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. 2016 Jan 14;529(7585):212-5.
doi: 10.1038/nature16504.

Diet-induced Extinctions in the Gut Microbiota Compound Over Generations

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Free PMC article

Diet-induced Extinctions in the Gut Microbiota Compound Over Generations

Erica D Sonnenburg et al. Nature. .
Free PMC article

Abstract

The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including immune function and metabolism. The reduced diversity of the gut microbiota in Western populations compared to that in populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota-accessible carbohydrates (MACs) found in dietary fibre have a crucial involvement in shaping this microbial ecosystem, and are notably reduced in the Western diet (high in fat and simple carbohydrates, low in fibre) compared with a more traditional diet. Here we show that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation. However, over several generations, a low-MAC diet results in a progressive loss of diversity, which is not recoverable after the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation, and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Extended Data Figure 1
Extended Data Figure 1. Collating data from studies of the microbiota of hunter-gatherers in Tanzania, agrarians from Malawi and Venezuela, and Westerners from the United States reveals that Western populations have depleted alpha diversity from birth through childbearing years and are missing bacterial taxa present in the traditional groups
a, Scatterplot of fecal microbiota of individuals plotted by phylogenetic diversity against age of the Hadza hunter-gatherers from Tanzania (n=16, green), agrarians from Malawi (n=81, red) and Venezuela (n=78, purple) and Americans (n=213, blue) b, Individuals plotted by unweighted UniFrac PC1 versus phylogenetic diversity. c, Individuals plotted by unweighted UniFrac PC1 versus age. d, Line plot of unique OTUs from fecal microbiota across populations (Americans, n=315; Malawi and Venezuela, n=213; Tanzania, n=27). OTUs (x-axis; black, present; white, absent) are considered present if represented by ≥ 0.001% of reads within each population. OTUs were sorted along the x-axis by their relative abundance in the U.S. and Tanzanian populations and further subdivided by their distributions within a population into tracks (red > 0.05%, yellow ≤ 0.05%, and green ≤ 0.01%, relative abundance). The line’s opacity is the proportion of that population that meets the criteria for that respective track.
Extended Data Figure 2
Extended Data Figure 2. Comparison of human donor and humanized mice
a, Taxa summary plot of the relative abundance of taxa from humanized mice feces (mice) (n=10) and human donor feces (human) (n=1). b, Alpha-diversity of the fecal microbiota from humanized mice (mice) and human donor (human) expressed as number of OTUs (top panel) and phylogenetic diversity (bottom panel). Error bars are shown as s.e.m.
Extended Data Figure 3
Extended Data Figure 3. Detailed schematic of multigeneration experiment
Generation 1. Humanized mice were fed a high-MAC diet for four weeks then switched to a low-MAC diet. One week after diet switch, the mice were bred to generate a litter of pups. After three additional weeks on the low-MAC diet, generation two pups were born and remained in the cage with their mother for three weeks (generation 1 still consuming the low-MAC diet). After pups were weaned, generation 1 mice were returned to the high-MAC diet for six weeks. Generation 2. Pups were weaned from their mother at three weeks old onto a low-MAC diet, which they consumed for 10 weeks. Breeding pairs for generation 2 mice were set-up at 7 weeks old. After three additional weeks on the low-MAC diet, generation 3 pups were born and remained in the cage with their mother for three weeks (generation 2 still consuming the low-MAC diet). After pups were weaned, generation 2 mice were returned to the high-MAC diet for six weeks. Generations 3 and 4 followed the same protocol as generation 2 described above.
Extended Data Figure 4
Extended Data Figure 4. Microbiota diversity is not regained upon direct weaning the diet-switching group onto the high-MAC diet
a, Alpha-diversity as measured by Shannon index of fecal microbiota from generation 5 mice from the high-MAC diet control (control) (n=6), generation 5, diet-switching group that was weaned directly onto the high-MAC diet (Gen 5 diet switching) (n=6), and generation 4 mice from the diet switching group after weaning and maintenance on the low-MAC diet for 13 weeks and returned to the high-MAC diet for four weeks (Gen 4 diet switching) (n=5). Error bars are shown as s.e.m. and P values are from a two-tailed Student’s t-test b, Principal coordinate analysis of unweighted UniFrac distance for 16S rRNA amplicon profiles from fecal samples collected from first generation control mice on a high-MAC diet (green), fourth generation, diet-switching mice (purple), and fifth generation mice from the diet-switching lineage weaned directly onto the high-MAC diet (orange). Control is plotted as weeks post-humanization and generation 4 and 5 are plotted as age.
Extended Data Figure 5
Extended Data Figure 5. Fraction of high-confidence OTUs from the Clostridiales order increases and from the Bacteroidales order decreases over multiple generations in the low-MAC consuming mice
a, Percent of high-confidence OTUs, grouped by order, detected in mice feces over four generations in the diet-switching lineage on the low-MAC diet (low) and high-MAC diet (hi) (n=5 for Gen 1; n=6 for Gen 2-4). b, Percent of high-confidence OTUs, grouped by order, detected in mice feces over four generations in the control high-MAC diet lineage at the equivalent time points to the high-MAC diet (a) and low-MAC diet (b) of the diet-switching group (n=5 for Gen 1; n=6 for Gen 2–4). c, Imputed gycloside hydrolase family members (GH) that show significant differences (at least 2-fold change and p<0.05, Bonferroni-corrected t test) between generation 4 diet-switching mice after four weeks on the high MAC diet (teal) (n=5) and the starting generation one mice (salmon) (n=10). Error bars depict s.e.m. No GH families showed significant changes in the control group.
