insights

                                                                                                                                                                                                                  Read Time: 4 minutes

A healthy intestinal microbiome is essential to optimal wellness, and knowledge surrounding this relationship has grown substantially in recent years. The connection between gut health and rheumatoid arthritis (RA) development is one example, as the gut microbiota has been proposed to be an important environmental factor of the disease.¹ RA is one of several conditions where gut permeability predates symptoms, and it may be possible to prevent joint damage by treating the gut. What is the state of research on arthritis, the microbiome, and gut permeability?

Inflammatory biomarkers are known to emerge years before a definitive diagnosis of rheumatoid arthritis is possible.² One theory dating back to the beginning of the 20^th century suggested that RA emerges from mucosal tissues and dysbiosis, and only later do problems occur in the synovial fluid and joints.^3,4 More recent research supports this chain of events. For example, research suggests that IgA antibodies, which are closely associated with mucosa, are elevated in preclinical and recently diagnosed RA patients.⁵ Studies continue to evaluate the relationship between RA risk and inflammatory indicators, including antibodies, cytokines, and proteins such as serum amyloid A (SAA).^6-8

People with RA have different gut microbial populations than people with other inflammatory diagnoses³—in particular, individuals newly diagnosed with RA have been found to have reduced levels of Faecalibacterium in the gut, a butyrate-generating beneficial bacterium.⁹ A small 2019 study found significant differences in the microbial distribution of various taxa from phylum to genus levels between 25 healthy subjects and 29 early RA patients.¹⁰ Phylum Bacteroidetes was enriched in early RA patients, while Actinobacteria, including the genus Collinsella, was enriched in healthy subjects. Functional analysis based on clusters of orthologous groups revealed that the genes related to the biosynthesis of menaquinone, known to be derived from gram-positive bacteria, were enriched in healthy subjects, while iron transport–related genes were enriched in early RA patients. Genes related to the biosynthesis of lipopolysaccharide, the gram-negative bacterial endotoxin, were enriched in clinically apparent RA patients.¹⁰

More recently, researchers in Japan performed a whole gut virome analysis based on the shotgun sequencing of 476 individuals with RA, systemic lupus erythematosus (SLE), multiple sclerosis (MS), and healthy controls.¹¹ The case-control comparison revealed that crAss-like phages, which are one of the main components of a healthy gut virome, significantly decreased in the gut of the patients with autoimmune diseases, specifically the patients with RA and SLE. Multiple bacterial targets of crAss-like phages were identified (e.g., Ruminococcus spp).¹¹ Higher levels of gingival disease and unhealthy oral microbiota are also associated with the early stage of RA.⁹ Taken together, these factors suggest that risk of RA development may be reduced for some patients if the signs are recognized early enough and gut health is restored.

In the following video, IFM educator Robert Rountree, MD, shares how he approaches arthritis and the importance of assessing the likely cause.

Influencing Outcomes

Another small but interesting September 2021 study, published in Genome Medicine, suggests that gut microbes and a patient’s outcome of RA may also be connected.¹² Researchers at the Mayo Clinic performed shotgun metagenomic sequencing on stool samples from 32 patients with RA at two separate clinical visits and compared the baseline gut microbiome compositions between RA patients who eventually showed improvement in disease activity and those who did not. They found several traits of the gut microbiome linked to future prognosis and used artificial intelligence to predict clinical outcomes with an accuracy of 90%. The results, write the authors, could implicate various aspects of the gut microbiome with improvement in chronic, debilitating symptoms in RA, raising the possibility of intervening on these markers, e.g., introducing specific desirable bacterial strains into the gut or targeting microbial metabolic pathways as a basis for therapeutic intervention.¹²

As research continues to suggest that gut dysbiosis may contribute to the development of some rheumatic diseases such as rheumatoid arthritis,¹³ what can you do for patients with intestinal permeability? Functional medicine helps clinicians understand the critical roles of gut mucosal integrity and microbial dysbiosis on patient health and provides key insights into preventing and treating chronic diseases related to gut dysfunction. Romilly Hodges, MS, CNS, IFMCP, provides an overview of the many factors that increase and decrease gut permeability in an informative blog post¹⁴ published on the website of IFM educator Kara Fitzgerald, ND.

