The Connection Between Leaky Gut and Arthritis

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                                                                                                                                                                                                                    Read time 3 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.2,3 One theory dating back to the beginning of the 20th century suggested that RA emerges from mucosal tissues and dysbiosis, and only later do problems occur in the synovial fluid and joints.4-7 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.8 People with RA have different gut microbial populations than people with other inflammatory diagnoses3—in particular, individuals newly diagnosed with RA have higher populations of Prevotella copri.9,10

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.11 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.11

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.12 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).12 Higher levels of gingival disease and unhealthy oral microbiota are also associated with the early stage of RA.1,13,14 Gut bacteria have also been found in the synovial fluid of RA mouse models, suggesting that treatment of mucosal surfaces and the microbiome may curtail or affect the development and course of RA.15 Taken together, these factors suggest that RA might be avoidable if the signs are recognized early enough and gut health can be restored.16

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

(Video Time: 2 minutes)

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.16 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.16

What can you do for patients with intestinal permeability? Romilly Hodges, MS, CNS, IFMCP, provides an overview of the many factors that increase and decrease gut permeability in an informative blog post published on the website of IFM educator Kara Fitzgerald, ND17

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. 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).

Learn More About Functional Medicine

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  1. Maeda Y, Takeda K. Host–microbiota interactions in rheumatoid arthritis. Exp Mol Med. 2019;51(12):1-6. doi:10.1038/s12276-019-0283-6
  2. Karlson EW, Chibnik LB, Tworoger SS, et al. Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum. 2009;60(3):641-652. doi:10.1002/art.24350
  3. 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:10.1002/art.39297
  4. Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol. 2014;26(1):101-107. doi:10.1097/BOR.0000000000000008
  5. Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S. The role of the microbiome in rheumatic diseases. Curr Rheumatol Rep. 2013;15(3):314. doi:10.1007/s11926-012-0314-y
  6. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J Autoimmun. 2020;110:102400. doi:10.1016/j.jaut.2019.102400
  7. 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:10.1136/annrheumdis-2019-216631
  8. Demoruelle MK, Deane KD, Holers VM. When and where does inflammation begin in rheumatoid arthritis? Curr Opin Rheumatol. 2014;26(1):64-71. doi:10.1097/BOR.0000000000000017
  9. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202. doi:10.7554/eLife.01202
  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:10.3390/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:10.1136/annrheumdis-2021-221267
  12.  Scher JU, Ubeda C, Equinda M, et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum. 2012;64(10):3083-3094. doi:10.1002/art.34539
  13.  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:10.1093/rheumatology/keaa835
  14.  Luckey D, Gomez A, Murray J, White B, Taneja V. Bugs & us: the role of the gut in autoimmunity. Indian J Med Res. 2013;138(5):732-743.
  15.  Taneja V. Arthritis susceptibility and the gut microbiome. FEBS Lett. 2014;588(22):4244-4249. doi:10.1016/j.febslet.2014.05.034
  16.  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:10.1186/s13073-021-00957-0
  17.  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 February 17, 2022.

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