title: Altered gut microbiota in female mice with persistent low body weights following removal of post-weaning chronic dietary restriction.
abstract: Nutritional interventions often fail to prevent growth failure in childhood and adolescent malnutrition and the mechanisms remain unclear. Recent studies revealed altered microbiota in malnourished children and anorexia nervosa. To facilitate mechanistic studies under physiologically relevant conditions, we established a mouse model of growth failure following chronic dietary restriction and examined microbiota in relation to age, diet, body weight, and anabolic treatment.
  
  
  
  Four-week-old female BALB/c mice (n = 12/group) were fed ad libitum (AL) or offered limited food to abolish weight gain (LF). A subset of restricted mice was treated with an insulin-like growth factor 1 (IGF1) analog. Food access was restored in a subset of untreated LF (LF-RF) and IGF1-treated LF mice (TLF-RF) on day 97. Gut microbiota were determined on days 69, 96-99 and 120 by next generation sequencing of the V3-5 region of the 16S rRNA gene. Microbiota-host factor associations were analyzed by distance-based PERMANOVA and quantified by the coefficient of determination R2for age, diet, and normalized body weight change (Δbwt). Microbial taxa on day 120 were compared following fitting with an overdispersed Poisson regression model. The machine learning algorithm Random Forests was used to predict age based on the microbiota.
  
  
  
  On day 120, Δbwt in AL, LF, LF-RF, and TLF-RF mice was 52 ± 3, -6 ± 1*, 40 ± 3*, and 46 ± 2 % (*, P < 0.05 versus AL). Age and diet, but not Δbwt, were associated with gut microbiota composition. Age explained a larger proportion of the microbiota variability than diet or Δbwt. Random Forests predicted chronological age based on the microbiota and indicated microbiota immaturity in the LF mice before, but not after, refeeding. However, on day 120, the microbiota community structure of LF-RF mice was significantly different from that of both AL and LF mice. IGF1 mitigated the difference from the AL group. Refed groups had a higher abundance of Bacteroidetes and Proteobacteria and a lower abundance of Firmicutes than AL mice.
  
  
  
  Persistent growth failure can be induced by 97-day dietary restriction in young female mice and is associated with microbiota changes seen in lean mice and individuals and anorexia nervosa. IGF1 facilitates recovery of body weights and microbiota.
authors.affiliation: Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Toyomasu
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Linden
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Szurszewski
authors.affiliation: Department of Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Center for Individualized Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Nelson
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Center for Individualized Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Center for Individualized Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Purna C
authors.initials: PC
authors.lastname: Kashyap
authors.affiliation: Division of Biomedical Statistics and Bioinformatics, Department of Health Sciences Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Department of Surgery, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.|Center for Individualized Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chia
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. Ordog.Tamas@mayo.edu.|Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. Ordog.Tamas@mayo.edu.|Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. Ordog.Tamas@mayo.edu.|Center for Individualized Medicine, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. Ordog.Tamas@mayo.edu.
authors.forename: Tamas
authors.identifier: 0000-0002-3940-7284
authors.initials: T
authors.lastname: Ordog
mesh_terms: D000818:Animals; D000856:Anorexia Nervosa / Q000235:genetics / Q000382:microbiology* / Q000503:physiopathology; D031204:Caloric Restriction; D005247:Feeding Behavior; D005260:Female; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D014886:Weaning; D015431:Weight Loss / Q000235:genetics*
chemical_list: D012336:RNA, Ribosomal, 16S
keywords: Animal model; Anorexia nervosa; Dietary restriction; Gut microbiota; Insulin-like growth factor 1 (IGF1); Machine learning; Protein-energy malnutrition