Learn more about the interplay between the digestive system and the rest of the body at IFM’s Applying Functional Medicine in Clinical Practice (AFMCP) and how IFM tools such as the DIGIN model and 5R framework help to personalize gut health interventions.

Related Articles

Windows of Opportunity for Preclinical Rheumatoid Arthritis

Antinuclear Antibodies and Autoimmune Disease

Rise of Autoimmune Disease Linked to Intestinal Permeability

References

1. Maeda Y, Takeda K. Host–microbiota interactions in rheumatoid arthritis. Exp Mol Med.2019;51(12):1-6. doi:1038/s12276-019-0283-6
2. Ramos-Remus C, Castillo-Ortiz JD, Aguilar-Lozano L, et al. Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease. Arthritis Rheumatol. 2015;67(11):2837-2844. doi:1002/art.39297
3. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun. 2020;110:102400. doi:1016/j.jaut.2019.102400
4. Manasson J, Blank RB, Scher JU. The microbiome in rheumatology: where are we and where should we go? Ann Rheum Dis. 2020;79(6):727-733. doi:1136/annrheumdis-2019-216631
5. Derksen VFAM, Allaart CF, Van der Helm-Van Mil AHM, Huizinga TWJ, Toes REM, van der Woude D. In rheumatoid arthritis patients, total IgA1 and IgA2 levels are elevated: implications for the mucosal origin hypothesis. Rheumatology (Oxford). 2022;62(1):407-416. doi:1093/rheumatology/keac237
6. Meng S, Jing L, Zhang W, Wang F, Dong Y, Dong D. Research progress on serological indices and their clinical application in rheumatoid arthritis. J Clin Lab Anal. 2022;36(9):e24576. doi:1002/jcla.24576
7. Zhou J, Dai Y, Lin Y, Chen K. Association between serum amyloid A and rheumatoid arthritis: a systematic review and meta-analysis. Semin Arthritis Rheum. 2022;52:151943. doi:1016/j.semarthrit.2021.12.011
8. Abdelhafiz D, Baker T, Glascow DA, Abdelhafiz A. Biomarkers for the diagnosis and treatment of rheumatoid arthritis – a systematic review. Postgrad Med. 2023;135(3):214-223. doi:1080/00325481.2022.2052626
9. Chu XJ, Cao NW, Zhou HY, et al. The oral and gut microbiome in rheumatoid arthritis patients: a systematic review. Rheumatology (Oxford). 2021:60(3):1054-1066. doi:1093/rheumatology/keaa835
10.  Jeong Y, Kim JW, You HJ, et al. Gut microbial composition and function are altered in patients with early rheumatoid arthritis. J Clin Med. 2019;8(5):E693. doi:3390/jcm8050693
11.  Tomofuji Y, Kishikawa T, Maeda Y, et al. Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease. Ann Rheum Dis. 2022;81(2):278-288. doi:1136/annrheumdis-2021-221267
12.  Gupta VK, Cunningham KY, Hur B, et al.Gut microbial determinants of clinically important improvement in patients with rheumatoid arthritis. Genome Med. 2021;13(1):149. doi:1186/s13073-021-00957-0
13.  Wang Y, Wei J, Zhang W, et al. Gut dysbiosis in rheumatic diseases: a systematic review and meta-analysis of 92 observational studies. EBioMedicine. 2022;80:104055. doi:1016/j.ebiom.2022.104055
14.  Hodges R, Kovalchik J, Herdell J. Expanding our view on leaky gut: beyond the ON/OFF idea. Dr. Kara Fitzgerald, Functional Medicine. Updated September 2020. Accessed May 1, 2023. http://www.drkarafitzgerald.com/2016/08/01/expanding-our-view-on-leaky-gut-beyond-the-onoff-idea/