Editorial
Prevotella copri and the microbial pathogenesis of rheumatoid arthritis
Prevotella copri y la patogenia microbiana de la artritis reumatoide
Josèc) Moreno
Hospital Juárez de Mèc)xico, Dirección de Investigación, Av. Instituto Politèc)cnico Naciona No. 5160, Col. Magdalena de las Salinas, Del. Gustavo A. Madero, C.P. 07760 Mèc)xico, D.F., Mexico
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José Andrés Prado, Luisa Cabello Ballesteros" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Fernando" "apellidos" => "León Vázquez" ] 1 => array:2 [ "nombre" => "Silvia" "apellidos" => "Herrero Hernández" ] 2 => array:2 [ "nombre" => "Cristina" "apellidos" => "Cuerpo Triguero" ] 3 => array:2 [ "nombre" => "M. 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Instituto Politèc)cnico Naciona No. 5160, Col. Magdalena de las Salinas, Del. Gustavo A. Madero, C.P. 07760 Mèc)xico, D.F., Mexico" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "<span class="elsevierStyleItalic">Prevotella copri</span> y la patogenia microbiana de la artritis reumatoide" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">To be able to decide what is relevant in science was never as difficult as today. The proliferation of journals and the Internet are a source of all kinds of new descriptions and interpretations, many of them right, but many others wrong or misleading. Such is the case for rheumatoid arthritis (RA) that, despite all the knowledge and new therapies, still remains an enormous challenge for its understanding. Although RA therapy has reached high levels of reasonability and many new drugs, especially biologicals, are now directed at mediators of inflammation and tissue damage known to participate in RA,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> most of its pathogenesis remains poorly understood. The recent finding that a high percentage of RA patients and mice with inflammatory RA-like arthritis are carriers of particular strains of bacteria in their microbiota<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2•4</span></a> could be a major advance in our understanding of the disease. But, without a critical approach, it might lead to additional confusion instead of the much needed clarification.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Historical perspective</span><p id="par0010" class="elsevierStylePara elsevierViewall">Although several hints of familial occurrence of RA had long indicated that the disease affected only genetically susceptible individuals, the major steps in our understanding of RA started with the discovery of rheumatoid factor in 1948.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> This was the first indicator of the autoimmune origin of RA that led to a great deal of research, but did little to our understanding of the pathogenesis of RA. The next major step was the finding of the predominance of T lymphocytes in the rheumatoid synovial membrane,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> later shown to be predominantly CD4+,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> leading to the hypothesis that RA was mediated by T cells. This was reinforced with the discovery of the association of the major histocompatibility complex (MHC) class II (MHCII) allele HLA-DR4<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> that led to the definition of the MHCII shared epitope (SE).<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> More recently, the advent of systems biology has led to the identification of many (>100) genetic susceptibility loci for RA.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Nevertheless, the single most important one still lies in the MHCII gene HLA-DRB1,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> where DRB1 alleles encoding the shared epitope with the amino acid sequence QKRAA in residues 70•74 of the HLA-DRβ chain, or related sequences are highly susceptible to developing RA with a particular pattern of autoantibodies.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Finally, toward the end of the 20th century, the discovery of antibodies directed at citrullinated proteins<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> reinstated B cells and humoral immunity as part of the RA pathogenesis.</p><p id="par0015" class="elsevierStylePara elsevierViewall">With regard to the microbial pathogenesis of RA, early in the 20th century, considering that RA was a form of tuberculosis (the major view at the time in France), Forestier introduced gold therapy.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Subsequent studies focused in the search of a specific etiologic agent for RA, including Mycoplasma<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and several viruses.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16•18</span></a> By the beginning of the 1980s, the hypothesis of a single infectious agent in the etiology of RA was essentially abandoned. However, there is an increased rate of clinical infections in patients with early but not with established RA.