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Gut Microbial Composition and Function Are Altered in Patients with Early Rheumatoid Arthritis

Identifieur interne : 000623 ( Ncbi/Merge ); précédent : 000622; suivant : 000624

Gut Microbial Composition and Function Are Altered in Patients with Early Rheumatoid Arthritis

Auteurs : Yunju Jeong ; Ji-Won Kim ; Hyun Ju You [Corée du Sud] ; Sang-Jun Park ; Jennifer Lee ; Ji Hyeon Ju ; Myeong Soo Park ; Hui Jin ; Mi-La Cho ; Bin Kwon ; Sung-Hwan Park ; Geun Eog Ji

Source :

RBID : PMC:6572219

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation of the joints and extra-articular manifestations. Recent studies have shown that microorganisms affect RA pathogenesis. However, few studies have examined the microbial distribution of early RA patients, particularly female patients. In the present study, we investigated the gut microbiome profile and microbial functions in early RA female patients, including preclinical and clinically apparent RA cases. Changes in microbiological diversity, composition, and function in each group were analyzed using quantitative insights into microbial ecology (QIIME) and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). The results revealed the dysbiosis due to decreased diversity in the early RA patients compared with healthy subjects. There were significant differences in the microbial distribution of various taxa from phylum to genus levels between healthy subjects and early RA patients. Phylum Bacteroidetes was enriched in early RA patients, while Actinobacteria, including the genus Collinsella, was enriched in healthy subjects. Functional analysis based on clusters of orthologous groups revealed that the genes related to the biosynthesis of menaquinone, known to be derived from gram-positive bacteria, were enriched in healthy subjects, while iron transport-related genes were enriched in early RA patients. Genes related to the biosynthesis of lipopolysaccharide, the gram-negative bacterial endotoxin, were enriched in clinically apparent RA patients. The obvious differences in microbial diversity, taxa, and associated functions of the gut microbiota between healthy subjects and early RA patients highlight the involvement of the gut microbiome in the early stages of RA.


Url:
DOI: 10.3390/jcm8050693
PubMed: 31100891
PubMed Central: 6572219

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PMC:6572219

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<name sortKey="Kwon, Bin" sort="Kwon, Bin" uniqKey="Kwon B" first="Bin" last="Kwon">Bin Kwon</name>
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<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
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<nlm:aff id="af1-jcm-08-00693">Research Center, BIFIDO Co., Ltd., 23-16, Nonggongdanji-gil, Hongcheon 25117, Korea;
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<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
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<name sortKey="Kim, Ji Won" sort="Kim, Ji Won" uniqKey="Kim J" first="Ji-Won" last="Kim">Ji-Won Kim</name>
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<nlm:aff id="af3-jcm-08-00693">Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 137-701, Korea;
<email>shyqw@naver.com</email>
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<name sortKey="You, Hyun Ju" sort="You, Hyun Ju" uniqKey="You H" first="Hyun Ju" last="You">Hyun Ju You</name>
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<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
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(S.-J.P.);
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<name sortKey="Park, Sang Jun" sort="Park, Sang Jun" uniqKey="Park S" first="Sang-Jun" last="Park">Sang-Jun Park</name>
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<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
<email>sjpark-90@snu.ac.kr</email>
(S.-J.P.);
<email>jh1030@snu.ac.kr</email>
(H.J.)</nlm:aff>
</affiliation>
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<name sortKey="Lee, Jennifer" sort="Lee, Jennifer" uniqKey="Lee J" first="Jennifer" last="Lee">Jennifer Lee</name>
<affiliation>
<nlm:aff id="af3-jcm-08-00693">Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 137-701, Korea;
<email>shyqw@naver.com</email>
(J.-W.K.);
<email>poohish@catholic.ac.kr</email>
(J.L.);
<email>juji@catholic.ac.kr</email>
(J.H.J.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ju, Ji Hyeon" sort="Ju, Ji Hyeon" uniqKey="Ju J" first="Ji Hyeon" last="Ju">Ji Hyeon Ju</name>
<affiliation>
<nlm:aff id="af3-jcm-08-00693">Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 137-701, Korea;
<email>shyqw@naver.com</email>
(J.-W.K.);
<email>poohish@catholic.ac.kr</email>
(J.L.);
<email>juji@catholic.ac.kr</email>
(J.H.J.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Park, Myeong Soo" sort="Park, Myeong Soo" uniqKey="Park M" first="Myeong Soo" last="Park">Myeong Soo Park</name>
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<nlm:aff id="af1-jcm-08-00693">Research Center, BIFIDO Co., Ltd., 23-16, Nonggongdanji-gil, Hongcheon 25117, Korea;
<email>tanklov0@snu.ac.kr</email>
(Y.J.);
<email>bifidopark@bifido.com</email>
(M.S.P.);
<email>kb@bifido.com</email>
