{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:43:47Z","timestamp":1768563827832,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,29]]},"group-title":"Neurology","reference-count":143,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 \u00b1 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion in\n                    <jats:italic>Akkermansia<\/jats:italic>\n                    ,\n                    <jats:italic>Lachnospiraceae,<\/jats:italic>\n                    and\n                    <jats:italic>Oscillospiraceae<\/jats:italic>\n                    , with an expansion of\n                    <jats:italic>Alloprevotella<\/jats:italic>\n                    ,\n                    <jats:italic>Prevotella-9<\/jats:italic>\n                    , and\n                    <jats:italic>Rhodospirillales<\/jats:italic>\n                    . Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K\n                    <jats:sub>2<\/jats:sub>\n                    production (linked to\n                    <jats:italic>Akkermansia<\/jats:italic>\n                    ), and a depletion in SCFA metabolism (linked to\n                    <jats:italic>Lachnospiraceae<\/jats:italic>\n                    and\n                    <jats:italic>Oscillospiraceae<\/jats:italic>\n                    ). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    These results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K\n                    <jats:sub>2<\/jats:sub>\n                    and SCFAs are associated with progression.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"23291875v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2023.06.26.23291875","type":"posted-content","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T16:35:12Z","timestamp":1688056512000},"source":"Crossref","is-referenced-by-count":2,"title":["Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0950-9618","authenticated-orcid":false,"given":"Theresa L","family":"Montgomery","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Mirza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deanna","family":"Dwyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine A","family":"Dowling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob WS","family":"Martens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitry N","family":"Krementsov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Mao-Draayer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023070313452230000_2023.06.26.23291875v1.1","doi-asserted-by":"publisher","DOI":"10.3399\/bjgp14X682609"},{"key":"2023070313452230000_2023.06.26.23291875v1.2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007035"},{"issue":"11","key":"2023070313452230000_2023.06.26.23291875v1.3","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/S1474-4422(17)30299-5","article-title":"Global, regional, and national burden of neurological disorders during 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015","volume":"16","year":"2017","journal-title":"The Lancet Neurology"},{"key":"2023070313452230000_2023.06.26.23291875v1.4","doi-asserted-by":"publisher","DOI":"10.1055\/s-0036-1579693"},{"key":"2023070313452230000_2023.06.26.23291875v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70042-5"},{"key":"2023070313452230000_2023.06.26.23291875v1.6","doi-asserted-by":"publisher","DOI":"10.2174\/187152712801661266"},{"key":"2023070313452230000_2023.06.26.23291875v1.7","doi-asserted-by":"crossref","unstructured":"Ochoa-Rep\u00e1raz, J. , T.O. Kirby , and L.H. Kasper , The Gut Microbiome and Multiple Sclerosis. Cold Spring Harb Perspect Med, 2018. 8(6).","DOI":"10.1101\/cshperspect.a029017"},{"key":"2023070313452230000_2023.06.26.23291875v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21640"},{"key":"2023070313452230000_2023.06.26.23291875v1.9","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028928"},{"key":"2023070313452230000_2023.06.26.23291875v1.10","doi-asserted-by":"crossref","unstructured":"Lobeck, L.J. , Multiple Sclerosis, in Encyclopedia of the Human Brain, V.S. Ramachandran , Editor. 