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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2023.1157918</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Gut dysbiosis in autoimmune diseases: Association with mortality</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Chang</surname>
<given-names>Sung-Ho</given-names>
</name>
<uri xlink:href="https://loop.frontiersin.org/people/2131919"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Choi</surname>
<given-names>Youngnim</given-names>
</name>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/209978"/>
</contrib>
</contrib-group>
<aff id="aff1">
<institution>Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University</institution>, <addr-line>Seoul</addr-line>, <country>Republic of Korea</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Piyush Baindara, University of Missouri, United States</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Shikha Negi, Cincinnati Children&#x2019;s Hospital Medical Center, United States; Vijeta Sharma, Hackensack Meridian Health, United States; Nisha Singh, University of Maryland, United States</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Youngnim Choi, <email xlink:href="mailto:youngnim@snu.ac.kr">youngnim@snu.ac.kr</email>
</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Intestinal Microbiome, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>31</day>
<month>03</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>13</volume>
<elocation-id>1157918</elocation-id>
<history>
<date date-type="received">
<day>03</day>
<month>02</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>15</day>
<month>03</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Chang and Choi</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Chang and Choi</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>To better understand the impact of gut dysbiosis on four autoimmune diseases [Sj&#xf6;gren&#x2019;s syndrome (SS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS)], this review investigated the altered gut bacteria in each disease and the shared ones among the four diseases. The enriched gut bacteria shared by three of the four autoimmune diseases were <italic>Streptococcus</italic>, <italic>Prevotella</italic>, and <italic>Eggerthella</italic>, which are associated with autoantibody production or activation of Th17 cells in immune-related diseases. On the other hand, <italic>Faecalibacterium</italic> comprises depleted gut bacteria shared by patients with SLE, MS, and SS, which is associated with various anti-inflammatory activities. The indexes of gut dysbiosis, defined as the number of altered gut bacterial taxa divided by the number of studies in SLE, MS, RA, and SS, were 1.7, 1.8, 0.7, and 1.3, respectively. Interestingly, these values presented a positive correlation trend with the standardized mortality rates &#x2014;2.66, 2.89, 1.54, and 1.41, respectively. In addition, shared altered gut bacteria among the autoimmune diseases may correlate with the prevalence of polyautoimmunity in patients with SLE, SS, RA, and MS, that is, 41 percent, 32.6 percent, 14 percent, and 1&#x2013;16.6 percent, respectively. Overall, this review suggests that gut dysbiosis in autoimmune diseases may be closely related to the failure of the gut immune system to maintain homeostasis.</p>
</abstract>
<kwd-group>
<kwd>autoimmunity</kwd>
<kwd>gut dysbiosis</kwd>
<kwd>Sj&#xf6;gren&#x2019;s syndrome</kwd>
<kwd>rheumatoid arthritis</kwd>
<kwd>systemic lupus erythematosus</kwd>
<kwd>multiple sclerosis</kwd>
</kwd-group>
<contract-num rid="cn001">2018R1A5A2024418, 2020R1A2C2007038, 2020R1A2C1100163</contract-num>
<contract-sponsor id="cn001">National Research Foundation of Korea<named-content content-type="fundref-id">10.13039/501100003725</named-content>
</contract-sponsor>
<counts>
<fig-count count="1"/>
<table-count count="4"/>
<equation-count count="0"/>
<ref-count count="107"/>
<page-count count="11"/>
<word-count count="5547"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>The etiology of autoimmune diseases is complex involving both genetic and environmental factors. Genetic risk factors for autoimmune diseases are composed of HLA and non-HLA genes expressed at different levels depending on the disease (<xref ref-type="bibr" rid="B34">Greiling et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B93">van der Meulen et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B30">Frazzei et&#xa0;al., 2022</xref>). On the other hand, environmental factors include smoking, lifestyle disorders, reduced sun exposure, and chronic stress (<xref ref-type="bibr" rid="B30">Frazzei et&#xa0;al., 2022</xref>). However, the scope of these factors to explain the cause of the rapid increase in autoimmune diseases over the decades is insufficient (<xref ref-type="bibr" rid="B17">Chen et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B24">Dinse et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B30">Frazzei et&#xa0;al., 2022</xref>). Recently, gut dysbiosis has attracted great attention as a risk factor for autoimmune diseases. However, it is unclear whether gut dysbiosis is a result or a cause of an autoimmune disease (<xref ref-type="bibr" rid="B44">Jubair et&#xa0;al., 2018</xref>). Autoimmune diseases such as primary Sj&#xf6;gren&#x2019;s syndrome (SS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) have been linked to gut dysbiosis (<xref ref-type="bibr" rid="B106">Zhang et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B15">Chen et&#xa0;al., 2016a</xref>; <xref ref-type="bibr" rid="B68">Nikitakis et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B52">Luo et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B9">Bellando-Randone et&#xa0;al., 2021</xref>). The causes of gut dysbiosis include depletion of the mucus layer, rapid dietary changes, use of antibiotics, infection and inflammation, and gastrointestinal surgery (<xref ref-type="bibr" rid="B94">Van de Wiele et&#xa0;al., 2016</xref>). Chen et&#xa0;al. proposed the following five mechanisms by which gut dysbiosis contributes to autoimmune diseases: 1) dysregulation of TLR in antigen presenting cells (APCs) and imbalance of Treg/Th17 ratio; 2) generation of new autoantigens due to the modification of host proteins induced by microbial enzymes; 3) microbial components similar to self-peptides, activating autoreactive B and T cells; 4) induction of immunopathology through the transport of microbial components or metabolites throughout the host; and 5) autoantibody generation against curli-DNA composites (<xref ref-type="bibr" rid="B17">Chen et&#xa0;al., 2017</xref>). In this review, the altered gut bacteria in SLE, MS, RA, and SS were investigated to better understand the impact of gut dysbiosis on autoimmune diseases. First, we investigated whether there are common taxa in different studies of gut dysbiosis for each disease. Second, we investigated whether the four autoimmune diseases share altered gut bacteria and whether there are altered gut bacteria unique to each autoimmune disease. Third, the altered gut bacteria&#x2019;s functions or mechanisms of action in immune-related diseases were investigated. Fourth, we explored whether the shared, altered gut bacteria are related to polyautoimmunity. Finally, we examined whether the degree of gut dysbiosis is related to the disease&#x2019;s standardized mortality rate (SMR).</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Gut dysbiosis in autoimmune diseases</title>
