title: Dysbiosis, inflammation, and response to treatment: a longitudinal study of pediatric subjects with newly diagnosed inflammatory bowel disease.
abstract: Gut microbiome dysbiosis has been demonstrated in subjects with newly diagnosed and chronic inflammatory bowel disease (IBD). In this study we sought to explore longitudinal changes in dysbiosis and ascertain associations between dysbiosis and markers of disease activity and treatment outcome.
  
  
  
  We performed a prospective cohort study of 19 treatment-naïve pediatric IBD subjects and 10 healthy controls, measuring fecal calprotectin and assessing the gut microbiome via repeated stool samples. Associations between clinical characteristics and the microbiome were tested using generalized estimating equations. Random forest classification was used to predict ultimate treatment response (presence of mucosal healing at follow-up colonoscopy) or non-response using patients' pretreatment samples.
  
  
  
  Patients with Crohn's disease had increased markers of inflammation and dysbiosis compared to controls. Patients with ulcerative colitis had even higher inflammation and dysbiosis compared to those with Crohn's disease. For all cases, the gut microbial dysbiosis index associated significantly with clinical and biological measures of disease severity, but did not associate with treatment response. We found differences in specific gut microbiome genera between cases/controls and responders/non-responders including Akkermansia, Coprococcus, Fusobacterium, Veillonella, Faecalibacterium, and Adlercreutzia. Using pretreatment microbiome data in a weighted random forest classifier, we were able to obtain 76.5 % accuracy for prediction of responder status.
  
  
  
  Patient dysbiosis improved over time but persisted even among those who responded to treatment and achieved mucosal healing. Although dysbiosis index was not significantly different between responders and non-responders, we found specific genus-level differences. We found that pretreatment microbiome signatures are a promising avenue for prediction of remission and response to treatment.
authors.affiliation: Graduate Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Shaw
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Madeline
authors.initials: M
authors.lastname: Bertha
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Hofmekler
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chopra
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Department of Computer Science, Aalto University School of Science, 02150, Espoo, Finland.
authors.forename: Tommi
authors.initials: T
authors.lastname: Vatanen
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Abhiram
authors.initials: A
authors.lastname: Srivatsa
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Jarod
authors.initials: J
authors.lastname: Prince
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Sauer
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zwick
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, GA, 30341, USA.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Satten
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Aleksandar D
authors.initials: AD
authors.lastname: Kostic
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA.|Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Mulle
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, 2015 Uppergate Drive, room 248, Atlanta, GA, 30322, USA. skugath@emory.edu.|Department of Human Genetics, Emory University, Atlanta, GA, 30322, USA. skugath@emory.edu.
authors.forename: Subra
authors.identifier: 0000-0002-8686-4189
authors.initials: S
authors.lastname: Kugathasan
mesh_terms: D000293:Adolescent; D001419:Bacteria / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D064806:Dysbiosis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000187:drug effects / Q000235:genetics; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007249:Inflammation; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007155:Immunologic Factors; D039841:Leukocyte L1 Antigen Complex
keywords: Crohn’s disease; Dysbiosis; Inflammatory bowel disease; Microbiome