Influence of the Microbiome in Spondyloarthritis

  • Healthy Human Microbiome vs Arthritis Microbiome

    Healthy Human Microbiome vs Arthritis Microbiome

    Studies have shown that healthy human gut microbiomes consist of approximately 1150 bacterial species, with most (50%–75%) being <i>Firmicutes</i> species, followed by <i>Bacteroides</i> (10%–50%), <i>Actinobacteria</i> (1%–10%), and <i>Proteobacteria</i> (<1%) species.<sup>2</sup> The microbiome in patients with arthritis has been found to be significantly different from that of healthy people, often with increases in nonbeneficial or harmful bacteria, and decreases in beneficial bacteria. Numerous bacterial species have been associated with arthritis, including <i>Bacteroides</i> species, <i>Prevotella</i> species (particularly <i>P copri</i>), and infectious pathogens such as <i>Chlamydia trachomatis, Salmonella, Campylobacter, Yersinia,</i> and <i>Shigella,</i> especially in cases of reactive arthritis.<sup>2</sup> <i>Photo credit: SPL / Science Source</i>

  • Different Arthritis, Different Microbiome

    Different Arthritis, Different Microbiome

    Microbiome profile studies have found microbe composition to vary across arthritic diseases and disease states. An ankylosing spondylitis (AS) study reported a higher abundance of 5 bacterial families: <i>Lachnospiraceae, Veillonellaceae, Prevotellaceae, Porphyromonadaceae,</i> and <i>Bacteroidaceae.</i><sup>3</sup> Among these, <i>Lachnospiracecae</i> and <i>Prevotellaceace</i> have been strongly associated with colitis and Crohn’s disease. In contrast, a study of children with enthesitis-related arthritis revealed lower levels of <i>Faecalibacterium prausnitzii,</i> a species considered protective against IBD.<sup>4</sup> In a rheumatoid arthritis (RA) study, patients with early, untreated RA were found to have diminished <i>Bacteroides</i> counts and increased <i>Prevotella</i> species, particularly <i>P copri,</i> compared with healthy controls and patients with psoriatic arthritis (PsA) or chronic, treated RA.<sup>5</sup> <i>P copri</i> is rare in the general population, and findings suggest that it might be involved in the onset of RA.<sup>5</sup> <i>Photo credit: CDC/ Dr Todd Parker; Assoc. Director for Lab. Science/DPEI and LRN Training Coordinator</i>

  • Decreased Bacterial Diversity in PsA

    Decreased Bacterial Diversity in PsA

    Patients with PsA have been shown to have decreased bacterial diversity, particularly of beneficial taxa. In one small study of 16 patients with PsA, 15 patients with skin psoriasis, and 17 healthy, matched controls, researchers found that both patient groups had a lower relative abundance of <i>Coprococcus</i> compared with controls.<sup>5</sup> Patients with PsA were also found to have a significant reduction in <i>Akkermansia, Ruminococcus,</i> and <i>Pseudobutyrivibrio</i> species, with the <i>Akkermansia</i> and <i>Ruminococcus</i> nearly absent. This gut microbiota profile was associated with changes in specific inflammatory proteins unique to this group, including an increase in cervical spine secretory immunoglobulin A (SIgA) levels and a decrease in receptor activator of nuclear factor kappa B ligand (RANKL) levels. The investigators found that microbiome composition in PsA patients was most like that of patients with IBD in a state of gut dysbiosis, with almost absent levels of <i>Akkermansia</i> and <i>Ruminococcus</i> species—both of which are critical to maintaining homeostasis of the gut mucosa.<sup>5</sup> <i>Photo credit: CDC/ Dr. Sam Formal, Walter Reed Army Institution of Research</i>

  • Significance of the Firmicutes Phylum

    Significance of the Firmicutes Phylum

    Even when bacterial diversity is preserved, key bacteria may be either over or underrepresented, potentially increasing patient’s susceptibility to inflammatory conditions. One such group of bacteria belong to the <i>Firmicutes</i> phylum. Assessment of the fecal microbiota of children with enthesitis-related arthritis showed decreased <i>Firmicutes</i> species vs healthy age-matched controls, particularly <i>F prausnitzii,</i> despite bacterial diversity being maintained.<sup>4</sup> In contrast, a study of psoriatic lesions found <i>Firmicutes</i> to be the most abundant and diverse phylum populating these lesions (46.2%), with patients having approximately double the proportion seen in healthy persons.<sup>6</sup> However, these findings were not confirmed in a more recent study that used biopsies rather than swabs.<sup>7</sup> Although the <i>Firmicutes</i> phylum is essential to gut health, being an important supplier of butyrate to the colonic epithelium,<sup>8</sup> its potential significance in psoriatic skin lesions remains unclear.

