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Clinical Trial
, 505 (7484), 559-63

Diet Rapidly and Reproducibly Alters the Human Gut Microbiome

Clinical Trial

Diet Rapidly and Reproducibly Alters the Human Gut Microbiome

Lawrence A David et al. Nature.


Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.


Fig. 1
Fig. 1. Short-term diet alters the gut microbiota
Ten subjects were tracked across each diet arm. (A) Fiber intake on the plant-based diet rose from a median baseline value of 9.3±2.1 to 25.6±1.1 g/1,000kcal (p=0.007; two-sided Wilcoxon signed-rank test), but was negligible on the animal-based diet (p=0.005). (B) Daily fat intake doubled on the animal-based diet from a baseline of 32.5±2.2% to 69.5±0.4% kcal (p=0.005), but dropped on the plant-based diet to 22.1±1.7% (p=0.02). (C) Protein intake rose on the animal-based diet to 30.1±0.5% kcal from a baseline level of 16.2±1.3% (p=0.005) and decreased on the plant-based diet to 10.0±0.3% (p=0.005). (D) Within-sample species diversity (α-diversity, Shannon’s Diversity Index), did not significantly change during either diet. (E) The similarity of each individual’s gut microbiota to their baseline communities (β-diversity, Jensen-Shannon distance) decreased on the animal-based diet (dates with q<0.05 identified with asterisks; Bonferroni-corrected, two-sided Mann-Whitney U test). Community differences were apparent one day after a tracing dye showed the animal-based diet reached the gut (blue arrows depict appearance of food dyes added to first and last diet day meals; Extended Data Fig. 3a).
Fig. 2
Fig. 2. Bacterial cluster responses to diet arms
Cluster log2 fold-changes on each diet arm were computed relative to baseline samples across all subjects and are drawn as circles. Clusters with significant fold-changes on the animal-based diet are colored in red, and clusters with significant fold-changes on both the plant- and animal-based diets are colored in both red and green. Uncolored clusters exhibited no significant fold-change on either the animal or plant-based diet (q<0.05, two-sided Wilcoxon signed-rank test). Bacterial membership in the clusters with the three largest positive and negative fold-changes on the animal-based diet are also displayed and colored by phylum: Firmicutes (purple), Bacteroidetes (blue), Proteobacteria (green), Tenericutes (red), and Verrucomicrobia (gray). Multiple OTUs with the same name are counted in parentheses.
Fig. 3
Fig. 3. Diet alters microbial activity and gene expression
Fecal concentrations of SCFAs from (A) carbohydrate and (B) amino acid fermentation (*p<0.05, two-sided Mann-Whitney U test; n=9–11 fecal samples/diet arm; Supplementary Table 11). The animal-based diet was associated with significant increases in gene expression (normalized to reads per kilobase per million mapped, or RPKM; n=13–21 datasets/diet arm) among (C) glutamine amidotransferases (K08681, vitamin B6 metabolism), (D) methyltransferases (K00599, polycyclic aromatic hydrocarbon degradation), and (E) beta-lactamases (K01467). (F) Hierarchical clustering of gut microbial gene expression profiles collected on the animal-based (red) and plant-based (green) diets. Expression profile similarity was significantly associated with diet (p<0.003; two-sided Fisher’s exact test excluding replicate samples), despite inter-individual variation that preceded the diet (Extended Data Figs. 6a,b). Enrichment on animal-based diet (red) and plant-based diet (green) for expression of genes involved in (G) amino acid metabolism and (H) central metabolism. Numbers indicate the mean fold-change between the two diets for each KEGG orthologous group assigned to a given enzymatic reaction (Supplementary Table 17). Enrichment patterns on the animal- and plant-based diets agree perfectly with patterns observed in carnivorous and herbivorous mammals, respectively2 (p<0.001, Binomial test). Note: Pyr Cx is represented by two groups, which showed divergent fold-changes. Asterisks in panels C-E and G,H indicate p<0.05, Student’s t test. Values in panels A-E are mean±sem. Abbreviations: glutamate dehydrogenase (GDH), glutamate decarboxylase (Glu Dx), succinate-semialdehyde dehydrogenase (SSADH), phosphoenolpyruvate carboxylase (PEPCx), pyruvate carboxylase (Pyr Cx), phosphotransferase system (PTS), PEP carboxykinase (PEPCk), oxaloacetate decarboxylase (ODx), pyruvate, orthophosphate dikinase (PPDk).
Fig. 4
Fig. 4. Foodborne microbes are detectable in the distal gut
(A) Common bacteria and fungi associated with the animal-based diet menu items, as measured by 16S rRNA and ITS gene sequencing, respectively. Taxa are identified on the genus (g) and species (s) level. A full list of foodborne fungi and bacteria on the animal-based diet can be found in Supplementary Table 21. Foods on the plant-based diet were dominated by matches to the Streptophyta, which derive from chloroplasts within plant matter (Extended Data Fig. 7a). (B-E). Fecal RNA transcripts were significantly enriched (q<0.1, Kruskal-Wallis test; n=6–10 samples/diet arm) for several food-associated microbes on the animal-based diet relative to baseline (BL) periods, including (B) Lactococcus lactis, (C) Staphylococcus carnosus, (D) Pediococcus acidilactici, and (E) a Penicillium sp. A complete table of taxa with significant expression differences can be found in Supplementary Table 22. (F) Fungal concentrations in feces before and 1–2 days after the animal-based diet were also measured using culture media selective for fungal growth (plate count agar with milk, salt, and chloramphenicol). Post-diet fecal samples exhibit significantly higher fungal concentrations than baseline samples (p<0.02; two-sided Mann-Whitney U test; n=7–10 samples/diet arm). (G) Increased RNA transcripts from the plant-derived Rubus chlorotic mottle virus transcripts increase on the plant-based diet (q<0.1, Kruskal-Wallis test; n=6–10 samples/diet arm). Barplots (B-G) all display mean±sem.
Fig. 5
Fig. 5. Changes in the fecal concentration of bile acids and biomarkers for Bilophila on the animal-based diet
(A) Deoxycholic acid, a secondary bile acid known to promote DNA damage and hepatic carcinomas, accumulates significantly on the animal-based diet (p<0.01, two-sided Wilcoxon signed-rank test; see Supplementary Table 23 for the diet response of other secondary bile acids). (B) RNA-Seq data also supports increased microbial metabolism of bile acids on the animal-based diet, as we observe significantly increased expression of microbial bile salt hydrolases (K01442) during that diet arm (q<0.05, Kruskal-Wallis test; normalized to reads per kilobase per million mapped, or RPKM; n=8–21 samples/diet arm). (C) Total fecal bile acid concentrations also increase significantly on the animal-based diet, relative to the preceding baseline period (p<0.05, two-sided Wilcoxon signed-rank test), but do not change on the plant-based diet (Extended Data Fig. 9). Bile acids have been shown to cause IBD in mice by stimulating the growth of the bacterium Bilophila, which is known to reduce sulfite to hydrogen sulfide via the sulfite reductase enzyme (dsrA; Extended Data Fig. 10). (D) Quantitative PCR showed a significant increase in microbial DNA coding for dsrA on the animal-based diet (p<0.05; two-sided Wilcoxon signed-rank test), and (E) RNA-Seq identified a significant increase in sulfite reductase expression (q<0.05, Kruskal-Wallis test; n=8–21 samples/diet arm). Barplots (B,E) display mean±sem.

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