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> This is not new, however, as in 1924 Billington and Crabbe already had considered that RA was triggered by hidden infections and the therapeutic approach proposed by them included removal of the infective focus, which in their view was, in decreasing order: dental (periodontal), throat/nose, gallbladder, and genitourinary.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> It is amazing to see how, nine decades later, our view has not changed much!</p><p id="par0020" class="elsevierStylePara elsevierViewall">Thus, RA can be non-specifically triggered or exacerbated by a number of infections<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> or by external chemical or physical agents, including tobacco smoking and silica, among others.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a> Although the mechanism of association is not entirely clear, one possible explanation is activation of the innate immune system leading to costimulation, followed by activation of autoreactive T cells.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">The microbiome</span><p id="par0025" class="elsevierStylePara elsevierViewall">More recently, as in other pathologic states, the role of normal or abnormal microbiome (but not specific pathogens) has attracted a great deal of (probably too much) attention. Undoubtedly, the great loads of bacteria in our bodies, mainly the gut, are of major importance in shaping our physiology,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> but we are still far from understanding many aspects of host•commensal interactions in normal and pathological states. For instance, males and females have qualitative and quantitative differences in immune competence and susceptibility to autoimmune disease.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> In mice, these appear to be explained by the effects of male androgens on the gut microbiota, which leads to a lower immunoreactivity and decreased susceptibility to autoimmune diabetes. RA is more frequent in females, which could be related to the microbiota.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Recent studies yielded evidence of two possible links between particular Gram-negative anaerobic bacilli and RA development in humans. The first one is periodontal disease caused by <span class="elsevierStyleItalic">Porphyromonas gingivalis</span><a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27,28</span></a> and the second is the prevalence, in the gut microbiota, of <span class="elsevierStyleItalic">Prevotella copri</span>.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">But wait! As interesting and potentially relevant as these findings appear, one must be careful. Let us not forget that through the years, the etiology of RA has been attributed to conditions ranging from infections such as tuberculosis,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> amebiasis,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> Epstein Barr virus,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Proteus<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a>; endocrine imbalance,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> to surgical procedures,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> to mention just a few. In some cases it led, mostly by serendipity, to useful therapies (i.e. gold), but in others to harmful failures (insulin causing hypoglycemia). Although some of these considerations have been completely wrong, others are of importance because they are clues to identifying some of the predisposing and triggering factors for RA. Indeed it was the notion that RA was caused by hypoadrenalism and not its inflammatory nature that led Hench to the use of cortisone for RA.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015"><span class="elsevierStyleItalic">Porphyromonas gingivalis</span> and periodontal disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">The possible link of particular periodontal pathogens to connective tissue damage, including RA, in the modern era was first proposed by Engel et al. (1978) in studies of human fibroblasts exposed to <span class="elsevierStyleItalic">Actinomyces viscous</span> extracts,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> whereas the relation of rapidly progressing periodontitis to HLA-DR4 was described by Katz et al.