Microbial Small RNAs to Predict Arthritis Outcomes

Little understood, the role of microbial sRNAs may be a pathway to personalizing treatment.

Nearly one quarter of small RNAs (sRNAs) circulating in the plasma are microbial in origin. Most microbial sRNAs are unmapped, yet the enigmatic fragments can significantly alter host gene expression. Microbial sRNAs are commonly packaged alongside virulence factors in free-floating outer membrane vesicles.

According to new research, the number of microbial sRNAs circulating in a person’s plasma correlates modestly to certain disease outcomes, including rheumatoid arthritis. Michelle Ormseth, M.D., 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.

“We found microbial sRNAs are quite abundant in human plasma, and the more an individual had, the lower their disease activity in rheumatoid arthritis.”

She first identified the microbial RNA-disease connection in a study of 167 rheumatoid arthritis patients. Said Ormseth, “We found microbial sRNAs are quite abundant in human plasma, and the more an individual had, the lower their disease activity in rheumatoid arthritis.”

Understanding Levels of Microbial sRNAs

To understand what contributes to microbial sRNA levels, Ormseth recently conducted a second study of 70 rheumatoid arthritis patients across nine medical centers. Each participant provided blood samples before and six months after starting a disease-modifying anti-rheumatic drug (DMARD). Drugs included methotrexate, adalimumab (anti-TNF inhibitor) or tocilizumab (anti-IL-6).

The study investigated if microbial sRNA levels change in response to DMARD treatment, and if levels could be used to predict disease outcomes.

Ormseth and colleagues used sequencing to measure microbial sRNAs in each blood sample. They removed human sRNA sequences from results, and leveraged databases of environmental, microbiome and fungal microbial genomes.

“We found the drugs did not change the composition of microbial sRNAs circulating in plasma,” Ormseth said. For example, similar levels of Staphylococcus aureus sRNAs were found in a patient’s plasma before and after treatment. “However, patients who improved with DMARD therapy had threefold higher total abundance of microbial sRNAs at baseline.”

“Patients who improved with DMARD therapy had threefold higher total abundance of microbial sRNAs at baseline.”

DMARD therapy was most successful in patients with high microbial sRNA levels. The researchers also found patients with more microbial sRNAs in their plasma at baseline were less likely to report joint pain over the course of the study.

Going Beyond the Microbiome

Ormseth’s work suggests that microbial sRNAs could play a significant role in a patient’s response to drugs in rheumatoid arthritis. Microbial sRNAs may also serve as a biomarker to help predict disease outcomes. These findings are supported by studies that point to the microbiome as a major contributor to inflammatory arthritis and rheumatic disease.

“There’s been a flurry of work in rheumatoid arthritis and other related autoimmune diseases on the microbiome; the microbes that are in our mouths, guts and lungs,” Ormseth said. “I’m very interested to look further to see if these microbial sRNAs are actually fine-tuning our immune system.”

Ormseth and colleagues are now 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.