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Editorial
Commensal Gut Bacteria and the Etiopathogenesis of Rheumatoid Arthritis
CHRISTOPHER J. EDWARDS, BSc, MD, FRCP,
Southampton University Hospitals NHS Trust, Southampton, United Kingdom Address reprint requests to Dr. C.J. Edwards, Department of Rheumatology, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK. E-mail:cedwards@soton.ac.uk Although the exact sequence of steps required to induce rheumatoid arthritis (RA) is unclear, both genetic and environmental factors appear to be important. In recent years the genetics of RA have been extensively studied, with a number of important gene associations described. These studies have confirmed the importance of major histocompatibility complex (MHC) genes and identified other loci that are currently being explored. However, estimates of heritability suggest that genetic factors are only responsible for around 50% of the risk of developing RA1. This means that environmental factors and gene-environment interactions must also play a significant role. Despite this understanding, much less attention has been focused on determining the important environmental exposures involved. It has been hard to define with certainty important environmental factors although some success has come from the description of a strong link between smoking and RA2. Infectious organisms are attractive as potential environmental triggers for the development of RA. They are ubiquitous, can alter immune functioning, and a number of infectious organisms have been strongly associated with seronegative spondyloarthropathies. We are all surrounded by an environment saturated with microorganisms that also live as commensal flora on and in our bodies. This results in our continuous exposure to a multitude of different bacteria and viruses. A number of these have previously been associated with RA, including Mycobacterium tuberculosis, Proteus mirabilis, Escherichia coli, Epstein-Barr virus, retroviruses, and parvovirus B193. However, no one specific organism has emerged as a key environmental factor responsible for the development of disease. Lack of success in defining a dominant microbial stimulus may be for a number of reasons. With the realization that the disease process in RA begins many years before clinical disease expression, the possibility is raised that we have been looking too late. The RA-associated autoantibodies rheumatoid factor (RF) and anti-citrullinated peptide may be present 10 years before onset of clinical disease4. Perhaps the important events in the development of RA occur decades before disease becomes overt, possibly even during infancy or childhood. Thus, studies that have largely concentrated on the time around disease onset would miss environmental factors that act early in life. Another attractive possibility is that one specific organism is less important than the total burden of infectious exposure over a period of time. This "burden" is a challenge to measure. One approach is to look at evidence of exposure to a panel of common infections. For example, the cumulative exposure of an individual to a wide range of infectious organisms (cytomegalovirus, hepatitis A, herpes simplex type I and II, Chlamydia pneumoniae and Helicobacter pylori) affects the level of immune activation as measured by interleukin 6 (IL-6) and highly sensitive C-reactive protein (hs-CRP) levels5. Perhaps a particular pattern or volume of infectious exposure might alter immune function and be important in RA etiopathogenesis. Further evidence for the role of broad infectious exposure to development of RA comes from animal models. In rodent adjuvant and collagen-induced arthritis the incidence and severity of arthritis are increased when animals are reared in a germ-free environment6,7. Similar findings have come from the study of allergies where increased exposure to infectious organisms appears to decrease the incidence and severity of disease. An important message from this work is that infectious exposure important to RA development may result from unrecognized occult exposures to microorganisms without clinical evidence of infection. Other clues to the importance of bacteria in RA come from studies of therapy. Both sulfasalazine and minocycline have been shown to be effective treatments in RA. Monocycline appears to inhibit matrix metalloproteinases, but both agents may act through antibacterial effects8. In addition, bacterial DNA and peptidoglycans have also been found in the synovium of individuals with RA9,10. There is no site of greater interaction between microorganisms and the human body than the digestive tract. Commensal gut bacteria interact with specialized gut mucosa-associated lymphoid tissue (MALT), and there are specific immunoglobulins active on mucosal surfaces (sIgA). The gut is a special site for the immune system as exposure to antigens through this route can produce tolerance. The number of bacteria present in the adult gut is 1–2 kg, of which more than half have never been cultured11. Despite the numbers in healthy individuals, these organisms appear to be beneficial, maintaining normal immune system function, denying space for pathogenic bacteria, and helping with digestion of food. However, despite this mainly symbiotic relationship even commensal gut bacteria can induce arthritis in animal models12-14. It also appears that the genetic background of an individual, including their MHC genes, influences the composition of the intestinal flora15. In this edition of The Journal Jussi Vaahtovuo and colleagues describe the presence of a different composition of fecal bacteria in individuals with RA when compared to controls16. They included individuals with recent onset RA (≤ 6 mo) and controls with fibromyalgia. Patients who had previously taken disease modifying antirheumatic drugs (DMARD) or prednisolone, who were currently taking antibiotics, or who had recently had gastroenteritis were excluded. The authors used flow cytometry, 16S rRNA hybridization, and DNA-staining. This molecular biological approach allowed analysis of the quantity of intestinal microbes and the bacterial genera present. The results showed less Bifidobacteria, Bacteriodes-Porphyromonas-Prevotella, Bacteroides fragilis subgroup, and Eubacterium rectale-Clostridium coccoides group in the guts of RA patients when compared to controls. The authors considered other causes of changed gut flora and excluded individuals with extreme dietary habits. The patients included were all from a similar geographical area, none had received DMARD, and smoking habits were similar in the RA and control groups. A role for commensal gut bacteria in allergy and inflammatory bowel disease has been demonstrated with similar evidence. Infants with eczema appear to have significantly lower counts of Bifidobacterium and Clostridium but higher counts of total lactic acid-producing bacteria in their guts when measured in stool samples17. Adults with Crohn's disease have less Bacteriodes-Porphyromonas-Prevotella in the gut versus healthy controls18,19. Questions remain. Is this a case of cause or effect? Do individuals with RA have a smaller total number of bacteria in the gut or smaller numbers of particular bacterial groups but with a broader spectrum of different bacteria (perhaps some being arthritogenic)? What effect does treatment have on the composition of gut microbes? Does the composition of gut microbes change following successful versus unsuccessful treatment? How might changes in gut flora produce changes in immune function that may lead to inflammatory joint disease? Does this explain the reported improvement in symptoms and signs seen in individuals with RA who start a vegetarian/vegan diet20,21? The important environmental drivers of RA are still being sought. However, it is conceivable that different compositions of gut flora may alter the normal physiological interactions within the intestine and expose the immune system to bacterial antigens with arthritogenic potential. Perhaps when looking for microbial triggers for RA in the environment we need to spend time looking at our most common exposure to bacteria in the form of the abundant commensal bacteria teeming on and in us every day. 2. Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis 2003;62:835-41. [MEDLINE] 3. Maini RN, Feldmann M. Immunopathogenesis of rheumatoid arthritis. In: Isenberg DA, Maddison PJ, Woo P, Glass D, Breedveld FC, editors. Oxford textbook of rheumatology. 3rd ed. Oxford: Oxford University Press; 2004:677-97. 4. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380-6. [MEDLINE] 5. Zhu J, Quyyumi AA, Norman JE, et al. Effects of total pathogen burden on coronary artery disease risk and C-reactive protein levels. Am J Cardiol 2000;85:140-6. [MEDLINE] 6. Breban MA, Moreau MC, Fournier C, Ducluzeau R, Kahn MF. Influence of the bacterial flora on collagen-induced arthritis in susceptible and resistant strains of rats. Clin Exp Rheumatol 1993;11:61-4. [MEDLINE] 7. Moudgil KD, Kim E, Yun OJ, Chi HH, Brahn E, Sercarz EE. Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 2001;166:4237-43. [MEDLINE] 8. Stone M, Fortin PR, Pacheco-Tena C, Inman RD. Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol 2003;30:2112-22. [MEDLINE] 9. Schrijver IA, Melief MJ, Tak PP, Hazenberg MP, Laman JD. Antigen-presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines. Arthritis Rheum 2000;43:2160-8. [MEDLINE] 10. van der Heijden IM, Wilbrink B, Tchetverikov I, et al. Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum 2000;43:593-8. [MEDLINE] 11. Gill SR, Pop M, Deboy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science 2006;312:1355-9. [MEDLINE] 12. Severijnen AJ, van Kleef R, Hazenberg MP, van de Merwe JP. Cell wall fragments from major residents of the human intestinal flora induce chronic arthritis in rats. J Rheumatol 1989;16:1061-8. [MEDLINE] 13. Zhang X, Rimpilainen M, Hoffmann B, Simelyte E, Aho H, Toivanen P. Experimental chronic arthritis and granulomatous inflammation induced by bifidobacterium cell walls. Scand J Immunol 2001;54:171-9. [MEDLINE] 14. Zhang X, Rimpilainen M, Simelyte E, Toivanen P. Characterisation of Eubacterium cell wall: peptidoglycan structure determines arthritogenicity. Ann Rheum Dis 2001;60:269-74. [MEDLINE] 15. Toivanen P, Vaahtovuo J, Eerola E. Influence of major histocompatibility complex on bacterial composition of fecal flora. Infect Immun 2001;69:2372-7. [MEDLINE] 16. Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol 2008;35:1500-5. 17. Mah KW, Bjorksten B, Lee BW, et al. Distinct pattern of commensal gut microbiota in toddlers with eczema. Int Arch Allergy Immunol 2006;140:157-63. [MEDLINE] 18. Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon. Gut 2003;52:237-42. [MEDLINE] 19. Sokol H, Seksik P, Rigottier-Gois L, et al. Specificities of the fecal microbiota in inflammatory bowel disease. Inflamm Bowel Dis 2006;12:106-11. [MEDLINE] 20. Hafstrom I, Ringertz B, Spangberg A, et al. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology Oxford 2001;40:1175-9. [MEDLINE] 21. Peltonen R, Nenonen M, Helve T, Hanninen O, Toivanen P, Eerola E. Faecal microbial flora and disease activity in rheumatoid arthritis during a vegan diet. Br J Rheumatol 1997;36:64-8. [MEDLINE]
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