2002, Academic Press: New York. p. 211\u2013225.","DOI":"10.1016\/B0-12-227210-2\/00224-7"},{"key":"2023070313452230000_2023.06.26.23291875v1.11","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20197"},{"key":"2023070313452230000_2023.06.26.23291875v1.12","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.67.2.148"},{"key":"2023070313452230000_2023.06.26.23291875v1.13","doi-asserted-by":"crossref","first-page":"11795735211050712","DOI":"10.1177\/11795735211050712","article-title":"Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis","volume":"13","year":"2021","journal-title":"J Cent Nerv Syst Dis"},{"key":"2023070313452230000_2023.06.26.23291875v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.08.003"},{"key":"2023070313452230000_2023.06.26.23291875v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew353"},{"key":"2023070313452230000_2023.06.26.23291875v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2016.07.016"},{"key":"2023070313452230000_2023.06.26.23291875v1.17","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3009759"},{"key":"2023070313452230000_2023.06.26.23291875v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/srep28484"},{"key":"2023070313452230000_2023.06.26.23291875v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12015"},{"key":"2023070313452230000_2023.06.26.23291875v1.20","doi-asserted-by":"crossref","first-page":"103557","DOI":"10.1016\/j.ebiom.2021.103557","article-title":"Alterations of the gut mycobiome in patients with MS","volume":"71","year":"2021","journal-title":"EBioMedicine"},{"key":"2023070313452230000_2023.06.26.23291875v1.21","doi-asserted-by":"crossref","unstructured":"Ordo\u00f1ez-Rodriguez, A. , et al., Changes in Gut Microbiota and Multiple Sclerosis: A Systematic Review. Int J Environ Res Public Health, 2023. 20(5).","DOI":"10.3390\/ijerph20054624"},{"key":"2023070313452230000_2023.06.26.23291875v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nature12721"},{"key":"2023070313452230000_2023.06.26.23291875v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.09.007"},{"key":"2023070313452230000_2023.06.26.23291875v1.24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180190"},{"issue":"7","key":"2023070313452230000_2023.06.26.23291875v1.25","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1113\/EP086110","article-title":"Short-chain fatty acids augment rat duodenal mucosal barrier function","volume":"102","year":"2017","journal-title":"Experimental physiology"},{"key":"2023070313452230000_2023.06.26.23291875v1.26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0173032"},{"key":"2023070313452230000_2023.06.26.23291875v1.27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137429"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.28","doi-asserted-by":"crossref","first-page":"8837","DOI":"10.1038\/s41598-019-45311-y","article-title":"Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation","volume":"9","year":"2019","journal-title":"Scientific Reports"},{"key":"2023070313452230000_2023.06.26.23291875v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.03.004"},{"key":"2023070313452230000_2023.06.26.23291875v1.30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904847106"},{"key":"2023070313452230000_2023.06.26.23291875v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/BF00887825"},{"key":"2023070313452230000_2023.06.26.23291875v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(90)91087-M"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.33","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1186\/s12967-021-02995-z","article-title":"Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL\/6 mice","volume":"19","year":"2021","journal-title":"J Transl Med"},{"key":"2023070313452230000_2023.06.26.23291875v1.34","first-page":"19","article-title":"Gut Microbiota and Chronic Constipation: A Review and Update","volume":"6","year":"2019","journal-title":"Front Med (Lausanne"},{"key":"2023070313452230000_2023.06.26.23291875v1.35","first-page":"79","article-title":"Neurogenic bowel dysfunction in patients with multiple sclerosis: prevalence, impact, and management strategies","volume":"8","year":"2018","journal-title":"Degener Neurol Neuromuscul Dis"},{"issue":"19","key":"2023070313452230000_2023.06.26.23291875v1.36","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1016\/j.cell.2022.08.021","article-title":"Gut microbiome of multiple sclerosis patients and paired household healthy controls reveal associations with disease risk and course","volume":"185","year":"2022","journal-title":"Cell"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-022-01148-1","article-title":"The gut microbiota in multiple sclerosis varies with disease activity","volume":"15","year":"2023","journal-title":"Genome Med"},{"key":"2023070313452230000_2023.06.26.23291875v1.38","doi-asserted-by":"crossref","unstructured":"Pellizoni, F.P. , et al., Detection of Dysbiosis and Increased Intestinal Permeability in Brazilian Patients with Relapsing-Remitting Multiple Sclerosis. Int J Environ Res Public Health, 2021. 