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Over the following years, studies from different groups established a link between <span class="elsevierStyleItalic">Porphyromonas gingivalis</span> and RA, leading some to believe that this bacterium was critical for the development of RA, or even the etiological agent, based on: (1) the high prevalence of <span class="elsevierStyleItalic">P. gingivalis</span> positive periodontal disease (PD) among RA patients and viceversa<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,35</span></a>; (2) the presence of high titers of anti-<span class="elsevierStyleItalic">P. gingivalis</span> antibodies in RA<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>; (3) <span class="elsevierStyleItalic">P. gingivalis</span> expresses an endogenous peptidyl-arginyl deiminase (PAD) capable of citrullinating human protein substrates<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>; (4) periodontal treatment leads to amelioration of RA activity.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> However, not all RA patients have PD and/or <span class="elsevierStyleItalic">P. gingivallis</span>.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,35</span></a> Moreover, anti-<span class="elsevierStyleItalic">P. gingivalis</span> antibodies do not predict rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Finally, native bacterial PAD, which is truncated, lacks enzymatic activity,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> as opposed to previous studies that used recombinant (non truncated) bacterial PAD.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Does it mean that <span class="elsevierStyleItalic">P. gingivalis</span> has no role in the pathogenesis of RA? Probably not, but it is not a specific pathogen, but an incidental infectious agent non-specifically triggering autoimmunity. Thus, <span class="elsevierStyleItalic">P. gingivalis</span> is not the etiologic agent of RA.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">The gut microbiota</span><p id="par0045" class="elsevierStylePara elsevierViewall">Recent studies have brought a new partner that might help the understanding of the relationship between microbes, RA and other autoimmune diseases. Dan Littman and coworkers studied the gut microbiota in patients with new onset RA (NORA), compared to established (chronic) RA, psoriatic arthritis (PsA) and healthy individuals.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> A high proportion of NORA patients had significantly increased ratio of Prevotella over Bacteroides organisms. The Prevotella species in NORA patients was <span class="elsevierStyleItalic">Prevotella copri</span> with statistical significances of <span class="elsevierStyleItalic">P. copri</span> prevalence in NORA vs. healthy individuals, chronic RA or PsA <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.00002612, 0.000001031 and 0.01698, respectively, very significant indeed. However, not all NORA patients had increased <span class="elsevierStyleItalic">P. copri</span>, indicating that it is a very important, but not unique, contributing factor for the development of RA.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Studies in mice have shown that the presence of segmented filamentous bacteria (SFB) in the microbiota contributes significantly to the development of autoimmune disease in genetically susceptible hosts.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It has been shown that the composition of the gut microbiota contributes to shape the immune system into a proinflammatory state through differentiation of CD4+ T lymphocytes to the Th17 subset.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Gut SFB, but not Bacteroides drive Th17 development and enhance arthritis in mice.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Littman and coworkers colonized mice intestines with <span class="elsevierStyleItalic">P. copri</span> to find that it favors Th17 development and experimental dextran sulfate sodium-induced colitis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> This suggests that the role of <span class="elsevierStyleItalic">P. copri</span> in human RA could be similar, as Th17 lymphocytes are the major inducers of tissue damage in RA.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> On the other hand, <span class="elsevierStyleItalic">Porphyromonas gingivalis</span> also drives Th17 cell differentiation.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43,44</span></a> Thus, Th17 induction represents an important link among at least two of the bacteria associated to RA and suggests that additional microbes will be identified in the future as associated to RA.</p><p id="par0055" class="elsevierStylePara elsevierViewall">One final observation of potential importance was that the increased prevalence of <span class="elsevierStyleItalic">P. copri</span> in NORA patients was inversely related to positivity for the shared epitope. The authors interpret this finding as an indication that the role of <span class="elsevierStyleItalic">P. copri</span> in RA could be more important in patients with a lower load of genetic susceptibility loci, where exogenous triggers of the disease are critical.