<p>Altered gut bacteria refer to the taxa whose enrichment or depletion in the gut bacteriota has been cross-validated by at least two studies with statistical significance (p &lt; 0.05, q &lt; 0.1, or false discovery rate &lt; 0.1). The taxonomic range of altered gut bacteria investigated in the four autoimmune diseases was at the family, genus, or species levels. Most altered bacteria were cross-validated at the genus or species levels because some papers only presented them at the genus or species levels.</p>
<sec id="s2_1">
<label>2.1</label>
<title>Altered gut bacteria in SLE</title>
<p>SLE is a prototypical autoimmune disease associated with loss of self-tolerance of the immune system, abnormal antibody response to cytoplasmic antigens, persistent autoantibody production, and subsequent systemic inflammation (<xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>). Its clinical signs include multiple symptoms, such as skin rash, glomerulonephritis, neurological disorders, and severe vasculitis, suggesting that the pathogenesis of SLE may be complex (<xref ref-type="bibr" rid="B35">Guo et&#xa0;al., 2020</xref>). A total of 22 altered gut bacterial genera/families were identified from the review of 13 papers published since 2014 (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). While <italic>Alistipes</italic>, <italic>Bacilli</italic>, <italic>Bacteroides</italic>, <italic>Clostridium</italic>, <italic>Eggerthella</italic>, <italic>Escherichia</italic>, <italic>Klebsiella</italic>, <italic>Lactobacillus</italic>, <italic>Prevotella</italic>, <italic>Ruminococcus</italic>, and <italic>Streptococcus</italic> are enriched, <italic>Bacteroides</italic>, <italic>Dialister</italic>, <italic>Faecalibacterium</italic>, <italic>Odoribacter</italic>, <italic>Roseburia</italic>, and <italic>Ruminococcus</italic> are depleted in the gut of SLE patients. Interestingly, <italic>Bacteroides</italic> and <italic>Ruminococcus</italic> were reported to be enriched or depleted depending on studies, but at the species level, different species were enriched or depleted with the exception of <italic>B. uniformis</italic>, which was reported to be enriched or depleted in different studies (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). Even in the same species, <italic>Bacteroides fragilis</italic> is classified into polysaccharide A-producing beneficial bacterium or enterotoxigenic bacterium, depending on strains (<xref ref-type="bibr" rid="B67">Nagao-Kitamoto and Kamada, 2017</xref>). Thus, <italic>B. fragilis</italic> enrichment in patients with SLE might be associated with enterotoxigenic strains. Among the 22 altered gut bacterial genera, <italic>Bacteroides</italic>, <italic>Escherichia</italic>, <italic>Ruminococcus</italic>, and <italic>Streptococcus</italic> have known functions associated with the induction of inflammatory response or autoimmunity in immune-related diseases (<xref ref-type="bibr" rid="B95">Vatanen et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>; <xref ref-type="bibr" rid="B39">Henke et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B77">Qiu et&#xa0;al., 2019</xref>), whereas <italic>Faecalibacterium</italic> and <italic>Ruminococcus</italic>_2 have anti-inflammatory mechanisms of action (<xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B59">Matsuoka et&#xa0;al., 2022</xref>). More details about this phenomenon have been described in Section 2.6.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Commonly altered gut bacteria in gut dysbiosis of patients with autoimmune diseases.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="center">Diseases (Ref count/Altered gut bacteria count)</th>
<th valign="middle" align="left">Enrichment</th>
<th valign="middle" align="left">Ref</th>
<th valign="middle" align="left">Depletion</th>
<th valign="middle" align="left">Ref</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">SLE<break/>(13/22)</td>
<td valign="top" align="left">
<italic>Alistipes</italic>
<break/>
<italic>Bacilli</italic>
<break/>
<italic>Bacteroides (fragilis, ovatus, uniformis, vulgatus)</italic>
<break/>
<italic>Clostridium (innocuum, leptum)</italic>
<break/>
<italic>Eggerthella (lenta)</italic>
<break/>
<italic>Enterobacteriaceae</italic>
<break/>
<italic>Escherichia (coli, shigella)</italic>
<break/>
<italic>Klebsiella</italic>
<break/>
<italic>Lactobacillaceae</italic>
<break/>
<italic>Lactobacillus (mucosae</italic>,<break/>
<italic>salivarius)</italic>
<break/>
<italic>Prevotella</italic>
<break/>
<italic>Ruminococcus (gnavus</italic>,<break/>
<italic>torques)</italic>
<break/>
<italic>Streptococcaceae</italic>
<break/>
<italic>Streptococcus (anginosus</italic>,<break/>
<italic>mutans, oligofermentans, parasanguinis)</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B35">Guo et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>)<break/>(<xref ref-type="bibr" rid="B93">van der Meulen et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B35">Guo et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B37">He et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B36">He et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B37">He et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B37">He et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B35">Guo et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B5">Azzouz et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)</td>
<td valign="top" align="left">
<italic>Bacteroides (cellulosilyticus, eggerthii, intestinalis, plebeius, salyersiae, uniformis)</italic>
<break/>
<italic>Dialister</italic>
<break/>
<italic>Faecalibacterium (prausnitzii)</italic>
<break/>
<italic>Lachnospiraceae</italic>
<break/>
<italic>Odoribacter</italic>
<break/>
<italic>Roseburia</italic>
<break/>
<italic>Ruminococcaceae</italic>
<break/>
<italic>Ruminococcus (2, callidus, lactaris, obeum)</italic>
<break/>*Firmicutes/Bacteroidetes ratio</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B5">Azzouz et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B37">He et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B34">Greiling et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B52">Luo et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B50">Li et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B34">Greiling et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B5">Azzouz et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B105">Zhang et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B16">Chen et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B98">Wen et&#xa0;al., 2021</xref>)<break/>(<xref ref-type="bibr" rid="B40">Hevia et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B34">Greiling et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B93">van der Meulen et&#xa0;al., 2019</xref>)</td>
</tr>
<tr>
<td valign="middle" align="center">MS<break/>(9/16)</td>
<td valign="top" align="left">
<italic>Actinomyces</italic>
<break/>
<italic>Akkermansia</italic> (<italic>muciniphila</italic>)<break/>
<italic>Clostridium</italic> (III, <italic>leptum</italic>)<break/>
<italic>Eggerthella</italic> (<italic>lenta</italic>)<italic>Streptococcus (anginosus, parasanguinis, salivarius/thermophilus)</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)<break/>(<xref ref-type="bibr" rid="B42">Jangi et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)</td>
<td valign="top" align="left">
<italic>Bacteroides (coprocola, coprophilus, stercoris)</italic>
<break/>
<italic>Butyricimonas</italic>
<break/>
<italic>Clostridium (sp) Eubacterium rectale</italic>
<break/>
<italic>Faecalibacterium</italic>
<break/>
<italic>Lachnospira (pectinoschiza)</italic>
<break/>
<italic>Lactobacillus</italic> (<italic>rogosae</italic>)<break/>
<italic>Megamonas funiformis</italic>
<break/>
<italic>Parabacteroides</italic>
<break/>
<italic>Prevotella</italic> (<italic>9, copri</italic>)<break/>
<italic>Sutterella (wadsworthensis)</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B90">Tremlett et&#xa0;al., 2016</xref>)<break/>(<xref ref-type="bibr" rid="B42">Jangi et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B26">Duscha et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>) (<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B90">Tremlett et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B15">Chen et&#xa0;al., 2016a</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B15">Chen et&#xa0;al., 2016a</xref>; <xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B42">Jangi et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B104">Zeng et&#xa0;al., 2019</xref>)<break/>(<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B42">Jangi et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="middle" align="center">RA<break/>(7/5)</td>
<td valign="top" align="left">
<italic>Bacteroides</italic> (<italic>sartorii</italic>)<break/>
<italic>Eggerthella</italic>
<break/>
<italic>Prevotella</italic> (<italic>amnii, copri, corporis, denticola, disiens, marshii</italic>)<break/>
<italic>Streptococcus, Streptococcaceae</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B82">Rodrigues et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B87">Sun et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B47">Kishikawa et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B18">Chen et&#xa0;al., 2016b</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)<break/>(<xref ref-type="bibr" rid="B84">Scher et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B55">Maeda et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B82">Rodrigues et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B47">Kishikawa et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B18">Chen et&#xa0;al., 2016b</xref>; <xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>)</td>
<td valign="top" align="left">
<italic>Ruminococcaceae</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B29">Forbes et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B87">Sun et&#xa0;al., 2019</xref>)</td>
</tr>
<tr>
<td valign="middle" align="center">SS<break/>(6/8)</td>
<td valign="top" align="left">
<italic>Prevotella</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Veillonella</italic>
</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B60">Mendez et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>)</td>
<td valign="top" align="left">
<italic>Bifidobacterium</italic>
<break/>
<italic>Blautia</italic>
<break/>
<italic>Dorea</italic>
<break/>
<italic>Faecalibacterium</italic>
<break/>
<italic>Lachnospira</italic>
<break/>*Firmicutes/Bacteroidetes ratio</td>
<td valign="top" align="left">(<xref ref-type="bibr" rid="B57">Mandl et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>)<break/>(<xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>)<break/>(<xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>)<break/>(<xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B60">Mendez et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B10">Bellocchi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>)<break/>(<xref ref-type="bibr" rid="B93">van der Meulen et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>The microbiome data presented for each disease are based on the statistical significance of each paper (p &lt; 0.05, q &lt; 0.1, or FDR &lt; 0.1). Parentheses indicate species, but species do not classify all genera. Also, some species are not classified for abundance at the genus level. The microbiome analysis in each paper was performed using human fecal samples. *: No count.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s2_2">
<label>2.2</label>
<title>Altered gut bacteria in MS</title>
<p>MS is an autoimmune disease in which the immune system destroys the myelin sheaths surrounding nerve axons in the central nervous system (CNS). MS is on the rise in developed countries and occurs three times higher in young women, for which an environmental factor, such as gut dysbiosis, than genetic factors seems to account (<xref ref-type="bibr" rid="B62">Miyake et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B13">Cekanaviciute et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B26">Duscha et&#xa0;al., 2020</xref>). This assumption is supported by the fact that the transfer of feces from MS patients exacerbates the disease in the animal models of MS (<xref ref-type="bibr" rid="B11">Berer et&#xa0;al., 2017</xref>). A total of 16 altered gut bacterial genera were found from the review of nine papers published since 2015 (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). While <italic>Actinomyces</italic>, <italic>Akkermansia</italic>, <italic>Clostridium</italic>, <italic>Eggerthella</italic>, and <italic>Streptococcus</italic> are enriched, <italic>Bacteroides</italic>, <italic>Butyricimonas</italic>, <italic>Clostridium</italic>, <italic>Eubacterium</italic>, <italic>Faecalibacterium</italic>, <italic>Lachnospira</italic>, <italic>Lactobacillus</italic>, <italic>Megamonas</italic>, <italic>Parabacteroides</italic>, <italic>Prevotella</italic>, and <italic>Sutterella</italic> are depleted in the gut of MS patients. <italic>Eggerthella</italic> and <italic>Streptococcus</italic> are associated with the induction of autoimmunity (<xref ref-type="bibr" rid="B91">Valour et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B79">Ravindra et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>; <xref ref-type="bibr" rid="B2">Alexander et&#xa0;al., 2022</xref>), whereas <italic>Butyricimonas</italic> and <italic>Faecalibacterium</italic> have reported anti-inflammatory functions (<xref ref-type="bibr" rid="B43">Jing et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B6">Bai et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>), as detailed in Section 2.6. Interestingly, the relative abundance of <italic>Prevotella_9</italic> and <italic>Sutterella</italic> increased in experimental autoimmune encephalomyelitis mice after receiving fecal microbiota transplantation from healthy mice, which, in turn, improved clinical scores (<xref ref-type="bibr" rid="B97">Wang et&#xa0;al., 2021</xref>). These results suggest that beneficial bacteria in the host may maintain the homeostasis of the immune system in MS.</p>
</sec>
<sec id="s2_3">
<label>2.3</label>
<title>Altered gut bacteria in RA</title>
<p>RA is a chronic autoimmune disease that causes joint destruction and functional impairment. Recently, the etiology of RA has been hypothesized to be a combination of genetic factors and gut dysbiosis (<xref ref-type="bibr" rid="B55">Maeda et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B44">Jubair et&#xa0;al., 2018</xref>). Particularly, the concordance rate for RA in monozygotic twins studied in Europe is 15 percent, which is insufficient to solely explain its etiology by genetic influences (<xref ref-type="bibr" rid="B1">Aho et&#xa0;al., 1986</xref>; <xref ref-type="bibr" rid="B86">Silman et&#xa0;al., 1993</xref>). Autoantibody production against citrullinated peptides produced by <italic>Porphyromonas gingivalis</italic> is a mechanism to induce RA (<xref ref-type="bibr" rid="B47">Kishikawa et&#xa0;al., 2020</xref>). Anti-citrullinated protein antibodies (ACPAs) have been detected in all high-risk RA patients and 93 percent of patients with RA (<xref ref-type="bibr" rid="B89">Tong et&#xa0;al., 2019</xref>). A total of five altered gut bacterial genera/families were identified from the review of seven papers published since 2013 (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). All four enriched genera, <italic>Bacteroides</italic>, <italic>Eggerthella</italic>, <italic>Prevotella</italic>, and <italic>Streptococcus</italic>, have known functions associated with the induction of inflammatory response or autoimmunity in immune-related diseases detailed in Section 2.6.</p>
</sec>
<sec id="s2_4">
<label>2.4</label>
<title>Altered gut bacteria in SS</title>
<p>SS is an autoimmune disease characterized by dry mouth and dry eyes (keratoconjunctivitis sicca). Eight genera were identified from the review of six papers published since 2017 (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). While <italic>Prevotella</italic>, <italic>Streptococcus</italic>, and <italic>Veillonella</italic> are enriched, <italic>Bifidobacterium, Blautia</italic>, <italic>Dorea</italic>, <italic>Faecalibacterium</italic>, and <italic>Lachnospira</italic> are depleted in the gut bacteriota of SS patients. Among these, <italic>Prevotella</italic> and <italic>Streptococcus</italic> have known functions associated with the induction of inflammatory response or autoimmunity in immune-related diseases, whereas <italic>Bifidobacterium</italic> and <italic>Faecalibacterium</italic> have anti-inflammatory mechanisms of action or efficacy, as detailed in Section 2.6 (<xref ref-type="bibr" rid="B55">Maeda et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B69">O&#x2019;Callaghan and van Sinderen, 2016</xref>; <xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>; <xref ref-type="bibr" rid="B102">Yao et&#xa0;al., 2021</xref>; <xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>).</p>
</sec>
<sec id="s2_5">
<label>2.5</label>
<title>Altered gut bacteria shared among the four autoimmune diseases versus those unique to each disease</title>
<p>We posed the pertinent question of whether altered gut bacteria are shared among the four autoimmune diseases. The altered taxa listed in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref> were classified into those shared among the four autoimmune diseases (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>) and those unique to each autoimmune disease (<xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref>).</p>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Altered gut bacteria shared in different autoimmune diseases.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="left">Diseases</th>
<th valign="middle" align="center">Enrichment</th>
<th valign="middle" align="left">Depletion</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">SLE, MS, RA, SS</td>
<td valign="top" align="left">
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left"/>
</tr>
<tr>
<td valign="top" align="left">SLE, MS, SS</td>
<td valign="top" align="left">
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left">
<italic>Faecalibacterium</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">SLE, RA, SS,</td>
<td valign="top" align="left">
<italic>Prevotella</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left"/>
</tr>
<tr>
<td valign="top" align="left">SLE, MS, RA</td>
<td valign="top" align="left">
<italic>Eggerthella</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left"/>
</tr>
<tr>
<td valign="top" align="left">SLE, MS</td>
<td valign="top" align="left">
<italic>Clostridium</italic>
<break/>
<italic>Eggerthella</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left">
<italic>Faecalibacterium</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">SLE, SS</td>
<td valign="top" align="left">
<italic>Prevotella</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left">
<italic>Faecalibacterium</italic>
<break/>Firmicutes/Bacteroidetes<break/>ratio</td>
</tr>
<tr>
<td valign="top" align="left">SLE, RA</td>
<td valign="top" align="left">
<italic>Bacteroides</italic>
<break/>
<italic>Eggerthella</italic>
<break/>
<italic>Prevotella</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left">
<italic>Ruminococcaceae</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">MS, SS</td>
<td valign="top" align="left">
<italic>Streptococcus</italic>
</td>
<td valign="top" align="left">
<italic>Faecalibacterium</italic>
<break/>
<italic>Lachnospira</italic>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Altered gut bacteria unique to each autoimmune disease.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="left">Diseases</th>
<th valign="middle" align="center">Enrichment</th>
<th valign="middle" align="left">Depletion</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="left">SLE</td>
<td valign="top" align="left">
<italic>Alistipes</italic>
<break/>
<italic>Bacilli</italic>
<break/>
<italic>Escherichia</italic>
<break/>
<italic>Klebsiella</italic>
<break/>
<italic>Lactobacillus</italic>
</td>
<td valign="top" align="left">
<italic>Dialister</italic>
<break/>
<italic>Odoribacter</italic>
<break/>
<italic>Roseburia</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">MS</td>
<td valign="top" align="left">
<italic>Actinomyces</italic>
<break/>
<italic>Akkermansia</italic>
</td>
<td valign="top" align="left">
<italic>Butyricimonas</italic>
<break/>
<italic>Eubacterium</italic>
<break/>
<italic>Lactobacillus</italic>
<break/>
<italic>Megamonas</italic>
<break/>
<italic>Parabacteroides</italic>
<break/>
<italic>Prevotella</italic>
<break/>
<italic>Sutterella</italic>
</td>
</tr>
<tr>
<td valign="top" align="left">RA</td>
<td valign="top" align="left"/>
<td valign="top" align="left"/>
</tr>
<tr>
<td valign="top" align="left">SS</td>
<td valign="top" align="left">
<italic>Veillonella</italic>
</td>
<td valign="top" align="left">
<italic>Bifidobacterium</italic>
<break/>
<italic>Blautia</italic>
<break/>
<italic>Dorea</italic>
</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Thereafter, we could identify taxa shared among four, three, and two diseases in various combinations (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>). Interestingly, <italic>Streptococcus</italic> was enriched in all four diseases. In addition to <italic>Streptococcus</italic>, <italic>Prevotella</italic> was commonly enriched in SLE, RA, and SS, and <italic>Eggerthella</italic> in SLE, MS, and RA. Meanwhile, SLE, MS, and SS shared the depletion of <italic>Faecalibacterium</italic> and the enrichment of <italic>Streptococcus</italic>. Comparing two autoimmune diseases, the SLE&#x2013;MS, SLE&#x2013;SS, and SLE&#x2013;RA combinations shared at least four altered gut bacterial taxa, and the MS&#x2013;SS combination shared three altered gut bacterial genera. Collectively, SLE shared altered gut bacteria (SAGB) through virtually all comparison groups.</p>
<p>In the case of uniquely altered gut bacteria in each autoimmunity, SLE, MS, and SS had eight, nine, and four genera, respectively, whereas RA had none (<xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref>). The abundance of <italic>Lactobacillus</italic> was changed in SLE and MS, but in the opposite direction&#x2014;enriched in SLE but depleted in MS. In addition, the depletion of <italic>Prevotella</italic> was unique to MS.</p>
</sec>
<sec id="s2_6">
<label>2.6</label>
<title>Potential contribution of altered gut bacteria to disease pathogenesis</title>
<p>To further understand the role of altered gut bacteria in the etiology of autoimmune diseases, we investigated whether the altered bacteria listed in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref> have known functions in immune-related diseases. Studies on gut bacteria&#x2019;s role and mechanism of action of gut bacteria in human autoimmunity are still limited. Thus, studies on immune-related diseases were also included. We hypothesized that the altered gut bacteria shared among different diseases might be associated with common immunologic pathways of the diseases and that the bacteria unique to each disease may be associated with the specific characteristics of the diseases.</p>
<p>
<italic>Streptococcus</italic>, enriched in all four autoimmune diseases, produces antigens that are cross-reactive with host-derived antigens (<xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>). These cross-reactive antigens can activate T cells and contribute to autoantibody production through molecular mimicries&#x2014;hallmarks of autoimmune diseases. This is the third model of immunopathology proposed by Chen et&#xa0;al. for autoimmune mechanisms (<xref ref-type="bibr" rid="B17">Chen et&#xa0;al., 2017</xref>). <italic>Streptococcus mutans/sanguinis</italic> bind to salivary proteins and glycoproteins to form biofilms (<xref ref-type="bibr" rid="B58">Matsumoto et&#xa0;al., 2004</xref>; <xref ref-type="bibr" rid="B99">Xie et&#xa0;al., 2020</xref>). In addition, bacterial biofilms are rich in bacterial extracellular DNA complexed with amyloid, which stimulates autoimmunity (<xref ref-type="bibr" rid="B32">Gallo et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B4">Andreasen et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B77">Qiu et&#xa0;al., 2019</xref>). Thus, DNA abundant in <italic>Streptococcus</italic>-induced biofilms might contribute to autoantibody production by forming a complex with <italic>E. coli</italic>-derived curli amyloid in the gut environment (<xref ref-type="bibr" rid="B14">Chen et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B77">Qiu et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B8">Barrasso et&#xa0;al., 2022</xref>). These results suggest that <italic>Streptococcus</italic> may be closely related to the development of autoimmune diseases through autoantibody production. However, further understanding of <italic>Streptococcus</italic> species and their strains involved in disease etiology is needed.</p>
<p>
<italic>Eggerthella lenta</italic> is commonly enriched in SLE, MS, and RA (<xref ref-type="table" rid="T1">
<bold>Tables&#xa0;1</bold>
</xref>, <xref ref-type="table" rid="T2">
<bold>2</bold>
</xref>). In an inflammatory bowel disease (IBD) model, <italic>E. lenta</italic> activates Th17 cells through the cardiac glycoside reductase 2 (Cgr2) enzyme, which metabolizes endogenous Ror&#x3b3;t inhibitors (<xref ref-type="bibr" rid="B2">Alexander et&#xa0;al., 2022</xref>). However, the activation of Th17 cells by <italic>E. lenta</italic> is affected by two variables. First, a high concentration of dietary arginine (3 percent/kg) can inhibit the function of the Cgr2 enzyme (<xref ref-type="bibr" rid="B2">Alexander et&#xa0;al., 2022</xref>). Second, <italic>E. lenta</italic> does not express Cgr2 depending on the strain, and Cgr2<sup>-</sup> strains do not activate Th17 cells. This result indicates that the contribution of <italic>E. lenta</italic> to the development of autoimmune diseases may depend on host dietary factors and bacterial strains. This finding relates to the first immunopathology model proposed by Chen et&#xa0;al. for autoimmune mechanisms (<xref ref-type="bibr" rid="B17">Chen et&#xa0;al., 2017</xref>). In addition, <italic>E. lenta</italic> was enriched in the gut of mice exposed to cigarette smoke for seven months (<xref ref-type="bibr" rid="B6">Bai et&#xa0;al., 2022</xref>). Furthermore, the transplantation of feces from smoking-exposed mice into germ-free mice induced enrichment of <italic>E. lenta</italic>, an impairment of the gut barrier in the colonic epithelium, and an increase in proinflammatory cytokines IL-17 and TNF (<xref ref-type="bibr" rid="B6">Bai et&#xa0;al., 2022</xref>). Notably, smoking is a common risk factor for SLE, MS, and RA (<xref ref-type="bibr" rid="B56">Majka and Holers, 2006</xref>; <xref ref-type="bibr" rid="B38">Healy et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B3">Amador-Patarroyo et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B66">Mowry et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B7">Baka et&#xa0;al., 2009</xref>), and Th17 cells are involved in the pathogenesis of these three diseases (<xref ref-type="bibr" rid="B101">Yang et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B65">Moser et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B81">Robert and Miossec, 2020</xref>).</p>
<p>
<italic>Prevotella</italic> is enriched in SLE, RA, and SS but depleted in MS. Specifically, <italic>P. copri</italic> is enriched in RA but depleted in MS (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). Interestingly, the colonization of germ-free mice with fecal samples from RA patients dominated by <italic>P. copri</italic> induced a Th17 cell-dependent autoimmune arthritis, suggesting that gut dysbiosis with enriched <italic>P. copri</italic> contributes to the development of RA (<xref ref-type="bibr" rid="B55">Maeda et&#xa0;al., 2016</xref>). Kishikawa et&#xa0;al. also suggested that enriched multiple <italic>Prevotella</italic> spp. are associated with the etiology of RA in Japanese patients (<xref ref-type="bibr" rid="B47">Kishikawa et&#xa0;al., 2020</xref>). However, clinical trials of IL-17 blockers presented limited clinical efficacy in RA compared with their efficacies in psoriasis or psoriatic arthritis (<xref ref-type="bibr" rid="B85">Schett et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B27">Fauny et&#xa0;al., 2020</xref>). This suggests that the roles of Th17 cells and IL-17 in the etiology of RA may be multi-faceted, as the presence of Foxp3<sup>+</sup>IL-17<sup>+</sup> T cells is observed in the subjects&#x2019; synovium (<xref ref-type="bibr" rid="B48">Komatsu et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B25">Dominguez-Villar and Hafler, 2018</xref>). Multiple <italic>Prevotella</italic> spp. have been suggested to be associated with the etiology of RA (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>); however, their mechanisms of action are more complex than previously recognized. Therefore, the roles of Th17 subtypes and multiple <italic>Prevotella</italic> spp. in the etiology of RA need to be clarified (<xref ref-type="bibr" rid="B71">Omenetti et&#xa0;al., 2019</xref>). Considering the role of Th17 cells in the pathogenesis of MS, further investigation is needed to determine the role of <italic>P. copri</italic> depletion in MS etiology.</p>
