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. 2013 Sep 6;341(6150):1241214.
doi: 10.1126/science.1241214.

Gut Microbiota From Twins Discordant for Obesity Modulate Metabolism in Mice

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Free PMC article

Gut Microbiota From Twins Discordant for Obesity Modulate Metabolism in Mice

Vanessa K Ridaura et al. Science. .
Free PMC article

Abstract

The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin's microbiota (Ob) with mice containing the lean co-twin's microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.

Figures

Fig. 1
Fig. 1. Reliable replication of human donor microbiota in gnotobiotic mice
(A) Features of the four discordant twin pairs. (B) Assembly of bacterial communities in mice that had received intact uncultured fecal microbiota transplants from the obese and lean co-twins in DZ pair 1. PCoA plot based on an unweighted UniFrac distance matrix and 97%ID OTUs present in sampled fecal communities. Circles correspond to a single fecal sample obtained at a given time point from a given mouse and are colored according to the experiment (n=3 independent experiments). Note that assembly is reproducible within members of a group of mice that have received a given microbiota, and between experiments. (C) Body composition, defined by qMR, was performed one day and 15 days post colonization (dpc) of each mouse in each recipient group. Mean values (± SEM) are plotted for the percent increase in fat mass and lean body mass at 15 dpc for all recipient mice of each of the four obese co-twins’ or lean co-twins’ fecal microbiota, normalized to the initial body mass of each recipient mouse. A two-way ANOVA indicated that there was a significant donor effect (p ≤ 0.05), driven by a significant difference in adiposity between mice colonized with a lean or obese co-twin donor’s fecal microbiota (adjusted p ≤ 0.05; Šidák’s multiple comparisons test). (D) Mean values (± SEM) are plotted for the percent change in fat mass at 15 dpc for all recipient mice of each of the four obese co-twins’ or lean co-twins’ fecal microbiota. Data are normalized to initial fat mass (n=3–12 animals/donor microbiota; 51–52 mice/BMI bin; total of 103 mice). ***, p ≤ 0.001, as judged by a one-tailed unpaired Student’s t-test. (E) Prolonged time course study for recipients of fecal microbiota from co-twins in discordant DZ pair 1 (mean values ± SEM plotted; n=4 mice/donor microbiota). The difference between the gain in adiposity calculated relative to initial fat mass (1 dpc) between the two recipient groups of mice is statistically significant (p ≤ 0.001, two-way ANOVA).
Fig. 2
Fig. 2. Co-housing Obch and Lnch mice transforms the adiposity phenotype of cagemates harboring the obese co-twin’s culture collection to a lean-like state
(A) Design of co-housing experiment. 8-week-old, male, germ-free C57BL/6J mice received culture collections from the lean (Ln) twin or the obese (Ob) co-twin in DZ twin pair 1. Five days after colonization, mice were co-housed in one of three configurations: control groups consisted of dually-housed Ob-Ob or Ln-Ln cagemates; the experimental group consisted of dually-housed Obch-Lnch cagemates (data shown from 5 cages/experiment; 2 independent experiments) or Obch-Lnch- GFch-GFch cagemates (n=3 cages/experiment). All mice were fed a LF/HPP diet. (B) Effects of co-housing on fat mass. Changes from the first day after co-housing to 10 d after co-housing were defined using whole body qMR. *, p ≤ 0.05, **, p ≤ 0.01 compared to Ob-Ob controls, as defined by one-tailed unpaired Student’s t-test. (C) Targeted GC/MS analysis of cecal short chain fatty acids. Compared to Ob-Ob controls, the concentrations of propionate and butyrate were significantly higher in the ceca of Obch, Ln-Ln, Lnch, and GFch mice. (D) Nontargeted GC/MS analysis of cecal levels of cellobiose and ‘maltose or a similar disaccharide’. *, p ≤ 0.05; **, p ≤ 0.01. (E) Evidence that bacterial species from the Lnch microbiota invade the Obch microbiota. Shown are SourceTracker-based estimates of the proportion of bacterial taxa in a given community that are derived from a cagemate. For Obch-Lnch co-housing experiments, Obch or Lnch microbiota were designated as sink communities, while the gut microbiota Ob-Ob or Ln-Ln controls [at 5 days post colonization (dpc)] were considered source communities. Red indicates species derived from the Lnch gut microbial community. Blue denotes species derived from the Obch microbiota. Black denotes unspecified source (i.e. both communities have this species), while orange indicates an uncertain classification by the SourceTracker algorithm. An asterisk placed next to a species indicates that it is a successful invader as defined in the text. Average relative abundance (RA) in the fecal microbiota is shown before co-housing (b, at 5 dpc) and after co-housing (a, at 15 dpc). The average fold-change (fc) in relative abundance for a given taxon, for all time points before and after co-housing is shown (excluding the first two days immediately after gavage of the microbiota and immediately after initiation of co-housing).
