title: The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids.
abstract: BACKGROUND
  Evidence suggests that the gut microbiome is involved in the development of cardiovascular disease, with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular, there was no strong evidence for association between cardiovascular disease and aberrant blood lipid levels.
  
  
  OBJECTIVE
  To identify intestinal bacteria taxa, whose proportions correlate with body mass index and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, sex, and host genetics.
  
  
  RESULTS
  We studied 893 subjects from the Life-Lines-DEEP population cohort. After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the gut microbiome explained ≤ 25.9% of high-density lipoprotein variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol.
  
  
  CONCLUSIONS
  Our studies suggest that the gut microbiome may play an important role in the variation in body mass index and blood lipid levels, independent of age, sex, and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides, and high-density lipoproteins.
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Cenit
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Ettje F
authors.initials: EF
authors.lastname: Tigchelaar
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Astrid
authors.initials: A
authors.lastname: Maatman
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Jackie A M
authors.initials: JA
authors.lastname: Dekens
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Eelke
authors.initials: E
authors.lastname: Brandsma
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Joanna
authors.initials: J
authors.lastname: Marczynska
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Floris
authors.initials: F
authors.lastname: Imhann
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Tiffany W
authors.initials: TW
authors.lastname: Poon
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: From the Department of Pediatrics (J.F., E.B., M.H.H.), Department of Genetics (J.F., M.J.B., M.C.C., E.F.T., A.M., J.A.M.D., J.M., L.F., C.W., A.Z.), and Department of Gastroenterology and Hepatology (F.I., R.K.W.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands (E.F.T., J.A.M.D., A.Z.); Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland (J.M.); Broad Institute of MIT and Harvard, Cambridge, MA (T.W.P., R.J.X., D.G.); and Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease (R.J.X.) and Center for Computational and Integrative Biology (R.J.X.), Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001419:Bacteria / Q000145:classification / Q000235:genetics; D015992:Body Mass Index; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000382:microbiology; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D012336:RNA, Ribosomal, 16S; D014280:Triglycerides; D002784:Cholesterol
keywords: HDL; body mass index; cardiovascular diseases; lipids; lipoproteins; metabolism