<p>
<italic>Faecalibacterium</italic> is commonly depleted in SLE, MS, and SS (<xref ref-type="table" rid="T1">
<bold>Tables&#xa0;1</bold>
</xref>, <xref ref-type="table" rid="T2">
<bold>2</bold>
</xref>). <italic>Faecalibacterium</italic> maintains homeostasis of the gut immune system by secreting anti-inflammatory compounds such as (<xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>), salicylic acid (<xref ref-type="bibr" rid="B61">Miquel et&#xa0;al., 2015</xref>), and microbial anti-inflammatory molecules (<xref ref-type="bibr" rid="B78">Quevrain et&#xa0;al., 2016</xref>). In addition, <italic>F. prausnitzii</italic> and its supernatant effectively increase the function of Short-chain fatty acid (SCFA)-producing bacteria (<xref ref-type="bibr" rid="B107">Zhou et&#xa0;al., 2021</xref>). SCFAs are produced through the breakdown of various indigestible dietary fibers and complex carbohydrates catalyzed by the gut microbiota (<xref ref-type="bibr" rid="B75">Park and Kim, 2021</xref>). Beneficial bacteria in the oral cavity and gut of healthy individuals can modulate the inflammatory response through the secretion of immunomodulators such as SCFAs (acetate, butyrate, and propionate) (<xref ref-type="bibr" rid="B28">Feng et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B21">Dalile et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B60">Mendez et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B96">Vijay and Valdes, 2021</xref>; <xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>). In addition, <italic>Faecalibacterium</italic>, which secretes SCFAs such as butyrate, is well known for its anti-inflammatory properties (<xref ref-type="bibr" rid="B94">Van de Wiele et&#xa0;al., 2016</xref>).</p>
<p>The anti-inflammatory effect of SCFAs is mediated through the induction of Treg cells and the alleviation of disease symptoms (<xref ref-type="bibr" rid="B53">Machiels et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B45">Kim et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B64">Moon et&#xa0;al., 2020b</xref>; <xref ref-type="bibr" rid="B96">Vijay and Valdes, 2021</xref>). Specifically, among the three types of SCFAs, butyrate and propionate were effective in inducing Foxp3, but acetate was not [untreated 30.4 percent, acetate 31.4 percent, propionate 41.9 percent (p &lt; 0.01), and butyrate 54.2 percent (p &lt; 0.01)] (<xref ref-type="bibr" rid="B31">Furusawa et&#xa0;al., 2013</xref>). In patients with relapsing-remitting MS (RRMS), SCFA concentrations in the fecal samples were significantly reduced compared to controls (<xref ref-type="bibr" rid="B88">Takewaki et&#xa0;al., 2020</xref>). However, the hypersecretion of SCFAs may also lead to side effects, such as bacterial invasion associated with the reduced mucus layer and inflammation (<xref ref-type="bibr" rid="B33">Gaudier et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B74">Park et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B19">Clarke, 2020</xref>; <xref ref-type="bibr" rid="B70">Okumura et&#xa0;al., 2021</xref>). Butyrate enemas reduced the thickness of the adherent mucus layer by approximately two-fold when administered to mice (<xref ref-type="bibr" rid="B33">Gaudier et&#xa0;al., 2009</xref>). The fact that RA developed only in mice with increased gut permeability suggests that bacterial invasion may be associated with a decrease in the mucus layer (<xref ref-type="bibr" rid="B19">Clarke, 2020</xref>). These results suggest that the decrease and hypersecretion of SCFAs may be related to the etiology of autoimmune diseases, which are long-term chronic diseases. Thus, more detailed studies on the role of SCFAs in autoimmune diseases may be needed.</p>
<p>
<italic>Bacteroides</italic> are enriched in SLE and RA (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). The structure and function of <italic>Bacteroides</italic>-derived LPS have been shown in relation to the development of type 1 diabetes (T1D). The immunostimulatory efficacy of <italic>Bacteroides</italic>-derived LPS was four times lower than that of <italic>Escherichia coli</italic>-derived LPS. While the <italic>E. coli</italic>-derived LPS delayed the onset of T1D in non-obese diabetic mice by inducing endotoxin resistance, <italic>Bacteroides</italic>-derived LPS neither induced endotoxin resistance nor delayed the development of T1D (<xref ref-type="bibr" rid="B95">Vatanen et&#xa0;al., 2016</xref>). As a result, <italic>Bacteroides</italic>-derived LPS caused more inflammatory responses than <italic>E. coli</italic>. A similar mechanism may play a role in the pathogenesis of SLE and RA. However, SLE patients also have depleted species that belong to the <italic>Bacteroides</italic> genus. In this context, species-specific modulation of immune function by <italic>Bacteroides</italic> must be studied.</p>
<p>
<italic>E. coli</italic>, enriched in SLE, can be divided into pathogenic and nonpathogenic strains (<xref ref-type="bibr" rid="B73">Palmela et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B51">Lorenz et&#xa0;al., 2020</xref>). Infection with <italic>E. coli</italic> expressing curli amyloid can induce the production of autoantibodies by forming a complex with DNA derived from bacteria or viruses. The amyloid/DNA complexes produce anti-nuclear autoantibodies and anti-dsDNA autoantibodies involved in SLE pathogenesis (<xref ref-type="bibr" rid="B23">Dema and Charles, 2016</xref>; <xref ref-type="bibr" rid="B77">Qiu et&#xa0;al., 2019</xref>). This was verified because curli amyloid-deficient mutant <italic>E. coli</italic> does not produce autoantibodies (<xref ref-type="bibr" rid="B32">Gallo et&#xa0;al., 2015</xref>). This finding may be related to the fifth model of immunopathology proposed by Chen et&#xa0;al. for autoimmune mechanisms (<xref ref-type="bibr" rid="B17">Chen et&#xa0;al., 2017</xref>).</p>
<p>Although <italic>Ruminococcus gnavus</italic> is a gram-positive bacterium, the complex glucorhamnan polysaccharide secreted from this bacterium induces TNF&#x3b1; through TLR4 in dendritic cells (<xref ref-type="bibr" rid="B39">Henke et&#xa0;al., 2019</xref>). In contrast, <italic>Ruminococcus_2</italic> is associated with the improvement of metabolic dysfunction. For example, the consumption of barley for eight months in subjects with metabolic dysfunction improved blood sugar levels and cholesterol levels, which accompanied the enrichment of <italic>Ruminococcus_2</italic> and <italic>Dialister</italic> in the subjects&#x2019; gut (<xref ref-type="bibr" rid="B59">Matsuoka et&#xa0;al., 2022</xref>). This suggests that the depletion of these commensal bacteria may be associated with the development of metabolic dysfunction. Abnormal metabolic reactions, such as elevations in glycolysis and mitochondrial oxidative metabolism, have also been reported in patients with SLE (<xref ref-type="bibr" rid="B103">Yin et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B36">He et&#xa0;al., 2020</xref>). Gut dysbiosis in patients with SLE includes enrichment of <italic>R. gnavus</italic> and depletion of <italic>Ruminococcus_2</italic> and <italic>Dialister</italic> (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). These results suggest that abnormal metabolism in SLE may be closely associated with gut dysbiosis.</p>
