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Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity

Nature Metabolism volume 3, pages 1042–1057 (2021)Cite this article

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Abstract

Obesity and its consequences are among the greatest challenges in healthcare. The gut microbiome is recognized as a key factor in the pathogenesis of obesity. Using a mouse model, we show here that a wild-derived microbiome protects against excessive weight gain, severe fatty liver disease and metabolic syndrome during a 10-week course of high-fat diet. This phenotype is transferable only during the first weeks of life. In adult mice, neither transfer nor severe disturbance of the wild-type microbiome modifies the metabolic response to a high-fat diet. The protective phenotype is associated with increased secretion of metabolic hormones and increased energy expenditure through activation of brown adipose tissue. Thus, we identify a microbiome that protects against weight gain and its negative consequences through metabolic programming in early life. Translation of these results to humans may identify early-life therapeutics that protect against obesity.

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Fig. 1: Wildlings are protected from excessive weight gain on HFD.
Fig. 2: Wildlings are protected from adverse metabolic effects of HFD.
Fig. 3: HFD-induced changes in the wildling and lab mouse microbiome.
Fig. 4: Impact of adult life microbiome on HFD response.
Fig. 5: Microbiota exposure in early-life programmes the response to HFD.
Fig. 6: Energy expenditure is increased in wildlings.
Fig. 7: Transfer of modified microbiome induces obesity resistance.

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Data availability

Raw sequence data from all 16S, shotgun metagenomics and RNA-sequencing experiments are deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA735448. Source data for the western blot are provided with this paper. Additional information and materials will be made available upon reasonable request.

Code availability

JAMS v.1.5.0 (https://github.com/johnmcculloch/JAMS_BW); virtual caloric chamber (https://sourceforge.net/projects/virtual-calorimeter/).

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Acknowledgements

We thank Y. Ma, Mouse Metabolism Core, NIDDK, for assistance with 14C-DG uptake studies; M. Walters and Yuhai Dai, NIDDK Clinical Core, for assistance with the Mesoscale assay; C. Ohuigin, W. Yuan, G. Wallace and V. Thovarai (Cancer Inflammation Program Microbiome and Genetics Core, NCI) for 16S rRNA gene sequencing; B. Tran (Sequencing Facility at Leidos Biomedical Research, Inc./Frederick National Laboratory for Cancer Research) for sequencing; A. M. Cypress, R. Wess, J. Pydi (NIDDK) and R. Das Neves (NCI) for discussion; and the University of Michigan Animal Phenotyping Core for faecal bomb calorimetry. This study was funded by the intramural research programmes of the NIDDK and NCI, NIH; and by the NIH Director’s Challenge Award program and the DDIR Innovation Award program (B.R.). B.H. was supported by research fellowship no. HI 2088/1–1 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany.

Author information

Author notes

  1. Benedikt Hild

    Present address: Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany

  2. Stephan P. Rosshart

    Present address: Translational Microbiome Research Laboratory, Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Medical Center – University of Freiburg, Freiburg, Germany

Authors and Affiliations

  1. Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA

    Benedikt Hild, Matthew S. Dreier, Ji Hoon Oh, Claire E. Thefaine, Stephan P. Rosshart & Barbara Rehermann

  2. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD, USA

    John A. McCulloch, Jonathan H. Badger & Giorgio Trinchieri

  3. Integrative Physiology Section, Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA

    Juen Guo & Kevin D. Hall

  4. Liver Diseases Virology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA

    Regina Umarova

  5. Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA

    Oksana Gavrilova

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Contributions

B.H. and B.R. conceived and designed the study. B.H., M.S.D., S.P.R. and B.R. designed the experiments. B.H. was responsible for the initial manuscript draft. B.H. and B.R. were responsible for the manuscript revision and editing. B.H., M.S.D., J.H.O., S.P.R. and O.G. performed the animal experiments. C.E.T. assisted with animal experiments. B.H., M.S.D. and J.H.B. analysed the 16S data. J.A.M. and G.T. analysed the metagenomic data. B.H. and R.U. analysed the transcriptomic data. J.G. and K.D.H. performed the virtual caloric chamber analysis. All authors discussed the data and commented on the manuscript.

Corresponding author

Correspondence to Barbara Rehermann.

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The authors declare no competing interests.

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Peer review information Primary handling editor: George Caputa. Nature Metabolism thanks Gerard Eberl, Cathryn Nagler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 HFD-induced changes in the cecal microbiome of lab and wildling mice.

Shotgun metagenomics data comparing the cecal microbiome of female wildling and lab mice at week 10 of chow or HFD. Lab mice on HFD: n = 5; lab mice on chow: n = 6; wildlings on HFD: n = 5; wildlings on chow: n = 5. a-c, Alpha-diversity, measured as number of observed unique taxa (a), Shannon index (b) and Simpson index (c) based on last-known taxa identified by shotgun metagenomics analysis of cecal microbiome of female wildling and lab mice at week 10 of chow diet or HFD. Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Unpaired two-tailed Student’s t test (Gaussian model) (a), Two-sided Wilcoxon signed rank test (b, c). (NS, not significant; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001). d, e, Heat maps generated by unsupervised clustering within lab (d) and wildling (e), showing the most variant last-known taxa (FDR-adjusted p < 0.05 by Mann Whitney Wilcoxon test) after filtering based on taxon genome completeness of >10% in at least 5% of samples and abundance of >250 parts per million in at least 15% of samples. Relative abundances are shown as z-scores, letters in front of last-known taxa describe taxonomy (s = species, f=family, g=genus, o=order, p=phylum).

