Ali I Mirza1, Feng Zhu1, Natalie Knox1, Jessica D Forbes1, Gary Van Domselaar1, Charles N Bernstein1, Morag Graham1, Ruth Ann Marrie1, Janace Hart1, E Ann Yeh1, Douglas L Arnold1, Amit Bar-Or1, Julia O'Mahony1, Yinshan Zhao1, William Hsiao1, Brenda Banwell1, Emmanuelle Waubant1, Helen Tremlett2. 1. From the Department of Medicine (Neurology) (A.I.M., F.Z., Y.Z., H.T.), The University of British Columbia, Vancouver; National Microbiology Laboratory (N.K., G.V.D., M.G.), Public Health Agency of Canada; Department of Medical Microbiology and Infectious Diseases (N.K., G.V.D., M.G.), Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences (C.N.B., R.A.M.), and Inflammatory Bowel Disease Clinical and Research Centre (C.N.B.), University of Manitoba, Winnipeg; Roy Romanow Provincial Laboratory (J.D.F.), Regina; Department of Pathology and Laboratory Medicine (J.D.F.), College of Medicine, University of Saskatchewan, Saskatoon, Canada; Department of Neurology (J.H., E.W.), University of California San Francisco; Department of Pediatrics (Neurology) (E.A.Y., J.O.), The Hospital for Sick Children, Toronto; Department of Neurology and Neurosurgery (D.L.A.), Montreal Neurological Institute, McGill University, Montreal, Canada; Centre for Neuroinflammation and Experimental Therapeutics and Department of Neurology (A.B.-O.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Faculty of Health Sciences (W.H.), Simon Fraser University, Burnaby, Canada; and The Children's Hospital of Philadelphia (B.B.), PA. 2. From the Department of Medicine (Neurology) (A.I.M., F.Z., Y.Z., H.T.), The University of British Columbia, Vancouver; National Microbiology Laboratory (N.K., G.V.D., M.G.), Public Health Agency of Canada; Department of Medical Microbiology and Infectious Diseases (N.K., G.V.D., M.G.), Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences (C.N.B., R.A.M.), and Inflammatory Bowel Disease Clinical and Research Centre (C.N.B.), University of Manitoba, Winnipeg; Roy Romanow Provincial Laboratory (J.D.F.), Regina; Department of Pathology and Laboratory Medicine (J.D.F.), College of Medicine, University of Saskatchewan, Saskatoon, Canada; Department of Neurology (J.H., E.W.), University of California San Francisco; Department of Pediatrics (Neurology) (E.A.Y., J.O.), The Hospital for Sick Children, Toronto; Department of Neurology and Neurosurgery (D.L.A.), Montreal Neurological Institute, McGill University, Montreal, Canada; Centre for Neuroinflammation and Experimental Therapeutics and Department of Neurology (A.B.-O.), University of Pennsylvania Perelman School of Medicine, Philadelphia; Faculty of Health Sciences (W.H.), Simon Fraser University, Burnaby, Canada; and The Children's Hospital of Philadelphia (B.B.), PA. helen.tremlett@ubc.ca.
Abstract
BACKGROUND AND OBJECTIVES: Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls. METHODS: Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with MS (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha diversity, relative abundance, and prevalence using Wilcoxon rank sum, ALDEx2, and Fisher exact tests, respectively. RESULTS: Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD-naive. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or DMD status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC -0.48, p = 0.039). Differences by DMD status included lower phosphate butyryl transferase for DMD-naive vs exposed patients with MS (LFC -1.0, p = 0.033). DISCUSSION: The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.
BACKGROUND AND OBJECTIVES: Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls. METHODS: Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with MS (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha diversity, relative abundance, and prevalence using Wilcoxon rank sum, ALDEx2, and Fisher exact tests, respectively. RESULTS: Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD-naive. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or DMD status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC -0.48, p = 0.039). Differences by DMD status included lower phosphate butyryl transferase for DMD-naive vs exposed patients with MS (LFC -1.0, p = 0.033). DISCUSSION: The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.
Authors: Nupur K Das; Andrew J Schwartz; Gabrielle Barthel; Naohiro Inohara; Qing Liu; Amanda Sankar; David R Hill; Xiaoya Ma; Olivia Lamberg; Matthew K Schnizlein; Juan L Arqués; Jason R Spence; Gabriel Nunez; Andrew D Patterson; Duxin Sun; Vincent B Young; Yatrik M Shah Journal: Cell Metab Date: 2019-11-07 Impact factor: 27.287
Authors: Brenda Banwell; Amit Bar-Or; Douglas L Arnold; Dessa Sadovnick; Sridar Narayanan; Melissa McGowan; Julia O'Mahony; Sandra Magalhaes; Heather Hanwell; Reinhold Vieth; Raymond Tellier; Thierry Vincent; Giulio Disanto; George Ebers; Katherine Wambera; Mary B Connolly; Jerome Yager; Jean K Mah; Fran Booth; Guillaume Sebire; David Callen; Brandon Meaney; Marie-Emmanuelle Dilenge; Anne Lortie; Daniela Pohl; Asif Doja; Sunita Venketaswaran; Simon Levin; E Athen Macdonald; David Meek; Ellen Wood; Noel Lowry; David Buckley; Conrad Yim; Mark Awuku; Pamela Cooper; François Grand'maison; J Burke Baird; Virender Bhan; Ruth Ann Marrie Journal: Lancet Neurol Date: 2011-03-31 Impact factor: 44.182