<p>A mouse model of spinal cord injury shows the neuroprotective effects of <italic>Butyricimonas</italic>, a genus depleted in patients with MS. <italic>Butyricimonas</italic> is depleted in mice with spinal cord injury but recovers by fecal microbiome transfer from healthy mice, which induces downregulated IL-1&#x3b2; and NF-&#x3ba;B signaling in the spinal cord (<xref ref-type="bibr" rid="B43">Jing et&#xa0;al., 2021</xref>). Therefore, these results suggest that the depletion of <italic>Butyricimonas</italic> in patients with MS may be closely related to its etiology (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>).</p>
<p>The <italic>Bifidobacterium</italic> genus was reported to be depleted in patients with SS in three papers (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>) (<xref ref-type="bibr" rid="B57">Mandl et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B12">Cano-Ortiz et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B63">Moon et&#xa0;al., 2020a</xref>). However, this commensal bacterium needed to be further classified for comparative analysis with other diseases because its relative abundance in gut dysbiosis differed depending on the species. For example, <italic>B. longum</italic> is effective in preventing IBD and treating diarrhea (<xref ref-type="bibr" rid="B69">O&#x2019;Callaghan and van Sinderen, 2016</xref>; <xref ref-type="bibr" rid="B102">Yao et&#xa0;al., 2021</xref>). On the other hand, <italic>B. bifidum</italic> can induce the differentiation of Th17 cells (<xref ref-type="bibr" rid="B80">Rinaldi et&#xa0;al., 2019</xref>). Based on these results, the <italic>Bifidobacterium</italic> genus in SS, an autoimmune disease, is likely to be <italic>B. longum</italic>, but it remains a task to be identified at the species level in the future.</p>
<p>We also investigated how many targeted therapies are shared among the four autoimmune diseases. This is because the altered gut bacteria that may be associated with the etiology of the disease are shared in autoimmune diseases. Petitdemange et&#xa0;al. reported targeted therapies shared in autoimmune or inflammatory diseases (<xref ref-type="bibr" rid="B76">Petitdemange et&#xa0;al., 2020</xref>). Four targeted therapies (abatacept, anakinra, ianalumab, and rituximab) are shared among the four autoimmune diseases (<xref ref-type="table" rid="T4">
<bold>Table&#xa0;4</bold>
</xref>). Among the targeted therapies shared by three diseases, seven (alemtuzumab, atacicept, evobrutinib, ocrelizumab, secukinumab, tabalumab, and ustekinumab) are shared among SLE, MS, and RA. Furthermore, seven (belimumab, etanercept, filgotinib, iscalimab, lanraplenib, omalizumab, and telitacicept) are shared among SLE, RA, and SS, and one (baminercept) is shared among MS, RA, and SS. These results suggest that targeted therapies in autoimmune diseases are related to overlapping immunological pathways due to common causes. It is tempting to say that the altered gut bacteria shared among diseases might be partially involved (<xref ref-type="bibr" rid="B76">Petitdemange et&#xa0;al., 2020</xref>). In particular, 52.6 percent (10 out of 19) of the treatments for these four diseases consisted of molecules that target B cells or antibody production, indicating that the altered gut bacteria may be closely related to autoantibody production.</p>
<table-wrap id="T4" position="float">
<label>Table&#xa0;4</label>
<caption>
<p>Targeted therapies and commensal bacteria shared by four autoimmune diseases.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="left">Diseases</th>
<th valign="middle" align="left">Targeted therapies (TGT)</th>
<th valign="middle" align="left">Mechanism of action of TGT</th>
<th valign="middle" align="left">Shared altered gut bacteria (SAGB)</th>
<th valign="middle" align="left">Mechanism of action of SAGB</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="left">SLE, MS, RA, SS</td>
<td valign="middle" align="left">Abatacept<break/>Anakinra<break/>Ianalumab<break/>Rituximab</td>
<td valign="middle" align="left">CTLA4-Ig fusion protein<break/>IL-1R antagonist<break/>Anti-BAFF receptor mAb<break/>Anti-CD20 mAb</td>
<td valign="middle" align="left">
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="middle" align="left">Autoantibody production<break/>Autoantibody production</td>
</tr>
<tr>
<td valign="middle" align="left">SLE, MS, RA</td>
<td valign="middle" align="left">Alemtuzumab<break/>Atacicept<break/>Evobrutinib<break/>Ocrelizumab<break/>Tabalumab<break/>Secukinumab<break/>Ustekinumab</td>
<td valign="middle" align="left">Anti-CD52 mAb<break/>BAFF and APRIL inhibitor<break/>BTK (B cell development) inhibitor<break/>Anti-CD20 mAb<break/>Anti-BAFF mAb<break/>Anti-IL-17 mAb<break/>Anti-IL-12 and IL-23 mAb</td>
<td valign="middle" align="left">
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Eggerthella lenta</italic>, <italic>Prevotella</italic> spp.</td>
<td valign="middle" align="left">Autoantibody production<break/>Autoantibody production<break/>Autoantibody production<break/>Autoantibody production<break/>IL-17 production</td>
</tr>
<tr>
<td valign="middle" align="left">SLE, RA, SS</td>
<td valign="middle" align="left">Belimumab<break/>Telitacicept<break/>Etanercept<break/>Filgotinib<break/>Iscalimab<break/>Lanraplenib<break/>Omalizumab</td>
<td valign="middle" align="left">Anti-BAFF mAb<break/>BAFF and APRIL inhibitor<break/>TNF&#x3b1; inhibitor<break/>JAK1 inhibitor<break/>Anti-CD40 mAb<break/>SYK-kinase inhibitor<break/>Anti-IgE mAb</td>
<td valign="middle" align="left">
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
<break/>
<italic>Streptococcus</italic>
</td>
<td valign="middle" align="left">Autoantibody production<break/>Autoantibody production<break/>Autoantibody production<break/>Autoantibody production</td>
</tr>
<tr>
<td valign="middle" align="left">MS, RA, SS</td>
<td valign="middle" align="left">Baminercept</td>
<td valign="middle" align="left">LT beta receptor-Ig fusion protein</td>
<td valign="middle" align="left"/>
<td valign="middle" align="left"/>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>mAb, monoclonal antibody; LT, Lymphotoxin.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s2_7">
<label>2.7</label>
<title>Association between shared gut bacteria and polyautoimmunity</title>
<p>Polyautoimmunity can be defined as the coexistence of one or more autoimmune diseases in one patient (<xref ref-type="bibr" rid="B83">Rojas-Villarraga et&#xa0;al., 2012</xref>). Polyautoimmunity in patients with SLE, SS, and RA has a prevalence of 41 percent, 32.6 percent, and 14 percent, respectively (<xref ref-type="bibr" rid="B72">Ordonez-Canizares et&#xa0;al., 2022</xref>). Although data on overall polyautoimmunity in patients with MS are unavailable, the prevalence of coexisting SS has been suggested to be between 1 and 16.6 percent (<xref ref-type="bibr" rid="B3">Amador-Patarroyo et&#xa0;al., 2012</xref>). These results may be related to the fact that autoimmune diseases share altered gut bacteria associated with the failure to maintain immune homeostasis (<xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref>). The enriched relative abundance of <italic>Bacteroides</italic>, <italic>Eggerthella</italic>, <italic>Prevotella</italic>, and <italic>Streptococcus</italic>, shared in autoimmune diseases, has been reported to be related to the promotion of immune responses in immune-related diseases. This is due to Bacteroides-derived LPS, metabolizing Ror&#x3b3;t inhibitors, Th17 cell induction, and antibodies to cross-reactive antigens, respectively (<xref ref-type="bibr" rid="B55">Maeda et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B95">Vatanen et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>; <xref ref-type="bibr" rid="B2">Alexander et&#xa0;al., 2022</xref>). In particular, as aforementioned, <italic>Streptococcus</italic>, which is shared by all four autoimmune diseases, has been suggested to be involved in autoantibody formation (<xref ref-type="bibr" rid="B20">Cunningham, 2019</xref>). This result might also be partially related to the fact that many therapies for these four diseases involve the inhibition of autoantibody production (<xref ref-type="table" rid="T4">