Extended Data Figure 6
Extended Data Figure 6. Inefficient inter-generational transfer of taxa driven to low abundance by low dietary MACs
Heat map of abundance of high-confidence sub-OTUs (number of sequencing reads, columns) from feces of the diet switching group (top panel) and control group (bottom panel). Each row represents an individual mouse fecal microbiota from four weeks post-humanization (initial), while consuming the low-MAC diet (week 9, lo, shaded yellow), and four weeks after switching to the high-MAC diet (week 15, hi, shaded grey). Corresponding time points from controls are also shaded. Top row shows the taxanomic assignment for the OTUs plotted, Bacteroidetes are green, Firmicutes are orange, and others are grey.
Extended Data Figure 7
Extended Data Figure 7. Reintroduction of lost taxa and a high-MAC diet restores microbiota diversity and composition with Clostridiales order decreasing and Bacteroidales order increasing in low-MAC consuming mice that receive a fecal transplant
a, Plot of percent representation of high-confidence OTUs from generation 4 mice feces in the diet-switching group at day 0 before the FMT (starting) (n=6) and then 3–14 days no FMT control (n=3) or post FMT (n=3). FMT donor is plotted on the right. b, Heat map of abundance of high-confidence sub-OTUs (number of sequencing reads, columns) from the feces of the diet switching group at day 0 (Gen 4), day 3 to day 14 that did not receive an FMT (control) (n=3 for each day), day 3 to day 14 that received an FMT (+ FMT), and the FMT donor. Each row represents an individual mouse fecal microbiota. Top row shows the taxonomic assignment for the OTUs plotted, Bacteroidetes are green, Firmicutes are orange, and others are grey.
Figure 1
Figure 1. Taxa reduction observed in low-MAC diet is largely reversible in a single generation
a, Schematic of mouse experiment. Humanized mice (n=10) were maintained on a high-MAC diet for four weeks after which half of the mice were switched to a low-MAC diet for 7 weeks. These mice were then switched back to the high-MAC diet for >4 weeks. b, Principle coordinate analysis of the UniFrac distance for 16S rRNA amplicon profiles from fecal samples collected from the diet switching mice (yellow, n=5) and control high-MAC diet mice (green, n=5). c, Distribution of OTUs fold changes for diet switching (blue, n=5) or control (red, n=5) groups comparing baseline (4 weeks post-humanization) versus week 9 (5 weeks post-low MAC diet for “diet switch” group; top panel) and baseline versus week 15 (4 weeks after return to high-MAC diet for “diet switch” group, bottom panel).
Figure 2
Figure 2. Inefficient inter-generational transfer of taxa driven to low abundance by low dietary MACs
a, Schematic of multigeneration mouse experiment. Second (n=6), third (n=6), and fourth generation mice (n=6) were weaned onto a low-MAC diet. After mice generated a litter of pups that were weaned, low-MAC diet mice were switched to the high-MAC diet for 4 weeks. A parallel group of control mice were maintained on the high-MAC diet throughout (generation 2, n=6; generation 3, n=6; generation 4, n=5). b, Microbiota diversity as measured by Shannon index observed in the microbiota of mice at five weeks old (top panel, n=6 for each group) or four weeks after shift to high-MAC diet (bottom panel, n=6 for each group) from three generations of diet switching mice (grey) or control high-MAC diet mice (black). Error bars are shown as s.e.m and P values are from two-tailed Student’s t-test. c, Principal coordinate analysis of UniFrac distance for 16S rRNA amplicon profiles from fecal samples collected from first generation mice from the control group consuming a high-MAC diet (green, n=5) or the diet switching group from generation 1 (yellow, n=5), 2 (blue, n=6), 3 (red, n=6), and 4 (purple, n=6). d, Heat map of abundance of high-confidence OTUs (number of sequencing reads, columns) from the diet switching group (top panel) and controls (bottom panel); taxonomic assignment is indicated at the top of each column (Bacteroidetes, green; Firmicutes, orange; other, grey). Each row represents an individual mouse microbiota from four weeks post-humanization (initial), while consuming the low-MAC diet (week 9, lo, shaded yellow), and four weeks after switching to the high-MAC diet (week 15, hi, shaded grey). Corresponding time points from controls are similarly shaded. N=5, 6, 6, and 6 for the diet-switching group and n=5, 6, 6, and 5 for the control group for generations one through four respectively.
Figure 3
Figure 3. Reintroduction of lost taxa and a high-MAC diet restores microbiota diversity and composition
a, Schematic of fecal transplant mouse experiment. b, Principal coordinate analysis of UniFrac distance for 16S rRNA amplicon profiles from fecal samples collected from fourth generation control mice on a high-MAC diet (green, n=6), fourth generation, diet-switching mice that received a fecal transplant (red, n=3), or did not (blue, n=3). c, Microbiota diversity as measured by Shannon index observed in the microbiota of mice that received a fecal transplant (red, n=3) or did not (blue, n=3). A green circle denotes the number of OTUs observed in fourth generation control mice consuming a high-MAC diet (n=6). Error bars are shown as s.e.m. d, Heat map of abundance of high-confidence OTUs (number of sequencing reads) from fourth generation diet-switching mice (n=3) three to 14 days after FMT (fecal microbiota transplant) and no FMT controls (n=3); taxonomic assignment is indicated at the top of each column (Bacteroidetes, green; Firmicutes, orange; other, grey). FMT donor (fourth generation control mice, n=5) and fourth generation diet-switching mice (n=5) four weeks after consuming high-MAC diet are also shown.

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