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Whatever the mechanism, it deserves further investigation as it is relevant for the understanding of RA and could have therapeutic implications.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In conclusion, RA is a complex genetically determined inflammatory condition of autoimmune origin, where external agents, mainly microbes, contribute in a variable manner to its onset and to its flares. Analysis of the available information must always be careful and one must not create artificial links to explain apparent contradictions. It usually leads to confusion, and waste of time and money that could be used for rational research. As Casaubon points in Umberto Eco's novel Focault's Pendulum “I believe that you can reach the point where there is no longer any difference between developing the habit of pretending to believe and developing the habit of believing.” Let us keep science free of this.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Historical perspective" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "The microbiome" ] 2 => array:2 [ "identificador" => "sec0015" "titulo" => "Porphyromonas gingivalis and periodontal disease" ] 3 => array:2 [ "identificador" => "sec0020" "titulo" => "The gut microbiota" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-09-24" "fechaAceptado" => "2014-11-07" "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:44 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Applying science in practice: the optimization of biological therapy in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Ramiro" 1 => "P. Machado" 2 => "J.A. Singh" 3 => "R.B. Landewe" 4 => "J.A. da Silva" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Arthritis Res Therapy" "fecha" => "2010" "volumen" => "12" "paginaInicial" => "220" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Periodontitis and <span class="elsevierStyleItalic">Porphyromonas gingivalis</span> in patients with rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.R. Mikuls" 1 => "J.B. Payne" 2 => "F. Yu" 3 => "G.M. Thiele" 4 => "R.J. Reynolds" 5 => "G.W. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 16 | 8 | 24 |
| 2024 October | 95 | 35 | 130 |
| 2024 September | 73 | 29 | 102 |
| 2024 August | 93 | 53 | 146 |
| 2024 July | 105 | 31 | 136 |
| 2024 June | 105 | 29 | 134 |
| 2024 May | 130 | 37 | 167 |
| 2024 April | 104 | 22 | 126 |
| 2024 March | 85 | 32 | 117 |
| 2024 February | 95 | 28 | 123 |
| 2024 January | 119 | 36 | 155 |
| 2023 December | 56 | 49 | 105 |
| 2023 November | 88 | 54 | 142 |
| 2023 October | 119 | 29 | 148 |
| 2023 September | 177 | 36 | 213 |
| 2023 August | 115 | 17 | 132 |
| 2023 July | 89 | 35 | 124 |
| 2023 June | 89 | 25 | 114 |
| 2023 May | 97 | 28 | 125 |
| 2023 April | 72 | 29 | 101 |
| 2023 March | 132 | 33 | 165 |
| 2023 February | 97 | 33 | 130 |
| 2023 January | 111 | 37 | 148 |
| 2022 December | 157 | 24 | 181 |
| 2022 November | 160 | 34 | 194 |
| 2022 October | 170 | 52 | 222 |
| 2022 September | 109 | 26 | 135 |
| 2022 August | 128 | 41 | 169 |
| 2022 July | 123 | 44 | 167 |
| 2022 June | 96 | 63 | 159 |
| 2022 May | 92 | 40 | 132 |
| 2022 April | 82 | 54 | 136 |
| 2022 March | 102 | 67 | 169 |
| 2022 February | 92 | 34 | 126 |
| 2022 January | 67 | 27 | 94 |
| 2021 December | 38 | 39 | 77 |
| 2021 November | 38 | 56 | 94 |
| 2021 October | 57 | 70 | 127 |
| 2021 September | 35 | 52 | 87 |
| 2021 August | 35 | 51 | 86 |
| 2021 July | 22 | 34 | 56 |
| 2021 June | 32 | 47 | 79 |
| 2021 May | 51 | 76 | 127 |
| 2021 April | 105 | 116 | 221 |
| 2021 March | 44 | 36 | 80 |
| 2021 February | 41 | 23 | 64 |
| 2021 January | 58 | 29 | 87 |
| 2020 December | 47 | 22 | 69 |
| 2020 November | 35 | 18 | 53 |
| 2020 October | 20 | 10 | 30 |
| 2020 September | 52 | 30 | 82 |
| 2020 August | 23 | 18 | 41 |
| 2020 July | 30 | 36 | 66 |
| 2020 June | 34 | 20 | 54 |
| 2020 May | 34 | 19 | 53 |
| 2020 April | 39 | 23 | 62 |
| 2020 March | 21 | 8 | 29 |
| 2020 February | 1 | 0 | 1 |
| 2018 May | 6 | 1 | 7 |
| 2018 April | 26 | 19 | 45 |
| 2018 March | 46 | 19 | 65 |
| 2018 February | 32 | 15 | 47 |
| 2018 January | 23 | 17 | 40 |
| 2017 December | 23 | 18 | 41 |
| 2017 November | 32 | 12 | 44 |
| 2017 October | 17 | 9 | 26 |
| 2017 September | 24 | 19 | 43 |
| 2017 August | 16 | 11 | 27 |
| 2017 July | 21 | 9 | 30 |
| 2017 June | 40 | 19 | 59 |
| 2017 May | 43 | 18 | 61 |
| 2017 April | 31 | 18 | 49 |
| 2017 March | 27 | 16 | 43 |
| 2017 February | 18 | 11 | 29 |
| 2017 January | 15 | 13 | 28 |
| 2016 December | 35 | 22 | 57 |
| 2016 November | 25 | 20 | 45 |
| 2016 October | 46 | 19 | 65 |
| 2016 September | 39 | 10 | 49 |
| 2016 August | 46 | 0 | 46 |
| 2016 July | 29 | 13 | 42 |
| 2015 December | 3 | 0 | 3 |
| 2015 September | 2 | 0 | 2 |
| 2015 August | 1 | 0 | 1 |
| 2015 July | 19 | 7 | 26 |
| 2015 June | 24 | 6 | 30 |
| 2015 May | 42 | 19 | 61 |
| 2015 April | 37 | 22 | 59 |
| 2015 March | 45 | 11 | 56 |
| 2015 February | 5 | 4 | 9 |
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