(B.K.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Jin, Hui" sort="Jin, Hui" uniqKey="Jin H" first="Hui" last="Jin">Hui Jin</name>
<affiliation>
<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
<email>sjpark-90@snu.ac.kr</email>
(S.-J.P.);
<email>jh1030@snu.ac.kr</email>
(H.J.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Cho, Mi La" sort="Cho, Mi La" uniqKey="Cho M" first="Mi-La" last="Cho">Mi-La Cho</name>
<affiliation>
<nlm:aff id="af5-jcm-08-00693">Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea;
<email>iammila@catholic.ac.kr</email>
</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Kwon, Bin" sort="Kwon, Bin" uniqKey="Kwon B" first="Bin" last="Kwon">Bin Kwon</name>
<affiliation>
<nlm:aff id="af1-jcm-08-00693">Research Center, BIFIDO Co., Ltd., 23-16, Nonggongdanji-gil, Hongcheon 25117, Korea;
<email>tanklov0@snu.ac.kr</email>
(Y.J.);
<email>bifidopark@bifido.com</email>
(M.S.P.);
<email>kb@bifido.com</email>
(B.K.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Park, Sung Hwan" sort="Park, Sung Hwan" uniqKey="Park S" first="Sung-Hwan" last="Park">Sung-Hwan Park</name>
<affiliation>
<nlm:aff id="af3-jcm-08-00693">Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 137-701, Korea;
<email>shyqw@naver.com</email>
(J.-W.K.);
<email>poohish@catholic.ac.kr</email>
(J.L.);
<email>juji@catholic.ac.kr</email>
(J.H.J.)</nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ji, Geun Eog" sort="Ji, Geun Eog" uniqKey="Ji G" first="Geun Eog" last="Ji">Geun Eog Ji</name>
<affiliation>
<nlm:aff id="af1-jcm-08-00693">Research Center, BIFIDO Co., Ltd., 23-16, Nonggongdanji-gil, Hongcheon 25117, Korea;
<email>tanklov0@snu.ac.kr</email>
(Y.J.);
<email>bifidopark@bifido.com</email>
(M.S.P.);
<email>kb@bifido.com</email>
(B.K.)</nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="af2-jcm-08-00693">Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
<email>sjpark-90@snu.ac.kr</email>
(S.-J.P.);
<email>jh1030@snu.ac.kr</email>
(H.J.)</nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Journal of Clinical Medicine</title>
<idno type="eISSN">2077-0383</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
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<front>
<div type="abstract" xml:lang="en">
<p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation of the joints and extra-articular manifestations. Recent studies have shown that microorganisms affect RA pathogenesis. However, few studies have examined the microbial distribution of early RA patients, particularly female patients. In the present study, we investigated the gut microbiome profile and microbial functions in early RA female patients, including preclinical and clinically apparent RA cases. Changes in microbiological diversity, composition, and function in each group were analyzed using quantitative insights into microbial ecology (QIIME) and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). The results revealed the dysbiosis due to decreased diversity in the early RA patients compared with healthy subjects. There were significant differences in the microbial distribution of various taxa from phylum to genus levels between healthy subjects and early RA patients. Phylum Bacteroidetes was enriched in early RA patients, while Actinobacteria, including the genus
<italic>Collinsella,</italic>
was enriched in healthy subjects. Functional analysis based on clusters of orthologous groups revealed that the genes related to the biosynthesis of menaquinone, known to be derived from gram-positive bacteria, were enriched in healthy subjects, while iron transport-related genes were enriched in early RA patients. Genes related to the biosynthesis of lipopolysaccharide, the gram-negative bacterial endotoxin, were enriched in clinically apparent RA patients. The obvious differences in microbial diversity, taxa, and associated functions of the gut microbiota between healthy subjects and early RA patients highlight the involvement of the gut microbiome in the early stages of RA.</p>
</div>
</front>
<back>
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<name sortKey="Wahle, M" uniqKey="Wahle M">M. Wahle</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Kurosu, M" uniqKey="Kurosu M">M. Kurosu</name>
</author>
<author>
<name sortKey="Begari, E" uniqKey="Begari E">E. Begari</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">J Clin Med</journal-id>
<journal-id journal-id-type="iso-abbrev">J Clin Med</journal-id>
<journal-id journal-id-type="publisher-id">jcm</journal-id>
<journal-title-group>
<journal-title>Journal of Clinical Medicine</journal-title>
</journal-title-group>
<issn pub-type="epub">2077-0383</issn>
<publisher>
<publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">31100891</article-id>
<article-id pub-id-type="pmc">6572219</article-id>
<article-id pub-id-type="doi">10.3390/jcm8050693</article-id>
<article-id pub-id-type="publisher-id">jcm-08-00693</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Gut Microbial Composition and Function Are Altered in Patients with Early Rheumatoid Arthritis</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Jeong</surname>
<given-names>Yunju</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-08-00693">1</xref>
<xref ref-type="aff" rid="af2-jcm-08-00693">2</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0498-5762</contrib-id>