18(9).","DOI":"10.3390\/ijerph18094621"},{"key":"2023070313452230000_2023.06.26.23291875v1.39","doi-asserted-by":"crossref","unstructured":"Tremlett, H. , et al., Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol, 2016.","DOI":"10.1111\/ene.13026"},{"key":"2023070313452230000_2023.06.26.23291875v1.40","doi-asserted-by":"crossref","first-page":"104468","DOI":"10.1016\/j.neuint.2019.104468","article-title":"Gut dysbiosis and lack of short chain fatty acids in a Chinese cohort of patients with multiple sclerosis","volume":"129","year":"2019","journal-title":"Neurochem Int"},{"key":"2023070313452230000_2023.06.26.23291875v1.41","doi-asserted-by":"crossref","first-page":"590783","DOI":"10.3389\/fimmu.2020.590783","article-title":"Alterations of the Fecal Microbiota in Chinese Patients With Multiple Sclerosis","volume":"11","year":"2020","journal-title":"Front Immunol"},{"key":"2023070313452230000_2023.06.26.23291875v1.42","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.3389\/fimmu.2020.01390","article-title":"Alterations in circulating fatty acid are associated with gut microbiota dysbiosis and inflammation in multiple sclerosis","volume":"11","year":"2020","journal-title":"Frontiers in immunology"},{"key":"2023070313452230000_2023.06.26.23291875v1.43","doi-asserted-by":"crossref","unstructured":"Choile\u00e1in, S.N. , et al., CXCR3+ T cells in multiple sclerosis correlate with reduced diversity of the gut microbiome. J Transl Autoimmun, 2020. 3: p. 100032.","DOI":"10.1016\/j.jtauto.2019.100032"},{"issue":"7","key":"2023070313452230000_2023.06.26.23291875v1.44","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nmeth.3869","article-title":"DADA2: High-resolution sample inference from Illumina amplicon data","volume":"13","year":"2016","journal-title":"Nature Methods"},{"issue":"12","key":"2023070313452230000_2023.06.26.23291875v1.45","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1038\/ismej.2017.119","article-title":"Exact sequence variants should replace operational taxonomic units in marker-gene data analysis","volume":"11","year":"2017","journal-title":"Isme j"},{"key":"2023070313452230000_2023.06.26.23291875v1.46","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks808"},{"issue":"D1","key":"2023070313452230000_2023.06.26.23291875v1.47","doi-asserted-by":"crossref","first-page":"D590","DOI":"10.1093\/nar\/gks1219","article-title":"The SILVA ribosomal RNA gene database project: improved data processing and web-based tools","volume":"41","year":"2012","journal-title":"Nucleic Acids Research"},{"key":"2023070313452230000_2023.06.26.23291875v1.48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0061217"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.49","doi-asserted-by":"crossref","first-page":"2180316","DOI":"10.1080\/19490976.2023.2180316","article-title":"Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis","volume":"15","year":"2023","journal-title":"Gut Microbes"},{"key":"2023070313452230000_2023.06.26.23291875v1.50","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2023070313452230000_2023.06.26.23291875v1.51","doi-asserted-by":"crossref","unstructured":"Douglas, G.M. , et al., PICRUSt2: An improved and extensible approach for metagenome inference. bioRxiv, 2019: p. 672295.","DOI":"10.1101\/672295"},{"key":"2023070313452230000_2023.06.26.23291875v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0548-6"},{"key":"2023070313452230000_2023.06.26.23291875v1.53","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz862"},{"key":"2023070313452230000_2023.06.26.23291875v1.54","doi-asserted-by":"publisher","DOI":"10.1016\/s0005-2728(97)00034-0"},{"issue":"7","key":"2023070313452230000_2023.06.26.23291875v1.55","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.bbabio.2014.01.015","article-title":"Biosynthesis and physiology of coenzyme Q in bacteria","volume":"1837","year":"2014","journal-title":"Biochimica et Biophysica Acta (BBA) - Bioenergetics"},{"key":"2023070313452230000_2023.06.26.23291875v1.56","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26084"},{"key":"2023070313452230000_2023.06.26.23291875v1.57","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711235114"},{"key":"2023070313452230000_2023.06.26.23291875v1.58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1711233114"},{"key":"2023070313452230000_2023.06.26.23291875v1.59","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25244"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.60","doi-asserted-by":"crossref","first-page":"16396","DOI":"10.1038\/s41598-019-52894-z","article-title":"Gut microbiome of treatment-naive MS patients of different ethnicities early in disease course","volume":"9","year":"2019","journal-title":"Sci Rep"},{"key":"2023070313452230000_2023.06.26.23291875v1.61","doi-asserted-by":"publisher","DOI":"10.1097\/JIM.0000000000000192"},{"key":"2023070313452230000_2023.06.26.23291875v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2015.12.005"},{"key":"2023070313452230000_2023.06.26.23291875v1.63","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01477-07"},{"issue":"2","key":"2023070313452230000_2023.06.26.23291875v1.64","doi-asserted-by":"crossref","first-page":"e450","DOI":"10.1038\/emm.2017.282","article-title":"Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions","volume":"50","year":"2018","journal-title":"Experimental & Molecular Medicine"},{"key":"2023070313452230000_2023.06.26.23291875v1.65","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1700492"},{"issue":"7","key":"2023070313452230000_2023.06.26.23291875v1.66","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.nrleng.2020.05.006","article-title":"The influence of interferon \u03b2-1b on gut microbiota composition in patients with multiple sclerosis","volume":"36","year":"2021","journal-title":"Neurolog\u00eda (English Edition"},{"key":"2023070313452230000_2023.06.26.23291875v1.67","doi-asserted-by":"crossref","first-page":"103798","DOI":"10.1016\/j.ebiom.2021.103798","article-title":"Alterations of host-gut microbiome interactions in multiple sclerosis","volume":"76","year":"2022","journal-title":"EBioMedicine"},{"key":"2023070313452230000_2023.06.26.23291875v1.68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00462"},{"key":"2023070313452230000_2023.06.26.23291875v1.69","doi-asserted-by":"crossref","first-page":"578648","DOI":"10.3389\/fimmu.2020.578648","article-title":"Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis","volume":"11","year":"2020","journal-title":"Front Immunol"},{"issue":"2","key":"2023070313452230000_2023.06.26.23291875v1.70","doi-asserted-by":"crossref","first-page":"583","DOI":"10.3233\/JAD-201497","article-title":"Gut Microbiota Changes and Their Correlation with Cognitive and Neuropsychiatric Symptoms in Alzheimer\u2019s Disease","volume":"81","year":"2021","journal-title":"J Alzheimers Dis"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.71","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12876-023-02791-7","article-title":"Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis","volume":"23","year":"2023","journal-title":"BMC Gastroenterology"},{"issue":"7","key":"2023070313452230000_2023.06.26.23291875v1.72","doi-asserted-by":"crossref","first-page":"e0236595","DOI":"10.1371\/journal.pone.0236595","article-title":"Interactions of Segmented Filamentous Bacteria (Candidatus Savagella) and bacterial drivers in colitis-associated colorectal cancer development","volume":"15","year":"2020","journal-title":"PLoS One"},{"issue":"8","key":"2023070313452230000_2023.06.26.23291875v1.73","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1167\/iovs.16-19733","article-title":"Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis","volume":"57","year":"2016","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"2023070313452230000_2023.06.26.23291875v1.74","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00406-13"},{"key":"2023070313452230000_2023.06.26.23291875v1.75","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813173106"},{"key":"2023070313452230000_2023.06.26.23291875v1.76","doi-asserted-by":"publisher","DOI":"10.1093\/pcp\/pcr034"},{"key":"2023070313452230000_2023.06.26.23291875v1.77","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.3389\/fmicb.2016.01339","article-title":"All Three Endogenous Quinone Species of Escherichia coli Are Involved in Controlling the Activity of the Aerobic\/Anaerobic Response Regulator ArcA","volume":"7","year":"2016","journal-title":"Front Microbiol"},{"key":"2023070313452230000_2023.06.26.23291875v1.78","doi-asserted-by":"crossref","unstructured":"Stecher, B ., The Roles of Inflammation, Nutrient Availability and the Commensal Microbiota in Enteric Pathogen Infection, in Metabolism and Bacterial Pathogenesis. 