<bold>Table&#xa0;4</bold>
</xref>) (<xref ref-type="bibr" rid="B76">Petitdemange et&#xa0;al., 2020</xref>).</p>
<p>Meanwhile, SLE, MS, and SS patients showed a decreased abundance of <italic>Faecalibacterium</italic> abundance. The decrease of <italic>Faecalibacterium</italic> has the potential to significantly impact the etiology of autoimmune diseases because they secrete various immune modulators, such as butyrate, salicylic acid, and microbial anti-inflammatory molecules, as aforementioned (<xref ref-type="bibr" rid="B61">Miquel et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B78">Quevrain et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B41">Houtman et&#xa0;al., 2022</xref>). These results suggest that the altered gut bacteria shared between autoimmune diseases might contribute to the development of polyautoimmunity (<xref ref-type="bibr" rid="B22">De Luca and Shoenfeld, 2019</xref>; <xref ref-type="bibr" rid="B100">Xu et&#xa0;al., 2021</xref>). However, a direct causal relationship between the shared, altered gut bacteria and polyautoimmunity remains to be further elucidated.</p>
</sec>
<sec id="s2_8">
<label>2.8</label>
<title>Association between altered gut bacteria and mortality</title>
<p>The total number of altered gut bacteria in each autoimmune disease differed depending on the disease&#x2014;22 in SLE, 16 in MS, 5 in RA, and 8 in SS (<xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>). As the number of altered taxa cross-validated across different studies can increase with the increased number of studies, we defined a gut dysbiosis index as the number of altered gut bacterial taxa divided by the number of studies. The gut dysbiosis indexes of SLE, MS, RA, and SA were 1.7, 1.8, 0.7, and 1.3, respectively. Based on these results, we investigated whether a higher degree of gut dysbiosis in SLE and MS was associated with mortality. The most recent papers from developed countries were used for similar comparative conditions for mortality due to each disease. The SMR of patients with MS was 2.89 [95 percent CI, 2.71 to 3.07; UK (period: 1980&#x2013;2007)], indicating a 189 percent higher risk of death than the general population (<xref ref-type="bibr" rid="B46">Kingwell et&#xa0;al., 2012</xref>). The SMR of patients with SLE was 2.66 [95 percent CI, 2.09 to 3.39; Korea (period: 1990&#x2013;2015)], indicating a 166 percent higher risk of death than the general population (<xref ref-type="bibr" rid="B49">Lee et&#xa0;al., 2016</xref>). However, the SMRs of patients with RA and SS were 1.54 [95 percent CI, 1.41 to 1.67; Netherlands (period: 1997&#x2013;2012)] (<xref ref-type="bibr" rid="B92">van den Hoek et&#xa0;al., 2017</xref>) and 1.15 [95 percent CI, 0.86 to 1.50; USA (period: 2006&#x2013;2015)] (<xref ref-type="bibr" rid="B54">Maciel et&#xa0;al., 2017</xref>), respectively. These values were slightly higher than or no different from the general population. Interestingly, the SMRs presented a positive correlation trend with the gut dysbiosis indexes (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>), suggesting that a high degree of gut dysbiosis may adversely affect immune homeostasis and increase mortality rates.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Association between the number of altered gut bacteria and mortality in patients with autoimmune diseases. The index of gut dysbiosis is defined as the number of altered gut bacterial taxa divided by the number of studies. R is Pearson&#x2019;s correlation coefficient.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1157918-g001.tif"/>
</fig>
</sec>
</sec>
<sec id="s3" sec-type="conclusions">
<label>3</label>
<title>Conclusion</title>
<p>The importance of gut dysbiosis in the etiology of autoimmune diseases is increasing. Thus, to better understand the impact of gut dysbiosis, we first investigated the cross-validated altered gut bacteria in each disease and further analyzed the altered gut bacteria shared between autoimmune diseases. Interestingly, the shared, altered gut bacteria enriched in autoimmune diseases are partially related to autoantibody production or the activation of Th17 cells in reports of immune-related diseases. In particular, the decrease of <italic>Faecalibacterium</italic> shared in SLE, MS, and SS, which secretes various immunomodulatory substances, can greatly affect the failure to maintain immune homeostasis. The SMR in patients with SLE and MS was higher than that of RA and SS, which was shown to be positively correlated with the total number of altered gut bacteria in four autoimmune diseases. In taxonomic abundance analysis, <italic>Bifidobacterium</italic>, <italic>Bacteroides</italic>, <italic>Lactobacillus</italic>, <italic>Prevotella</italic>, and <italic>Ruminococcus</italic> should be classified at the species level, not the genus level, as their relative abundance may vary depending on the species. However, the abundance of <italic>Bacteroides fragilis</italic> and <italic>Prevotella copri</italic> varies according to diseases or strains, even if the species are the same, so further research is needed. In addition, the non-cross-validated microbiome, excluded from this study, is left for future tasks by accumulating more data. This review suggests that the altered gut bacteria in patients with autoimmune diseases may be closely related to abnormal immune activity and weakened anti-inflammatory activity. In addition, the increased number and sharing of altered gut bacteria are likely to be associated with disease exacerbation and polyautoimmunity, respectively. However, the direct causal relationship between altered gut bacteria and each autoimmune disease remains to be clarified.</p>
</sec>
<sec id="s4" sec-type="author-contributions">
<title>Author contributions</title>
<p>S-HC and YC contributed the concept and design of the paper. S-HC and YC participated in the review and editing. All authors contributed to the article and approved the submitted version.</p>
</sec>
</body>
<back>
<sec id="s5" sec-type="funding-information">
<title>Funding</title>
<p>This study was supported by the National Research Foundation of Korea (Daejun, Korea) through grants 2018R1A5A2024418 and 2020R1A2C2007038 awarded to YC and grant 2020R1A2C1100163 awarded to S-HC.</p>
</sec>
<sec id="s6" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s7" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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