<name>
<surname>Kim</surname>
<given-names>Ji-Won</given-names>
</name>
<xref ref-type="aff" rid="af3-jcm-08-00693">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>You</surname>
<given-names>Hyun Ju</given-names>
</name>
<xref ref-type="aff" rid="af2-jcm-08-00693">2</xref>
<xref ref-type="aff" rid="af4-jcm-08-00693">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Park</surname>
<given-names>Sang-Jun</given-names>
</name>
<xref ref-type="aff" rid="af2-jcm-08-00693">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lee</surname>
<given-names>Jennifer</given-names>
</name>
<xref ref-type="aff" rid="af3-jcm-08-00693">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ju</surname>
<given-names>Ji Hyeon</given-names>
</name>
<xref ref-type="aff" rid="af3-jcm-08-00693">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Park</surname>
<given-names>Myeong Soo</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-08-00693">1</xref>
</contrib>
<contrib contrib-type="author">
<contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3803-0745</contrib-id>
<name>
<surname>Jin</surname>
<given-names>Hui</given-names>
</name>
<xref ref-type="aff" rid="af2-jcm-08-00693">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cho</surname>
<given-names>Mi-La</given-names>
</name>
<xref ref-type="aff" rid="af5-jcm-08-00693">5</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kwon</surname>
<given-names>Bin</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-08-00693">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Park</surname>
<given-names>Sung-Hwan</given-names>
</name>
<xref ref-type="aff" rid="af3-jcm-08-00693">3</xref>
<xref rid="c1-jcm-08-00693" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ji</surname>
<given-names>Geun Eog</given-names>
</name>
<xref ref-type="aff" rid="af1-jcm-08-00693">1</xref>
<xref ref-type="aff" rid="af2-jcm-08-00693">2</xref>
<xref rid="c1-jcm-08-00693" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="af1-jcm-08-00693">
<label>1</label>
Research Center, BIFIDO Co., Ltd., 23-16, Nonggongdanji-gil, Hongcheon 25117, Korea;
<email>tanklov0@snu.ac.kr</email>
(Y.J.);
<email>bifidopark@bifido.com</email>
(M.S.P.);
<email>kb@bifido.com</email>
(B.K.)</aff>
<aff id="af2-jcm-08-00693">
<label>2</label>
Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
<email>dhlover1@snu.ac.kr</email>
(H.J.Y.);
<email>sjpark-90@snu.ac.kr</email>
(S.-J.P.);
<email>jh1030@snu.ac.kr</email>
(H.J.)</aff>
<aff id="af3-jcm-08-00693">
<label>3</label>
Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-gu, Seoul 137-701, Korea;
<email>shyqw@naver.com</email>
(J.-W.K.);
<email>poohish@catholic.ac.kr</email>
(J.L.);
<email>juji@catholic.ac.kr</email>
(J.H.J.)</aff>
<aff id="af4-jcm-08-00693">
<label>4</label>
Institute of Health and Environment, Graduate School of Public Health, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea</aff>
<aff id="af5-jcm-08-00693">
<label>5</label>
Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea;
<email>iammila@catholic.ac.kr</email>
</aff>
<author-notes>
<corresp id="c1-jcm-08-00693">
<label>*</label>
Correspondence:
<email>rapark@catholic.ac.kr</email>
(S.-H.P.);
<email>geji@snu.ac.kr</email>
(G.E.J.); Tel.: +82-2-880-6282 (G.E.J.); Fax: +82-2-884-0305 (G.E.J.)</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>16</day>
<month>5</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection">
<month>5</month>
<year>2019</year>
</pub-date>
<volume>8</volume>
<issue>5</issue>
<elocation-id>693</elocation-id>
<history>
<date date-type="received">
<day>30</day>
<month>3</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>14</day>
<month>5</month>
<year>2019</year>
</date>
</history>
<permissions>
<copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access">
<license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract>
<p>Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation of the joints and extra-articular manifestations. Recent studies have shown that microorganisms affect RA pathogenesis. However, few studies have examined the microbial distribution of early RA patients, particularly female patients. In the present study, we investigated the gut microbiome profile and microbial functions in early RA female patients, including preclinical and clinically apparent RA cases. Changes in microbiological diversity, composition, and function in each group were analyzed using quantitative insights into microbial ecology (QIIME) and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt). The results revealed the dysbiosis due to decreased diversity in the early RA patients compared with healthy subjects. There were significant differences in the microbial distribution of various taxa from phylum to genus levels between healthy subjects and early RA patients. Phylum Bacteroidetes was enriched in early RA patients, while Actinobacteria, including the genus
<italic>Collinsella,</italic>
was enriched in healthy subjects. Functional analysis based on clusters of orthologous groups revealed that the genes related to the biosynthesis of menaquinone, known to be derived from gram-positive bacteria, were enriched in healthy subjects, while iron transport-related genes were enriched in early RA patients. Genes related to the biosynthesis of lipopolysaccharide, the gram-negative bacterial endotoxin, were enriched in clinically apparent RA patients. The obvious differences in microbial diversity, taxa, and associated functions of the gut microbiota between healthy subjects and early RA patients highlight the involvement of the gut microbiome in the early stages of RA.</p>
