title: Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes.
abstract: BACKGROUND
  Obesity and type 2 diabetes (T2D) are linked both with host genetics and with environmental factors, including dysbioses of the gut microbiota. However, it is unclear whether these microbial changes precede disease onset. Twin cohorts present a unique genetically-controlled opportunity to study the relationships between lifestyle factors and the microbiome. In particular, we hypothesized that family-independent changes in microbial composition and metabolic function during the sub-clinical state of T2D could be either causal or early biomarkers of progression.
  
  
  METHODS
  We collected fecal samples and clinical metadata from 20 monozygotic Korean twins at up to two time points, resulting in 36 stool shotgun metagenomes. While the participants were neither obese nor diabetic, they spanned the entire range of healthy to near-clinical values and thus enabled the study of microbial associations during sub-clinical disease while accounting for genetic background.
  
  
  RESULTS
  We found changes both in composition and in function of the sub-clinical gut microbiome, including a decrease in Akkermansia muciniphila suggesting a role prior to the onset of disease, and functional changes reflecting a response to oxidative stress comparable to that previously observed in chronic T2D and inflammatory bowel diseases. Finally, our unique study design allowed us to examine the strain similarity between twins, and we found that twins demonstrate strain-level differences in composition despite species-level similarities.
  
  
  CONCLUSIONS
  These changes in the microbiome might be used for the early diagnosis of an inflamed gut and T2D prior to clinical onset of the disease and will help to advance toward microbial interventions.
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Moran
authors.initials: M
authors.lastname: Yassour
authors.affiliation: School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Lim
authors.affiliation: School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea.
authors.forename: Hyun Sun
authors.initials: HS
authors.lastname: Yun
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA.|The Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Tickle
authors.affiliation: School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea.
authors.forename: Joohon
authors.initials: J
authors.lastname: Sung
authors.affiliation: Samsung Medical Center, Sungkyunkwan School of Medicine, 25-2 Sungkyunkwan-ro, Jongno-gu, Seoul, South Korea.
authors.forename: Yun-Mi
authors.initials: YM
authors.lastname: Song
authors.affiliation: Busan Paik Hospital, Inje College of Medicine, 197 Inje-ro, Gimhae-si, Gyeongsangnam-do, South Korea.
authors.forename: Kayoung
authors.initials: K
authors.lastname: Lee
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Franzosa
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA.
authors.forename: Xochitl C
authors.initials: XC
authors.lastname: Morgan
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Janssen Human Microbiome Institute, Janssen Research and Development, Cambridge, Massachusetts, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.|Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.|Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.|Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.|Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Birren
authors.affiliation: School of Public Health, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, South Korea.
authors.forename: GwangPyo
authors.initials: G
authors.lastname: Ko
authors.affiliation: The Broad Institute, 415 Main St, Cambridge, MA, 02142, USA. chuttenh@hsph.harvard.edu.|Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA, 02115, USA. chuttenh@hsph.harvard.edu.
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
mesh_terms: D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000382:microbiology*; D064806:Dysbiosis / Q000382:microbiology*; D005243:Feces / Q000382:microbiology; D005260:Female; D000069196:Gastrointestinal Microbiome; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000382:microbiology*; D010802:Phylogeny; D012307:Risk Factors; D014430:Twins, Monozygotic; D061327:Verrucomicrobia / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification*