title: Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children.
abstract: Gut microbiota has been implicated as a pivotal contributing factor in diet-related obesity; however, its role in development of disease phenotypes in human genetic obesity such as Prader-Willi syndrome (PWS) remains elusive. In this hospitalized intervention trial with PWS (n = 17) and simple obesity (n = 21) children, a diet rich in non-digestible carbohydrates induced significant weight loss and concomitant structural changes of the gut microbiota together with reduction of serum antigen load and alleviation of inflammation. Co-abundance network analysis of 161 prevalent bacterial draft genomes assembled directly from metagenomic datasets showed relative increase of functional genome groups for acetate production from carbohydrates fermentation. NMR-based metabolomic profiling of urine showed diet-induced overall changes of host metabotypes and identified significantly reduced trimethylamine N-oxide and indoxyl sulfate, host-bacteria co-metabolites known to induce metabolic deteriorations. Specific bacterial genomes that were correlated with urine levels of these detrimental co-metabolites were found to encode enzyme genes for production of their precursors by fermentation of choline or tryptophan in the gut. When transplanted into germ-free mice, the pre-intervention gut microbiota induced higher inflammation and larger adipocytes compared with the post-intervention microbiota from the same volunteer. Our multi-omics-based systems analysis indicates a significant etiological contribution of dysbiotic gut microbiota to both genetic and simple obesity in children, implicating a potentially effective target for alleviation.
  
  
  BACKGROUND
  Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader-Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Chenhong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Yin
authors.affiliation: CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Hongde
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authors.lastname: Li
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Guojun
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authors.lastname: Wu
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Menghui
authors.initials: M
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Linghua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Yaping
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authors.lastname: Hou
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Haimei
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Lv
authors.affiliation: CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Benhua
authors.initials: B
authors.lastname: Zeng
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Huaqing
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authors.lastname: Fu
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Naisi
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authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China ; Whistler Center for Carbohydrate Research, Department of Food Science, Purdue University, 745 Agriculture Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Hamaker
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China ; Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bridgewater
authors.affiliation: School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK.
authors.forename: David
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authors.lastname: Weinkove
authors.affiliation: Institut of cardiometabolism and Nutrition, Pitié-Salpêtrière, Paris, France.
authors.forename: Karine
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authors.lastname: Clement
authors.affiliation: Institut National de la Recherche Agronomique, 78350 Jouy en Josas, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Dore
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Elaine
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authors.lastname: Holmes
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Shang Biochip Company, Shanghai 201203, China.
authors.forename: Huasheng
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authors.lastname: Xiao
authors.affiliation: Shanghai-MOST Key Laboratory for Disease and Health Genomics, Shang Biochip Company, Shanghai 201203, China.
authors.forename: Guoping
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authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Shengli
authors.initials: S
authors.lastname: Yang
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Peer
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authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Department of Laboratory Animal Science, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wei
authors.affiliation: CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Huiru
authors.initials: H
authors.lastname: Tang
authors.affiliation: Medical Genetic Centre and Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
authors.forename: Xiaozhuang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Microbial Metabolism and Ministry of Education Key Laboratory of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
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mesh_terms: D000293:Adolescent; D000818:Animals; D000942:Antigens, Bacterial / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D064806:Dysbiosis / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000382:microbiology*; D005260:Female; D000069196:Gastrointestinal Microbiome; D006801:Humans; D008297:Male; D051379:Mice; D011218:Prader-Willi Syndrome / Q000097:blood / Q000178:diet therapy* / Q000235:genetics / Q000382:microbiology*
chemical_list: D000942:Antigens, Bacterial; D004040:Dietary Carbohydrates
keywords: Genome interaction network; Gut microbiota; Metabolomics; Metagenomics; Obesity; Prader–Willi syndrome