</abstract>
<kwd-group>
<kwd>rheumatoid arthritis</kwd>
<kwd>autoimmune disease</kwd>
<kwd>gut microbiome</kwd>
<kwd>
<italic>Collinsella</italic>
</kwd>
<kwd>microbial diversity</kwd>
<kwd>dysbiosis</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group>
<fig id="jcm-08-00693-f001" orientation="portrait" position="float">
<label>Figure 1</label>
<caption>
<p>Comparison of bacterial diversity and communities between early rheumatoid arthritis patients (ER) and healthy controls (CT). (
<bold>A</bold>
,
<bold>B</bold>
) Faith’s phylogenetic diversity comparisons were performed for ER and CT groups using Wilcoxon rank-sum tests. Comparisons among CT, PC, and ST groups were performed using Kruskal–Wallis tests. Lines inside the box represent the median, while whiskers represent the lowest and highest values within the 1.5 interquartile range (IQR). Outliers and individual sample values are shown as dots. (
<bold>C</bold>
,
<bold>D</bold>
) Principal coordinate plot based on the weighted-UniFrac distance matrix.</p>
</caption>
<graphic xlink:href="jcm-08-00693-g001a"></graphic>
<graphic xlink:href="jcm-08-00693-g001b"></graphic>
</fig>
<fig id="jcm-08-00693-f002" orientation="portrait" position="float">
<label>Figure 2</label>
<caption>
<p>Heat map of the 20 most abundant genera in each sample. The color intensity in each cell indicates the proportion of a given genus in a sample. Significantly abundant taxa in either of the two groups (*
<italic>p</italic>
< 0.05, Wilcoxon rank-sum test; **
<italic>p</italic>
< 0.01, Wilcoxon rank-sum test) are included.</p>
</caption>
<graphic xlink:href="jcm-08-00693-g002"></graphic>
</fig>
<fig id="jcm-08-00693-f003" orientation="portrait" position="float">
<label>Figure 3</label>
<caption>
<p>Featured taxa based on LDA effect size (LEfSe) analysis and random forest predictive analysis of CT and ER groups. (
<bold>A</bold>
) Selected taxa based on LEfSe analysis. (
<bold>B</bold>
) Selected taxa based on random forest analysis of the top 20 abundant genera. (
<bold>C</bold>
) Relative abundance of the genus Collinsella.</p>
</caption>
<graphic xlink:href="jcm-08-00693-g003"></graphic>
</fig>
<fig id="jcm-08-00693-f004" orientation="portrait" position="float">
<label>Figure 4</label>
<caption>
<p>Featured COGs by PICRUSt. (
<bold>A</bold>
) Differentially abundant COGs between ER and CT groups based on LEfSe analysis. (
<bold>B</bold>
,
<bold>C</bold>
) The relative abundance of COG1629 and 4771. (
<bold>D</bold>
) Differentially abundant COGs among CT, PC, and ST groups based on LEfSe analysis. (
<bold>E</bold>
) Spearman correlation analysis of COG2148 and DAS28.</p>
</caption>
<graphic xlink:href="jcm-08-00693-g004"></graphic>
</fig>
<table-wrap id="jcm-08-00693-t001" orientation="portrait" position="float">
<object-id pub-id-type="pii">jcm-08-00693-t001_Table 1</object-id>
<label>Table 1</label>
<caption>
<p>Clinical features of early rheumatoid arthritis patients and healthy controls.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin" rowspan="1" colspan="1"></th>
<th colspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">ER</th>
<th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">CT</th>
</tr>
<tr>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PC</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ST</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Total</th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">N</td>
<td align="center" valign="middle" rowspan="1" colspan="1">17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12</td>
<td align="center" valign="middle" rowspan="1" colspan="1">29</td>
<td align="center" valign="middle" rowspan="1" colspan="1">25</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Age</td>
<td align="center" valign="middle" rowspan="1" colspan="1">47.71 ± 6.57</td>
<td align="center" valign="middle" rowspan="1" colspan="1">44.33 ± 14.65</td>
<td align="center" valign="middle" rowspan="1" colspan="1">46.31 ± 10.58</td>
<td align="center" valign="middle" rowspan="1" colspan="1">42.32 ± 12.46</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Sex (F/M)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">17/0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">12/0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">29/0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">25/0</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">** DAS28</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.26 ± 0.43</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.84 ± 1.52</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.92 ± 1.28</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">** CRP (mg/dL)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.11 ± 0.19</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.28 ± 1.77</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.59 ± 1.26</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">** ESR (mm/h)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9.06 ± 5.83</td>
