Alterations of host-gut microbiome interactions in multiple sclerosis

Authors

Claudia Cantoni, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.Follow
Qingqi Lin, Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, USA.
Yair Dorsett, Department of Medicine, UConn Health, Farmington, CT, USA.
Laura Ghezzi, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Dino Ferrari Center, University of Milan, Milan, Italy.
Zhongmao Liu, Department of Statistics, University of Connecticut, Storrs, CT USA.
Yeming Pan, Department of Statistics, University of Connecticut, Storrs, CT USA.
Kun Chen, Department of Statistics, University of Connecticut, Storrs, CT USA.
Yanhui Han, Department of Food Science, University of Massachusetts, Amherst, Massachusetts USA.
Zhengze Li, Department of Food Science, University of Massachusetts, Amherst, Massachusetts USA.
Hang Xiao, Department of Food Science, University of Massachusetts, Amherst, Massachusetts USA.
Matthew Gormley, Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
Yue Liu, Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
Suresh Bokoliya, Department of Medicine, UConn Health, Farmington, CT, USA.
Hunter Panier, Department of Medicine, UConn Health, Farmington, CT, USA.
Cassandra Suther, Department of Food Science, University of Massachusetts, Amherst, Massachusetts USA.
Emily Evans, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Li Deng, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
Alberto Locca, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Robert Mikesell, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Kathleen Obert, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Pamela Newland, Barnes Jewish College, Goldfarb School of Nursing, St. Louis, MO, USA.
Yufeng Wu, Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, USA.
Amber Salter, Division of Biostatistics, School of Medicine, Washington University, St. Louis, MO, USA.
Anne H. Cross, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA.
Phillip I. Tarr, Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
Amy Lovett-Racke, Department of Microbial Infection and Immunity, Ohio State University, Columbus, OH, USA.
Laura Piccio, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW 2050, Australia. Electronic address: picciol@wustl.edu.
Yanjiao Zhou, Department of Medicine, UConn Health, Farmington, CT, USA. Electronic address: yazhou@uchc.edu.

Document Type

Article

Abstract

BACKGROUND: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. METHODS: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. FINDINGS: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. INTERPRETATION: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. FUNDING: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Diet, Microbiome, Multi-omics, Multiple sclerosis

Medical Subject Headings

Chromatography, Liquid; Gastrointestinal Microbiome (genetics); Humans; Metabolome; Metagenomics; Multiple Sclerosis (etiology); Tandem Mass Spectrometry

Publication Date

2-1-2022

Publication Title

EBioMedicine

E-ISSN

2352-3964

Volume

76

First Page

103798

PubMed ID

35094961

Digital Object Identifier (DOI)

10.1016/j.ebiom.2021.103798

Recommended Citation

Cantoni, Claudia; Lin, Qingqi; Dorsett, Yair; Ghezzi, Laura; Liu, Zhongmao; Pan, Yeming; Chen, Kun; Han, Yanhui; Li, Zhengze; Xiao, Hang; Gormley, Matthew; Liu, Yue; Bokoliya, Suresh; Panier, Hunter; Suther, Cassandra; Evans, Emily; Deng, Li; Locca, Alberto; Mikesell, Robert; Obert, Kathleen; Newland, Pamela; Wu, Yufeng; Salter, Amber; Cross, Anne H.; Tarr, Phillip I.; Lovett-Racke, Amy; Piccio, Laura; and Zhou, Yanjiao, "Alterations of host-gut microbiome interactions in multiple sclerosis" (2022). Translational Neuroscience. 2319.
https://scholar.barrowneuro.org/neurobiology/2319