Call it a gut reaction.
Doctors don’t know what triggers the body’s immune system to attack the joints that cause rheumatoid arthritis, but Veena Taneja, Ph.D., an immunologist at the Mayo Clinic Center for Individualized Medicine, has long suspected a link between the trillions of microbes living and working inside our digestive systems and the disease.
So Dr. Taneja and her colleagues went to work trying to find the connection between the microbiome of the gut — sometimes called the “forgotten organ” — and rheumatoid arthritis, a mysterious and painful autoimmune disorder that causes inflammation in the joints.
Now emerging research from Mayo Clinic has identified bacteria living in the intestine as the possible cause. The study suggests dysbiosis — a form of microbial imbalance on or inside the body — in rheumatoid arthritis patients results from the abundance of certain rare bacterial lineages. A correlation between the intestinal microbiota and metabolic signatures could determine a predictive profile for the cause and progression of RA, as rheumatoid arthritis is often called.
To date, there has been limited information on the role of gut microbiota in rheumatoid arthritis. In this study, the Mayo Clinic researchers aimed to define a microbial and metabolite profile that could predict disease status.
“Doctors don’t know what triggers the body’s immune system to attack the joints that cause rheumatoid arthritis,” says Dr. Taneja, senior author of the study. “Infections have been suspected as the offenders but now the emerging research has helped us understand that the bacteria living in our intestine may be the potential culprits.”
Dr. Taneja and her colleagues, to identify a rheumatoid arthritis biomarker profile, sequenced the 16S ribosomal DNA of fecal samples from RA patients and random healthy non-RA controls. Analysis of metabolites and their association with specific taxa was performed to investigate a potential link. The role of an RA-associated microbe was confirmed using a human epithelial cell line and a humanized mouse model of arthritis.
With more than 1.5 million Americans living with rheumatoid arthritis, the clinical applications of the study are significant. It may lead to new diagnostic methods for people with rheumatoid arthritis and possible novel treatments, according to John Davis III, M.D., and Eric Matteson, M.D., both rheumatologists at Mayo Clinic and co-authors on the study.
"We have been able to show the gut microbiome may be used as a biomarker for rheumatoid arthritis,” says, Dr. Davis. “The biomarkers observed in this study may improve our diagnostic ability for these patients and gives us the opportunity to develop and test targeted therapies that enhance control of their RA.”
“The study also provides important insight into the mechanisms of immune tolerance and loss of tolerance which may result in diseases such as rheumatoid arthritis,” adds Dr. Matteson.
Patients with rheumatoid arthritis exhibited decreased gut microbial diversity compared with controls, which correlated with disease duration and autoantibody levels. An analysis suggested an expansion of rare taxa, Actinobacteria, with a decrease in a taxa that is generally found in high abundance in healthy individuals, in patients with RA compared with controls. Prediction models suggested that three genera, Collinsella, Eggerthella, and Faecalibacterium, segregated with RA. The abundance of Collinsella correlated strongly with high levels of alpha-aminoadipic acid and asparagine as well as production of the proinflammatory cytokine IL-17A. A role for Collinsella in altering gut permeability and disease severity was confirmed in experimental arthritis.
“Using genomic sequencing technology, we analyzed the gut microbe compositions of rheumatoid arthritis patients and were able to pin down some gut microbes, which were normally rare and of low abundance but expanded in rheumatoid arthritis patients,” Dr. Taneja says. “Using mouse models, we for the first time demonstrated a direct causal link between the gut microbe Collinsella and the arthritis phenotype.”
Further studies will determine if certain bugs can be used as biomarkers for rheumatoid arthritis and if the heterogeneous nature of the disease is dependent on the bugs in the gut.
Additional co-authors on the study include Jun Chen, Ph.D.; Kerry Wright, M.B.B.S; Patricio Jeraldo, Ph.D.; Eric Marietta, Ph.D.; Joseph Murray, M.D.; and Heidi Nelson, M.D.; all from Mayo Clinic.