<td align="center" valign="middle" rowspan="1" colspan="1">27.17 ± 17.78</td>
<td align="center" valign="middle" rowspan="1" colspan="1">16.55 ± 15.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">RF (IU/mL)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">188.20 ± 285.93</td>
<td align="center" valign="middle" rowspan="1" colspan="1">288.10 ± 245.74</td>
<td align="center" valign="middle" rowspan="1" colspan="1">203.90 ± 266.85</td>
<td align="center" valign="middle" rowspan="1" colspan="1">-</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ACCP (CU)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1048.00 ± 2815.19</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">765.30 ± 705.84</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">942.10 ± 2239.86</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">-</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>The values are presented as the mean ± standard deviation or frequency. Comparisons of parameters between early RA (ER) and healthy controls (CT) or patients with preclinical RA (PC) and patients with clinically apparent RA (ST) groups were statistically assessed through Wilcoxon’s rank-sum tests. The double asterisk indicates statistically significant different of each value between PC and ST with
<italic>p</italic>
-value less than 0.01. DAS28: disease activity score 28 joints, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, RF: Rheumatoid factor, ACCP: anti-cyclic citrullinated peptide.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="jcm-08-00693-t002" orientation="portrait" position="float">
<object-id pub-id-type="pii">jcm-08-00693-t002_Table 2</object-id>
<label>Table 2</label>
<caption>
<p>Differentially enriched taxa in early rheumatoid patients and healthy controls showing the top 20 taxa at each level.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"></th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Taxa</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">
<italic>p</italic>
-value</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">FDR</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CT Mean (%)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">ER Mean (%)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Fold Change</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CT Prevalence (%)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">ER Prevalence (%)</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="9" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Enriched taxa in ER</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Phylum</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Bacteroidetes</td>
<td align="center" valign="middle" rowspan="1" colspan="1">* 0.011</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.091</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">34.78</td>
<td align="center" valign="middle" rowspan="1" colspan="1">43.07</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.24</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Class</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Bacteroidia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">* 0.014</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.089</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">34.67</td>
<td align="center" valign="middle" rowspan="1" colspan="1">43.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.24</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Order</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Bacteroidales</td>
<td align="center" valign="middle" rowspan="1" colspan="1">* 0.014</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.093</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">34.67</td>
<td align="center" valign="middle" rowspan="1" colspan="1">43.03</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.24</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
<td align="center" valign="middle" rowspan="1" colspan="1">100</td>
</tr>
<tr>
<td colspan="9" align="center" valign="middle" rowspan="1">Enriched taxa in CT</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Phylum</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Actinobacteria</td>
<td align="center" valign="middle" rowspan="1" colspan="1">* 0.014</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.091</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2.85</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.52</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.54</td>
<td align="center" valign="middle" rowspan="1" colspan="1">92</td>
<td align="center" valign="middle" rowspan="1" colspan="1">69</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Class</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Erysipelotrichi</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0027</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.028</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.44</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.65</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.45</td>
<td align="center" valign="middle" rowspan="1" colspan="1">96</td>