  • Involvement of the Skin Microbiome in PsA

    Involvement of the Skin Microbiome in PsA

    No pathogen has yet been definitively identified to increase susceptibility to PsA, but histological evidence of inflammation in psoriatic skin lesions has led researchers to consider variations in the microbiome at this site. Support for involvement of the skin microbiome comes from psoriasis studies that have reported overexpression of endogenous antimicrobial peptides, such as cathelicidins and human beta-defensin 2 (HBD-2) in psoriatic skin lesions.<sup>9</sup> Additionally, patients with active psoriatic skin disease have been found to have increased serum HBD-2 levels, which has been associated with immune-modulatory and chemotactic effects.<sup>9</sup> Studies examining differences in skin microbe composition in psoriasis patients developing PsA versus those who do not may provide new insights into the pathogenesis of PsA.

  • Interaction Between HLA-B27 and the Microbiome

    Interaction Between HLA-B27 and the Microbiome

    Approximately 90% of people with SpA carry the HLA-B27 gene.<sup>10</sup> A relationship between this gene and AS was first reported in the early 1970s, and it remains the strongest association between a genetically determined factor and a genetically complex, immune-mediated disease.<sup>11</sup> In animal models, overexpression of HLA-B27 has been associated with the development of inflammatory disease mimicking SpA, with disease development being dependent on the animals’ microbiota, indicating microbiota have a key role in shaping the immune system.<sup>12</sup> It has been suggested that HLA-B27 alters the intestinal microbiome, potentially triggering an immune response, but the vast diversity of gut flora make it difficult to quantify how HLA-B27 alters this flora.<sup>11</sup> <i>Photo credit: Biophoto Associates / Science Source</i>

  • Targeting the Intestinal Microbiome With Antibiotics

    Targeting the Intestinal Microbiome With Antibiotics

    Therapies targeting intestinal bacteria have been used for many decades, such as antibiotics to modulate the risk of certain forms of arthritis, including RA and juvenile arthritis, but the benefits remain unsubstantiated.<sup>13</sup> Additionally, most trials have found antibiotics to be ineffective in modifying the course of SpA, and some evidence suggests that they may contribute to the development of some autoimmune disorders when used indiscriminately at an early age.<sup>13,14</sup> Nevertheless, several studies have shown some promise, including a small, 12-week study assessing moxifloxacin in AS.<sup>15</sup> In the trial, moxifloxacin was deemed safe and well tolerated, and was associated with improvement in the inflammatory symptoms of AS. Moxifloxacin was assessed because of its efficacy against enterobacteria, such as Klebsiella pneumoniae, which has been associated with AS. <i>Photo credit: Steve Gschmeissner / Science Source</i>

  • Altering Gut Flora with Probiotics

    Altering Gut Flora with Probiotics

    Probiotics are often used as an adjunct or nonpharmacological approach to treating various forms of arthritis, but studies have shown mixed results. A 12-week study assessing the effect of an orally administered probiotic on disease activity, fatigue, quality of life, and intestinal symptoms in patients with active SpA demonstrated no significant benefit over placebo.<sup>16</sup> In contrast, a study assessing 8 weeks of <i>Lactobacillus casei</i> 01 supplementation in patients with RA showed improvements in disease activity and inflammatory status versus placebo.<sup>17</sup> A major challenge with studying probiotics is the complexity of selecting the strains and formulations most likely to have a beneficial impact on the microbiome of the arthritis type studied. Furthermore, sufficient randomized clinical trials to guide clinical practice are lacking. Until more definitive data are available, decisions on probiotics are likely to continue to be guided by anecdotal evidence. <i>Photo credit: MicroScape / Science Source</i>

  • Other Targeting Strategies

    Other Targeting Strategies

    Numerous other strategies are being investigated or have been proposed to target the microbiome in patients with arthritis, including modulating the composition of bacteria or their byproducts to eliminate inflammatory responses, using agents with immunomodulating properties (eg, polysaccharides, structural proteins, short-chain fatty acids), and fecal microbial transplantation to combat the intestinal dysbiosis observed with certain forms of arthritis, such as PsA.<sup>13</sup> As assessment of the human microbiome continues to improve and more strains are catalogued, researchers will be better equipped to find effective treatment targets.

