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. 2009 Nov 11;1(6):6ra14.
doi: 10.1126/scitranslmed.3000322.

The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice

Peter J Turnbaugh  1 , Vanessa K Ridaura, Jeremiah J Faith, Federico E Rey, Rob Knight, Jeffrey I Gordon
Affiliations

The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice

Peter J Turnbaugh et al. Sci Transl Med. .

Abstract

Diet and nutritional status are among the most important modifiable determinants of human health. The nutritional value of food is influenced in part by a person's gut microbial community (microbiota) and its component genes (microbiome). Unraveling the interrelations among diet, the structure and operations of the gut microbiota, and nutrient and energy harvest is confounded by variations in human environmental exposures, microbial ecology, and genotype VSports手机版. To help overcome these problems, we created a well-defined, representative animal model of the human gut ecosystem by transplanting fresh or frozen adult human fecal microbial communities into germ-free C57BL/6J mice. Culture-independent metagenomic analysis of the temporal, spatial, and intergenerational patterns of bacterial colonization showed that these humanized mice were stably and heritably colonized and reproduced much of the bacterial diversity of the donor's microbiota. Switching from a low-fat, plant polysaccharide-rich diet to a high-fat, high-sugar "Western" diet shifted the structure of the microbiota within a single day, changed the representation of metabolic pathways in the microbiome, and altered microbiome gene expression. Reciprocal transplants involving various combinations of donor and recipient diets revealed that colonization history influences the initial structure of the microbial community but that these effects can be rapidly altered by diet. Humanized mice fed the Western diet have increased adiposity; this trait is transmissible via microbiota transplantation. Humanized gnotobiotic mice will be useful for conducting proof-of-principle "clinical trials" that test the effects of environmental and genetic factors on the gut microbiota and host physiology. Nearly full-length 16S rRNA gene sequences are deposited in GenBank under the accession numbers GQ491120 to GQ493997. .

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Figures

Fig. 1
Fig. 1. Design of human microbiota transplant experiments
(A) The initial (first-generation) humanization procedure, including the diet shift. Brown arrows indicate fecal collection time points. (B) Reciprocal microbiota transplantations. Microbiota from first-generation humanized mice fed LF/PP or Western diets were transferred to LF/PP or Western diet-fed germ-free recipients. (C) Colonization of germ-free mice starting with a frozen human fecal sample. (D) Characterization of the postnatal assembly and daily variation of the humanized mouse gut microbiota. (E) Sampling of the humanized mouse gut microbiota along the length of the gastrointestinal tract.
Fig. 2
Fig. 2. The effects of switching from the LF/PP diet to the Western diet on the humanized mouse gut microbiota
(A) 16S rRNA gene surveys [analyzed by unweighted UniFrac-based principal coordinates analysis (PCoA)] from the human donor (green), first-generation humanized mice fed LF/PP (red) or Western (blue) diets, second-generation microbiota transplant recipients consuming the LF/PP (light blue) or Western (purple) diets, and mice humanized with a frozen sample fed LF/PP (yellow) or Western (orange) diets (total of 340 samples with >800 sequences/sample). Weighted UniFrac resulted in a similar overall clustering pattern (data not shown). Principal coordinate 1 (PC1) and PC2 are the x- and y-axis, respectively, and have been scaled on the basis of percent variance. PC3 is depicted by the shading of each point. Percent variance is shown in parentheses. dpc, days post colonization with a human donor sample; dpd, days post diet switch. (B) Taxonomic distribution [RDP level 3 (class level taxa) (27)] of two generations of humanized mice fed a LF/PP or Western diet. Values represent the average relative abundance across all samples within the indicated group. C, cecal samples while all other samples are fecal; M, month. (C) 16S rRNA gene sequences (analyzed by unweighted UniFrac-based PCoA) from the mice in the experiment described in fig. 1A. The x- and y-axes are scaled based on the percent variance accounted for by each component (shown in parentheses). Each box corresponds to a single timepoint. dpc, days post colonization with the human donor sample; dpd, days post diet switch.
Fig. 3
Fig. 3. Postnatal assembly of the humanized gut microbiota
(A) Rarefaction curves measuring bacterial diversity in the fecal communities (species-level phylotypes defined by ≥97% identity). The curves are based on V2 16S rRNA gene sequences obtained from mice prior to weaning (P14) and after weaning (P28). Values are mean±95% CI. (B) Taxonomic distribution [RDP level 3 (27)] of the gut microbiota sampled from mice from postnatal days P14 to P85. Values represent the average relative abundance across all samples within a given group.
Fig. 4
Fig. 4. Clustering and taxonomic analysis of the gut microbiota of humanized mice consuming a LF/PP or Western diet
(A) 16S rRNA gene surveys (analyzed by unweighted UniFrac PCoA) of the humanized microbiota along the length of the gut (N=148 samples with >500 sequences/sample). Weighted UniFrac results in a similar overall clustering pattern. PC1 and PC2 are the x- and y-axis respectively. Percent variance is shown in parentheses. (B) Taxonomic distribution [RDP level 3 (27)] in communities distributed along the length of the gut. Values represent the average relative abundance across all samples within a given group.
Fig. 5
Fig. 5. Clustering of the distal gut microbiome, the C. innocuum SB23 transcriptome, and the community meta-transcriptome in the ceca of humanized mice
Microbiome/transcriptome profiles were normalized by z-score, used to construct a correlation distance matrix, clustered with UPGMA, and visualized (see SM; Matlab v7.7.0). (A) Clustering of fecal microbial gene content in the human donor’s microbiome and two groups of humanized mice starting at day one post colonization (N=3–5 mice/group; fecal DNA was pooled prior to sequencing). All mice were maintained on the LF/PP diet (red) for 28 days, at which point group2 was transferred to the Western diet (blue). (B) Clustering of C. innocuum SB23 gene expression in humanized mice fed the LF/PP (red) or Western (blue) diet. (C) Clustering of the gut microbiome’s meta-transcriptome in humanized mice fed a LF/PP (red) or a Western (blue) diet. Black circles represent validated clusters (inconsistency threshold=0.75, ‘cluster’ function in Matlab v7.7.0). dpc, days post colonization with a human donor sample; dpd, days post diet switch. (D) qRT-PCR validation of C. innocuum SB23 gene expression in humanized mice (N=3–5 samples/group; see SM). Mean values±SEM are plotted (*P<0.05, Student’s t-test).
Fig. 6
Fig. 6. Transmissibility of adiposity from humanized mice to germ-free recipients
(A) The effects of Western and LF/PP diets on epididymal fat pad weight (expressed as a percentage of total body weight) in humanized gnotobiotic mice (N=5–8 mice/group; N=2 independent groups). (B) Percent increase in total body fat (measured by DEXA) after colonization of germ-free mice with a microbiota harvested from humanized donors fed the Western or the LF/PP diet (N=4–5 mice/group). Recipients were fed a LF/PP diet. Mean values±SEM are plotted (*P<0.05, Student’s t-test).
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