<td align="center" valign="middle" rowspan="1" colspan="1">72</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Class</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Coriobacteriia</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0029</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.028</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.35</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.48</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="middle" rowspan="1" colspan="1">80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">48</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Order</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Erysipelotrichales</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0027</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.029</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.44</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.65</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.45</td>
<td align="center" valign="middle" rowspan="1" colspan="1">96</td>
<td align="center" valign="middle" rowspan="1" colspan="1">72</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Order</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Coriobacteriales</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0029</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.029</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.35</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.48</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="middle" rowspan="1" colspan="1">80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">48</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Family</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Erysipelotrichaceae</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0027</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.029</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.44</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.65</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.45</td>
<td align="center" valign="middle" rowspan="1" colspan="1">96</td>
<td align="center" valign="middle" rowspan="1" colspan="1">72</td>
</tr>
<tr>
<td align="center" valign="middle" rowspan="1" colspan="1">Family</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Coriobacteriaceae</td>
<td align="center" valign="middle" rowspan="1" colspan="1">** 0.0029</td>
<td align="center" valign="middle" rowspan="1" colspan="1">
<bold>0.029</bold>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.35</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.48</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="middle" rowspan="1" colspan="1">80</td>
<td align="center" valign="middle" rowspan="1" colspan="1">48</td>
</tr>
<tr>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Genus</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<italic>Collinsella</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">** 0.0041</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">
<bold>0.082</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.00</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.36</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">76</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">41</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>Comparisons were analyzed using Wilcoxon rank-sum tests. The single- and double-asterisk indicates statistically significant different of each value between CT and ER with
<italic>p</italic>
-value less than 0.05 and 0.01. Bold values indicate a significant comparison with a false discovery rate (FDR) <0.1.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations>
<list>
<country>
<li>Corée du Sud</li>
</country>
<region>
<li>Région capitale de Séoul</li>
</region>
<settlement>
<li>Séoul</li>
</settlement>
<orgName>
<li>Université nationale de Séoul</li>
</orgName>
</list>
<tree>
<noCountry>
<name sortKey="Cho, Mi La" sort="Cho, Mi La" uniqKey="Cho M" first="Mi-La" last="Cho">Mi-La Cho</name>
<name sortKey="Jeong, Yunju" sort="Jeong, Yunju" uniqKey="Jeong Y" first="Yunju" last="Jeong">Yunju Jeong</name>
<name sortKey="Ji, Geun Eog" sort="Ji, Geun Eog" uniqKey="Ji G" first="Geun Eog" last="Ji">Geun Eog Ji</name>
<name sortKey="Jin, Hui" sort="Jin, Hui" uniqKey="Jin H" first="Hui" last="Jin">Hui Jin</name>
<name sortKey="Ju, Ji Hyeon" sort="Ju, Ji Hyeon" uniqKey="Ju J" first="Ji Hyeon" last="Ju">Ji Hyeon Ju</name>
<name sortKey="Kim, Ji Won" sort="Kim, Ji Won" uniqKey="Kim J" first="Ji-Won" last="Kim">Ji-Won Kim</name>
<name sortKey="Kwon, Bin" sort="Kwon, Bin" uniqKey="Kwon B" first="Bin" last="Kwon">Bin Kwon</name>
<name sortKey="Lee, Jennifer" sort="Lee, Jennifer" uniqKey="Lee J" first="Jennifer" last="Lee">Jennifer Lee</name>
<name sortKey="Park, Myeong Soo" sort="Park, Myeong Soo" uniqKey="Park M" first="Myeong Soo" last="Park">Myeong Soo Park</name>
<name sortKey="Park, Sang Jun" sort="Park, Sang Jun" uniqKey="Park S" first="Sang-Jun" last="Park">Sang-Jun Park</name>
<name sortKey="Park, Sung Hwan" sort="Park, Sung Hwan" uniqKey="Park S" first="Sung-Hwan" last="Park">Sung-Hwan Park</name>
</noCountry>
<country name="Corée du Sud">
<region name="Région capitale de Séoul">
<name sortKey="You, Hyun Ju" sort="You, Hyun Ju" uniqKey="You H" first="Hyun Ju" last="You">Hyun Ju You</name>
</region>
</country>
</tree>
</affiliations>
</record>

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