The Intestinal Mucosal Microbiome and Circulating Microbial Extracellular Vesicles in Rheumatoid Arthritis
Abstract
Rheumatoid arthritis (RA) is disease characterized by an autoimmune attack on the joints and can lead to long term pain and disability and shorten lifespan by nearly 10 years. RA affects Veterans disproportionately, possibly due to environmental factors. One of these factors may be bacteria in the intestine. Researchers have studied bacteria in the stool rather than the bacteria on or in the lining of the intestine. However, these intestinal lining bacteria are likely the ones important for health and disease because they are so close to human immune cells and blood vessels. Thus, the bacteria themselves and certain bacterial products could enter the circulation more easily. Some of these products that bacteria make can affect inflammation in people and thus affect RA. One product that bacteria make are structures called extracellular vesicles (ECVs). Bacteria and other microbes pinch off part of their cell wall to make ECVs so that the ECVs contain some of the same substances on their membrane which the bacteria have. Some of these substances can cause inflammation. Also, the bacteria package ECVs with short segments of nucleic acids (small RNAs or sRNAs). Bacteria use the sRNAs to regulate human genes, particularly genes affecting how the immune system works. The bacteria likely do this to promote their own survival. We studied the sRNAs (not by isolating the ECVs, but by looking at all sRNAs) in the blood of patients with RA and people who do not have RA and found that RA patients had different bacterial sRNAs compared to people without RA and that the higher the abundance of some sRNAs, the lower the disease activity and the better patients responded to a new drug. We also found that one of these bacterial sRNAs decreases an immune response that also causes pain. So, some of the bacterial sRNAs are associated with good outcomes in RA patients. The problem is that we have not yet studied the whole package – the ECV with the sRNAs inside. This is important because the membrane of the ECV as well as the sRNA inside can alter inflammation, potentially in conflicting ways. Our central hypothesis is that intestinal lining bacteria are different in RA patients and via ECVs transfer bacterial sRNAs to the circulation and thus affect disease. To examine this, we propose an innovative study in which we will (1) collect intestinal biopsies and compare the bacteria present in these specimens from patients with and without RA who are getting a routine screening colonoscopy. (2) We will collect blood from the patients undergoing colonoscopy and from additional Veterans with and without RA and purify the bacterial ECVs from the blood. (3) We will treat cells with the isolated ECVs, measure changes in cellular inflammatory proteins, and determine if these differ in cells treated with ECVs from RA versus non-RA patients. (4) We will measure bacterial sRNAs that the ECVs transfer to cells and determine if these differ in RA versus non-RA patients. (5) We will test the function of sRNAs that are most abundant and transferred from RA ECVs to cells. (6) We will statistically measure what percentage of the variability in the bacterial sRNAs in the blood can be explained by the bacteria present in the intestinal biopsies. These studies will lay the important foundations necessary before applying for additional funding to broaden these experiments and incorporate manipulations of the intestinal wall bacteria, ECVs and sRNAs to change RA in animal models and eventually human patients. This pilot project directly addresses the Fiscal Year 2022 Peer Reviewed Medical Research Program Strategic Goal to determine the impact of microbiome on the Portfolio Category Autoimmune Disorders and Immunology in the Topic Area Rheumatoid Arthritis. Studying the bacteria of the intestinal wall and the circulating bacterial ECVs which can transport sRNAs to human cells, and their impact on inflammation is critical to understanding how the bacteria in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310044
Entities
People
- Michelle Ormseth
Organizations
- United States Army
- Vanderbilt University