthritis or change in relation to drug treatment.
The researchers used next generation sequencing to analyze plasma sRNAs in people with and without rheumatoid arthritis, and in a separate cohort of patients before and after starting a disease-modifying antirheumatic drug (DMARD). The drugs included methotrexate, adalimumab (anti-TNF inhibitor) or tocilizumab (anti-IL-6). The team removed human sRNA sequences from results, and leveraged databases of environmental, microbiome and fungal microbial genomes to identify sRNA sources.
“We found microbial sRNAs were quite abundant in rheumatoid arthritis patients, and the more an individual had, the lower their disease activity,” Ormseth said. “We saw this across both patient cohorts.”
“Microbial sRNAs were quite abundant in rheumatoid arthritis patients, and the more an individual had, the lower their disease activity.”
Patients with high levels of microbial sRNAs also had improved drug responses. The researchers found patients with more microbial sRNAs in their plasma before starting a DMARD regimen were less likely to report symptoms like joint pain six months later.
The study lists ten bacterial species whose genome counts varied between patients with and without rheumatoid arthritis. It also highlights a group of microbial sRNAs, called tDRs, that are made by multiple bacteria. “Several microbial tDRs closely structurally related were significantly increased among patients with [rheumatoid arthritis] and were also associated with lower measures of disease activity,” the researchers wrote.
Ormseth says the microbial sRNAs could hold untapped therapeutic potential. “I’m very interested to look further to see if these microbial sRNAs are actually fine-tuning our immune system.”
Her team is also testing if antibiotics that alter the gut microbiome change microbial sRNAs levels. More precisely, the researchers would like to determine which sRNAs are altered by antibiotics and the impact of the alterations on disease outcomes.