Introduction: Rheumatoid Arthritis is an autoimmune disease that affects 350 million people worldwide. RA is a result of both genetic indicators and environmental factors. It can cause pain and swelling in the joints, and if it is not treated properly it can lead to chronic joint swelling. Genetic factors have been identified that can increase risk for RA, but genetic predisposition is not enough to explain current disease occurrence. Previous studies suggest that specific gut microbiota plays a role in regulating the immune response and reaction that can cause RA. Currently, the interactions between the vast array of microbiota and the immune response are being explored in determining the pathogenesis of RA. Studies performed on mice have shown that introduction into non germ inoculated mice of segmented filamentous bacteria is enough to prompt disease. Previous studies have established a connection between certain diseases and overabundance of specific gut bacteria, however, the mechanism by which these bacteria interact with the immune system to cause symptoms has not been determined.
Hypothesis: In this paper the authors wanted to investigate the role of microbiota in the systemic immune response that leads to the joint inflammation characteristic of RA. The authors performed 16S sequencing on fecal samples of 44 subjects, 114 samples in total. They used the sequencing to determine if there is a correlation between the pervasiveness of certain bacteria and occurrence of disease, the different genes and mechanisms of the gut bacteria that can cause diseases.
Aims:
Aim 1: Show a correlation between specific gut microbiota and disease incidence.
Aim 2: Determine how the bacteria interacts with the immune system to cause the systemic response that leads to symptoms of RA.
Aim 3: Use the knowledge of bacteria mechanisms and interactions to understand the pathogenesis of RA.
Summary: The first thing that researchers did was sequence the samples gathered and determined a statistically relevant amount of Prevotellaceae in subjects with different forms of RA. The isolated samples related most closely to Prevotella copri, with some variation. Researchers suggested that variation from subject to subject might be a part of the slight different manifestations of RA symptoms. Not only did P. copri differ from subject to subject, but P. copri present in healthy individuals presents differently than it does in NORA subjects, showing different metabolic activity and genes. Researchers wanted to also establish a connection between human alleles and P. copri abundance. They sequenced the DNA of all subjects and showed that there was a correlation between amounts of P. copri in the gut and the existence of the SE allele. The researchers also wanted to determine if the presence of P. copri is enough to cause a response in mice already at risk for RA. They exposed mice to P. copri and observed that those exposed to it showed an increase in inflammation and decrease in weight loss, suggesting that raising the concentration of P. copri in the gut is enough to limit the growth of other microbes and trigger RA symptoms in genetically predisposed mice. Ultimately the authors surmised from the data presented that P. copri succeeds best in an inflammatory environment and can perpetuate inflammatory responses to increase host inflammation.
Critique: Although the paper is certainly interesting and informative, it seems like it could have been more digestible if it was broken up into different papers with more specific and succinct topics. The authors covered several different issues and tied them together even though they might be more coherent as several different papers.
Significance: The findings of the paper were significant because they produced novel data on P. copri virulence, and detailed how it acts in subjects with RA. Understanding how different bacteria affect the immune system to cause disease is crucial in treating those diseases. In addition, understanding the complicated and systemic processes that lead to disease will allow us treat other diseases in new and more affective ways.
Questions:
1. If you’re a subject who is susceptible for RA, are there ways in which you can monitor your levels of P. copri or try to reduce them?
2. Could RA be treated by something like a fecal transplant and diet monitoring if gut microbiota plays such a large role in its virulence?
3. Would it be possible to target the genes that allow P. copri to stimulate inflammation in the host? To specifically engineer an antibiotic that acts against the virulence factors that were established as belonging to P. copri in the paper?