2015. p. 297\u2013320.","DOI":"10.1128\/9781555818883.ch14"},{"key":"2023070313452230000_2023.06.26.23291875v1.79","doi-asserted-by":"crossref","unstructured":"Pelosi, L. , et al., Evolution of Ubiquinone Biosynthesis: Multiple Proteobacterial Enzymes with Various Regioselectivities To Catalyze Three Contiguous Aromatic Hydroxylation Reactions. mSystems, 2016. 1(4).","DOI":"10.1128\/mSystems.00091-16"},{"key":"2023070313452230000_2023.06.26.23291875v1.80","doi-asserted-by":"crossref","first-page":"669355","DOI":"10.3389\/fphys.2021.669355","article-title":"Shifts in the Oral Microbiota During a Four-Week Commercial Saturation Dive to 200 Meters","volume":"12","year":"2021","journal-title":"Front Physiol"},{"key":"2023070313452230000_2023.06.26.23291875v1.81","doi-asserted-by":"publisher","DOI":"10.1038\/ismej.2013.80"},{"key":"2023070313452230000_2023.06.26.23291875v1.82","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.07.004"},{"key":"2023070313452230000_2023.06.26.23291875v1.83","doi-asserted-by":"publisher","DOI":"10.1136\/gut.52.2.237"},{"key":"2023070313452230000_2023.06.26.23291875v1.84","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01004-06"},{"key":"2023070313452230000_2023.06.26.23291875v1.85","doi-asserted-by":"publisher","DOI":"10.1111\/apa.12059"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.86","first-page":"1","article-title":"Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers","volume":"9","year":"2009","journal-title":"BMC gastroenterology"},{"issue":"9-10","key":"2023070313452230000_2023.06.26.23291875v1.87","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00508-018-1328-x","article-title":"Vitamin K2 in multiple sclerosis patients","volume":"130","year":"2018","journal-title":"Wien Klin Wochenschr"},{"key":"2023070313452230000_2023.06.26.23291875v1.88","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218632"},{"key":"2023070313452230000_2023.06.26.23291875v1.89","doi-asserted-by":"publisher","DOI":"10.1016\/j.jada.2007.09.008"},{"key":"2023070313452230000_2023.06.26.23291875v1.90","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-13-05816.2003"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.91","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/jn\/134.1.167","article-title":"Menaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain","volume":"134","year":"2004","journal-title":"J Nutr"},{"issue":"11","key":"2023070313452230000_2023.06.26.23291875v1.92","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/S0022-2275(20)38426-1","article-title":"Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain","volume":"29","year":"1988","journal-title":"J Lipid Res"},{"key":"2023070313452230000_2023.06.26.23291875v1.93","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(90)90557-F"},{"issue":"11","key":"2023070313452230000_2023.06.26.23291875v1.94","first-page":"2746","article-title":"Vitamin K status influences brain sulfatide metabolism in young mice and rats","volume":"126","year":"1996","journal-title":"J Nutr"},{"issue":"3","key":"2023070313452230000_2023.06.26.23291875v1.95","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1021\/jm301485d","article-title":"Structure-activity relationship study of vitamin k derivatives yields highly potent neuroprotective agents","volume":"56","year":"2013","journal-title":"J Med Chem"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.96","first-page":"e12255","article-title":"Association of vitamin K with cognitive decline and neuropathology in community-dwelling older persons","volume":"8","year":"2022","journal-title":"Alzheimer\u2019s & Dementia: Translational Research & Clinical Interventions"},{"issue":"8","key":"2023070313452230000_2023.06.26.23291875v1.97","doi-asserted-by":"crossref","first-page":"e0203057","DOI":"10.1371\/journal.pone.0203057","article-title":"Vitamin K enhances the production of brain sulfatides during remyelination","volume":"13","year":"2018","journal-title":"PLOS ONE"},{"key":"2023070313452230000_2023.06.26.23291875v1.98","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2005.08.001"},{"issue":"3","key":"2023070313452230000_2023.06.26.23291875v1.99","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.3390\/ijms24032720","article-title":"Gut Microbiota Changes during Dimethyl Fumarate Treatment in Patients with Multiple Sclerosis","volume":"24","year":"2023","journal-title":"International Journal of Molecular Sciences"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.100","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3390\/life11010055","article-title":"The Core of Gut Life: Firmicutes Profile in Patients with Relapsing-Remitting Multiple Sclerosis","volume":"11","year":"2021","journal-title":"Life"},{"issue":"15 Supplement","key":"2023070313452230000_2023.06.26.23291875v1.101","first-page":"P2.355","article-title":"The Gut Microbiome in Relapsing Multiple Sclerosis Patients Compared to Controls","volume":"90","year":"2018","journal-title":"Neurology"},{"key":"2023070313452230000_2023.06.26.23291875v1.102","doi-asserted-by":"crossref","unstructured":"Jalanka, J. , et al., The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls. Int J Mol Sci, 2019. 20(2).","DOI":"10.3390\/ijms20020433"},{"key":"2023070313452230000_2023.06.26.23291875v1.103","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2011703117"},{"key":"2023070313452230000_2023.06.26.23291875v1.104","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciab207"},{"issue":"4","key":"2023070313452230000_2023.06.26.23291875v1.105","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1212\/WNL.42.4.883","article-title":"HLA-DQB1 genotype in Sardinian multiple sclerosis: Evidence for a key role of DQB1* 0201 and* 0302 alleles","volume":"42","year":"1992","journal-title":"Neurology"},{"key":"2023070313452230000_2023.06.26.23291875v1.106","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2370.1998.00101.x"},{"key":"2023070313452230000_2023.06.26.23291875v1.107","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7742(07)79023-2"},{"key":"2023070313452230000_2023.06.26.23291875v1.108","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi206"},{"key":"2023070313452230000_2023.06.26.23291875v1.109","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2100024"},{"key":"2023070313452230000_2023.06.26.23291875v1.110","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22366"},{"key":"2023070313452230000_2023.06.26.23291875v1.111","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.11.1444"},{"key":"2023070313452230000_2023.06.26.23291875v1.112","first-page":"1263","volume":"391","year":"2018","journal-title":"Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study"},{"key":"2023070313452230000_2023.06.26.23291875v1.113","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02768-14"},{"key":"2023070313452230000_2023.06.26.23291875v1.114","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01043-13"},{"key":"2023070313452230000_2023.06.26.23291875v1.115","unstructured":"R Core Team, R., R: A language and environment for statistical computing. 2013."},{"key":"2023070313452230000_2023.06.26.23291875v1.116","unstructured":"Tavar\u00e9, S. Some probabilistic and statistical problems in the analysis of DNA sequences. 1986."},{"key":"2023070313452230000_2023.06.26.23291875v1.117","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq706"},{"issue":"1","key":"2023070313452230000_2023.06.26.23291875v1.118","first-page":"352","volume":"8","year":"2016","journal-title":"Using DECIPHER v2. 0 to analyze big biological sequence data in R"},{"key":"2023070313452230000_2023.06.26.23291875v1.119","doi-asserted-by":"publisher","DOI":"10.2307\/4615964"},{"key":"2023070313452230000_2023.06.26.23291875v1.120","doi-asserted-by":"publisher","DOI":"10.1038\/163688a0"},{"key":"2023070313452230000_2023.06.26.23291875v1.121","doi-asserted-by":"publisher","DOI":"10.1002\/j.1538-7305.1948.tb01338.x"},{"key":"2023070313452230000_2023.06.26.23291875v1.122","doi-asserted-by":"crossref","unstructured":"Fisher, R.A. , A.S. Corbet , and C.B. Williams , The relation between the number of species and the number of individuals in a random sample of an animal population. The Journal of Animal Ecology, 1943: p. 42\u201358.","DOI":"10.2307\/1411"},{"key":"2023070313452230000_2023.06.26.23291875v1.123","unstructured":"Chazdon, R.L. , et al., Statistical methods for estimating species richness of woody regeneration in primary and secondary rain forests of northeastern Costa Rica. 1998."},{"key":"2023070313452230000_2023.06.26.23291875v1.124","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.71.12.8228-8235.2005"},{"key":"2023070313452230000_2023.06.26.23291875v1.125","doi-asserted-by":"publisher","DOI":"10.2307\/1942268"},{"issue":"631-637","key":"2023070313452230000_2023.06.26.23291875v1.126","first-page":"719","volume":"10","year":"2007","journal-title":"The vegan package"},{"key":"2023070313452230000_2023.06.26.23291875v1.127","doi-asserted-by":"crossref","unstructured":"Agglomerative Nesting (Program AGNES), in Finding Groups in Data. 1990. p. 199\u2013252.","DOI":"10.1002\/9780470316801.ch5"},{"key":"2023070313452230000_2023.06.26.23291875v1.128","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-017-0237-y"},{"key":"2023070313452230000_2023.06.26.23291875v1.129","unstructured":"Shetty, S.A. , et al., microbiomeutilities: An R package for utilities to guide in-depth marker gene amplicon data analysis. Ecophysiological insights into the human intestinal microbiota: from single strains to defined consortia, 2018: p. 95."},{"key":"2023070313452230000_2023.06.26.23291875v1.130","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.21105\/joss.03201","article-title":"microViz: an R package for microbiome data visualization and statistics","volume":"6","year":"2021","journal-title":"Journal of Open Source Software"},{"key":"2023070313452230000_2023.06.26.23291875v1.131","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009442"},{"key":"2023070313452230000_2023.06.26.23291875v1.132","unstructured":"Lahti, L. and S.A. shetty , microbiome; R Package Version 1.18.0. Available online: http:\/\/microbiome.github.io, 2012-2019."},{"key":"2023070313452230000_2023.06.26.23291875v1.133","unstructured":"Aphalo, P. , J, K. Slowikowski , and S. Mouksassi , ggpmisc: Miscellaneous Extensions to \u2018ggplot2\u2019. https:\/\/docs.r4photobiology.info\/ggpmisc\/, https:\/\/github.com\/aphalo\/ggpmisc., 2023."},{"key":"2023070313452230000_2023.06.26.23291875v1.134","unstructured":"Kassambara, A. and M.A. Kassambara , Package \u2018ggcorrplot\u2019. R package version 0.1, 2019. 3(3)."},{"key":"2023070313452230000_2023.06.26.23291875v1.135","unstructured":"Kassambara, A. , et al., survminer: Drawing Survival Curves using\u2019ggplot2\u2019. R package version 0.4. 9 . 2021. 2021."},{"issue":"10","key":"2023070313452230000_2023.06.26.23291875v1.136","first-page":"28","article-title":"Package \u2018survival\u2019","volume":"128","year":"2015","journal-title":"R Top Doc"},{"key":"2023070313452230000_2023.06.26.23291875v1.137","unstructured":"Sjoberg, D. , D, et al ., ggsurvfit: Flexible Time-to-Event Figures. Available online: http:\/\/www.danieldsjoberg.com\/ggsurvfit\/, 2023."},{"key":"2023070313452230000_2023.06.26.23291875v1.138","unstructured":"Harrison, E. , T. Drake , and R. Ots , Package \u2018finalfit\u2019. Retrieved February, 2020. 29: p. 2020."},{"key":"2023070313452230000_2023.06.26.23291875v1.139","doi-asserted-by":"publisher","DOI":"10.1159\/000323281"},{"key":"2023070313452230000_2023.06.26.23291875v1.140","first-page":"1","article-title":"Building predictive models in R using the caret package","volume":"28","year":"2008","journal-title":"Journal of statistical software"},{"key":"2023070313452230000_2023.06.26.23291875v1.141","unstructured":"Wilson, T. , modelmisc: Miscellaneous tools for modelling. Available online: https:\/\/github.com\/wilsontom\/modelmisc\/, 2018."},{"key":"2023070313452230000_2023.06.26.23291875v1.142","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti623"},{"key":"2023070313452230000_2023.06.26.23291875v1.143","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-1"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.06.26.23291875","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:36:12Z","timestamp":1768505772000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2023.06.26.23291875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,29]]},"references-count":143,"URL":"https:\/\/doi.org\/10.1101\/2023.06.26.23291875","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41598-024-64369-x","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2023,6,29]]},"subtype":"preprint"}}