Fig. 3
Fig. 3. Effect of co-housing on metabolic profiles in mice consuming a LF/HPP diet
(A) Spearman’s correlation analysis of cecal metabolites and cecal bacterial species-level taxa in samples collected from Obch, Lnch, GFch, Ln39ch, ObchLn39 cagemates and from Ob-Ob and Ln-Ln controls (correlations with p ≤ 0.0001 are shown). Taxonomic assignments were made using a modified NCBI taxonomy (23). Bacterial species and cecal metabolites enriched in animals colonized with either the Ln or Ob culture collections are colored red and blue, respectively. An asterisk in the colored box indicates that that a taxon or metabolite is significantly enriched in mice colonized with Ln (red) or Ob (blue) culture collections. Bacterial species colored red denote significant invaders from Lnch mouse into the gut microbiota of Obch cagemates. (B) Cecal bile acids measured by UPLC-MS. Note that levels are plotted as log transformed spectral abundances. Significance of differences relative to Ob-Ob controls were defined using a two-way ANOVA with Holm- Šidák’s correction for multiple hypotheses; *, p ≤ 0.05; **, p ≤ 0.01; ****, p ≤ 0.001. (C, D) Quantitative RT-PCR assays of FXR and Fgf15 mRNA levels in the distal ileum. Data are normalized to Ln-Ln controls. (E) qRT-PCR of hepatic Cyp7a1 mRNA, normalized to Ln-Ln controls. *, p ≤ 0.05; **, p ≤ 0.01; ****, p ≤ 0.001 (defined by one-tailed, unpaired Student’s t-test using Ob-Ob mice as reference controls). (F) Correlating cecal bile acid profiles with the FXR-Fgf15-Cyp7A signaling pathway in the different groups of mice. The dendrogram in the upper panel highlights the differences in the profiles of 37 bile acid species between Ob-Ob controls versus the other three treatment groups. The dendrogram was calculated using the Bray-Curtis dissimilarity index and the average relative abundance of each bile acid species among all mice belonging to a given treatment group.
Fig. 4
Fig. 4. Effects of NHANES-based LoSF/HiFV and HiSF/LoFV diets on bacterial invasion, body mass and metabolic phenotypes
(A, B) Mean ± SEM percent change in total body mass (panel A) and body composition (fat and lean body mass, normalized to initial body mass on day 4 after gavage, panel B) occurring between 4d and 14d after colonization with culture collections from the Ln or Ob co-twin in DZ pair 1. Co-housing Ln and Ob mice prevents an increased body mass phenotype in Obch cagemates fed the representative human diet that was low in saturated fats and high in fruits and vegetables (LoSF/HiFV) (n=3–5 cages/treatment group; 26 animals in total). **, p ≤ 0.01 based on a one way ANOVA after Fisher’s LSD test (also see table S13). (C) Spearman’s correlation analysis between bacterial species-level taxa and metabolites in cecal samples collected from mice, colonized with culture collections from DZ twin pair 1 Ln and Ob co-twins and fed a LoSF/HiFV diet. Red and blue squares indicate metabolites or taxa that are significantly enriched in samples collected from dually-housed Ln-Ln or Ob-Ob controls respectively. (D, E) Mean± SEM of changes in body mass and body composition in mice colonized with intact uncultured microbiota from DZ twin pair 2 and fed the representative human diet that was high in saturated fats and low in fruits and vegetables (HiSF/LoFV). Ob-Ob controls have greater lean body mass than Ln-Ln controls but this phenotype is not rescued in Obch animals (see table S14 for statistics). Note that the HiSF/LoFV diet produces a significantly greater increase in body mass, specifically fat mass, in mice harboring the lean co-twins microbiota (Ln-Ln and Lnch) compared to when they are fed the LoSF/HiFV diet (see panels A, B versus D, E; two-way ANOVA with Holm-Sidak’s correction for multiple hypotheses).
Fig. 5
Fig. 5. Invasion analysis of species-level taxa in Obch or Lnch mice fed the NHANES-based LoSF/HiFV diet
Red indicates species derived from the Lnch gut microbial community. Blue denotes species derived from the Obch microbiota. The mean relative abundance of each species-level taxon before (b; 3 and 4 dpc) and after (a; 8, 10 and 14 dpc) co-housing is noted. Fold-change (fc) in relative abundance of taxa before and after colonization (see legend to Fig. 2E). An asterisk (*) denotes bacterial species that satisfy our criteria for classification as successful invaders (see text).
Fig. 6
Fig. 6. Acylcarnitine profile in the skeletal muscle of mice colonized with the Ob or Ln culture collections from DZ twin pair 1 and fed the LoSF/HiFV diet
Each column represents a different animal and each row a different acylcarnitine. The identities and levels of these acylcarnitines were determined by targeted MS/MS (see table S15 for mean values ± SEM for each treatment group). A two-way ANOVA with Holm- Šidák’s correction was used to calculate whether the level of each acylcarnitine was significantly different between Ob-Ob versus Ln-Ln, Lnch or Obch animals. * p ≤ 0.05.

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