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Studies have shown that the intestinal microbiome can affect extra-intestinal sites such as joints, skin, and the body's immune response.1 Research has suggested that gut microbe composition plays a role in the pathogenesis of inflammatory diseases like spondyloarthritis (SpA), particularly in genetically susceptible persons, and may provide a novel strategy for treating and preventing various forms of arthritis and their associated comorbidities (such as inflammatory bowel disease [IBD]). However, studies evaluating the connection between SpA and the microbiome remain scarce, with much evidence coming from animal studies, small human studies, or studies of other inflammatory diseases. 

 

Additionally, the methods used to evaluate the microbiome have varied across studies, making it difficult to compare results, but next-generation sequencing technologies promise to improve assessment of the human microbiome and enable identification of previously uncharted bacterial populations, potentially opening the door to a wider set of microbiome-directed treatments in the future.2


References

  1. Eppinga H, Konstantinov SR, Peppelenbosch MP, Thio HB. The microbiome and psoriatic arthritis. Curr Rheumatol Rep. 2014;16(3):407. doi: 10.1007/s11926-013-0407-2
  2. Gill T, Asquith M, Rosenbaum JT, Colbert RA. The intestinal microbiome in spondyloarthritis. Curr Opin Rheumatol. 2015;27(4):319-325. doi: 10.1097/BOR.0000000000000187
  3. Costello ME, Ciccia F, Willner D, et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 2014 Nov 21. doi: 10.1002/art.38967
  4. Stoll ML, Kumar R, Morrow CD, et al. Altered microbiota associated with abnormal humoral immune responses to commensal organisms in enthesitis-related arthritis. Arthritis Res Ther. 2014;16(6):486. doi: 10.1186/s13075-014-0486-0
  5. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 2015;67(1):128-139. doi: 10.1002/art.38892
  6. Gao Z, Tseng CH, Strober BE, Pei Z, Blaser MJ. Substantial alterations of the cutaneous bacterial biota in psoriatic lesions. PLoS One. 2008;3(7):e2719. doi: 10.1371/journal.pone.0002719
  7. Fahlén A, Engstrand L, Baker BS, Powles A, Fry L. Comparison of bacterial microbiota in skin biopsies from normal and psoriatic skin. Arch Dermatol Res. 2012;304(1):15-22. doi: 10.1007/s00403-011-1189-x
  8. Khan MT, Duncan SH, Stams AJM, et al. The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic-anoxic interphases. The ISME Journal. 2012;6(8):1578-1585. doi: 10.1038/ismej.2012.5
  9. Castelino M, Eyre S, Upton M, Ho P, Barton A. The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. Rheumatology (Oxford). 2014;53(5):777-784. doi: 10.1093/rheumatology/ket319
  10. Canadian Spondylitis Association. What is spondyloarthritis? http://www.spondylitis.ca/spondyloarthritis/what-is-spondyloarthritis/. Accessed November 29, 2016.
  11. Rosenbaum JT, Davey MP. Hypothesis: Time for a gut check: HLA B27 predisposes to ankylosing spondylitis by altering the microbiome. Arthritis and Rheumatism. 2011;63(11):3195-3198. doi:10.1002/art.30558
  12. Gill T, Asquith M, Rosenbaum JT, Colbert RA. The intestinal microbiome in spondyloarthritis. Curr Opin Rheumatol. 2015;27(4):319-325. doi: 10.1097/BOR.0000000000000187
  13. Scher JU, Littman DR, Abramson SB. Microbiome in inflammatory arthritis and human rheumatic diseases. Arthritis Rheumatol. 2016;68(1):35-45. doi: 10.1002/art.39259
  14. Inman RD. Mechanisms of disease: infection and spondyloarthritis. Nat Clin Pract Rheumatol. 2006;2(3):163-169. doi: 10.1038/ncprheum0118
  15. Ogrendik M. Treatment of ankylosing spondylitis with moxifloxacin. South Med J. 2007;100(4):366-370. doi: 10.1097/SMJ.0b013e31802fa2a8
  16. Jenks K, Stebbings S, Burton J, Schultz M, Herbison P, Highton J. Probiotic therapy for the treatment of spondyloarthritis: a randomized controlled trial. J Rheumatol. 2010;37(10):2118-2125. doi: 10.3899/jrheum.100193
  17. Vaghef-Mehrabany E, Alipour B, Homayouni-Rad A, Sharif SK, Asghari-Jafarabadi M, Zavvari S. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition. 2014;30(4):430-435. doi:10.1016/j.nut.2013.09.007

 

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