Source data

Extended Data Fig. 2 Food consumption of wildling and lab mice on chow and HFD.

Data points represent daily kcal consumption per mouse, based on weekly measurements per cage over the course of chow or HFD diet. a, Data set refers to food consumption during experiments described in Fig. 1b; n = 55 lab mice on HFD, n = 42 lab mice on chow, n = 60 wildlings on HFD, n = 30 wildlings on chow. b, refers to Fig. 1d, n = 20 lab mice on HFD, n = 15 lab mice on chow, n = 23 wildlings on HFD, n = 17 wildlings on chow. c, refers to Fig. 4b, lab mice plus lab microbiota: n = 10 lab mice on chow, n = 24 lab mice on HFD; lab mice plus wildling microbiota: n = 10 mice on chow, n = 25 mice on HFD. d, refers to Fig. 4f; n = 10 lab mice, n = 10 wildlings. e, refers to Fig. 4j, n = 18 lab mice, n = 20 for wildlings. f, refers to Fig. 5c, n = 5 lab mice fostered by lab mice, n = 5 lab mice fostered by wildlings. g, refers to Fig. 5e, n = 8 lab mice fostered by lab mice, n = 8 lab mice fostered by wildlings. h, refers to Fig. 5h, n = 7 lab mice co-housed with lab mice, n = 10 lab mice co-housed with wildlings. i, refers to Fig. 5j, n = 13 lab mice co-housed with lab mice, n = 19 lab mice co-housed with wildlings. j, refers to Fig. 5m, n = 15 lab mice co-housed with lab mice, n = 10 lab mice co-housed with wildlings. k, refers to Fig. 5n, n = 15 lab mice co-housed with lab mice, n = 22 lab mice co-housed with wildlings. Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Unpaired two-tailed Student’s t test (Gaussian model) (c, d, f, g, h, i), two-sided Wilcoxon rank sum test (a, b, e, j, k). (NS, not significant; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, exact p-values are shown in the Source Data).

Source data

Extended Data Fig. 3 Fecal bomb calorimetry and rectal temperature of lab and wildling mice on chow and HFD.

a, b, Food energy intake (a) and fecal energy loss (bomb calorimetry) (b) in female lab or wildling mice on chow or HFD. N = 40 mice on chow and n = 40 mice on HFD examined per group over two independent experiments. c, Rectal temperature of male lab or wildling mice at week 9 of chow or HFD. N = 15 lab mice on chow, n = 20 lab mice on HFD, n = 17 wildlings on chow, n = 21 wildlings on HFD examined over two independent experiments. Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Two-sided Wilcoxon rank sum test (NS, not significant; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, exact p-values are shown in the Source Data).

Source data

Extended Data Fig. 4 Liver transcriptome of lab and wildling mice on HFD.

Bulk RNA sequencing of liver tissue from n = 7 lab mice (grey) and n = 7 wildlings (red) after 10 weeks of HFD. a, Unsupervised clustering of all metabolism-related gene transcripts that are significantly differently expressed. b, Volcano Plot. c, Comparison of lipogenesis-related gene transcripts (log2-fold expression) in liver tissue of the two groups of mice. Significance was determined as FDR ≤ 0.1.

Extended Data Fig. 5 Tissue-specific 2-deoxyglucose (2-DG) uptake in lab and wildling mice housed at 18 °C or 28 °C.

a, b, 2-DG uptake per milligram iBAT in female (a) or male (b) lab mice and wildlings at either 18 °C or 28 °C. c-h, 2-DG uptake in iWAT (c, d), pgWAT (e, f) or gastrocnemius muscle (g, h) in female (a, c, e, g) or male (b, d, f, h) lab or wildling mice held at 18 °C and 28 °C. N = 8 lab mice and n = 13 wildlings at 18 °C, n = 8 lab mice and n = 10 wildlings at 28 °C (a, c, e, g). N = 8 lab mice and n = 12 wildlings at 18 °C, n = 8 lab mice and n = 10 wildlings at 28 °C (b, d, f, h). Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. NS, not significant. Unpaired two-sided Student’s t test (Gaussian model) (a, b, d, e), two-sided Wilcoxon rank sum test (c, f, g, h). (NS, not significant; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, exact p-values are shown in the Source Data).

Source data

Extended Data Fig. 6 Western Blot analysis of AMPKalpha1, tyrosine hydroxylase and UCP1 in iBAT.

a, iBAT from lab and wildling mice at week 10 of HFD was analyzed by Western blot to quantitate the expression of tyrosine hydroxylase, AMPKalpha1 and UCP1 (upper bands) relative to GAPDH (lower bands). Brain lysate was used in the right lane (marked by asterisk). Representative Western Blot images for male mice (n = 6 mice per group). Unprocessed Western Blots are shown in Source Data. The experiment was independently repeated once for males and twice for females with similar results. b-g, The density of Western blot bands was quantified and normalized to each sample’s respective GAPDH band. Normalized expression levels are shown for tyrosine hydroxylase (b, c), AMPKalpha1 (d, e) and UCP1 (f, g) for female (b, d, f) and male (c, e, g) mice. N = 12 mice per group (b, c, e, g); n = 6 mice per group except n = 5 for the lab mouse group in blot 2 (d), n = 7 mice per group in blot 1, n = 6 mice per group in blot 2 (f). Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Two-sided Wilcoxon signed rank test (NS, not significant; ** p = 0.007538).

Source data

Extended Data Fig. 7 Metabolic hormones of lab and wildling mice on chow and HFD.

Serum concentration of metabolic hormones of lab mice and wildlings at baseline (week 10 of age on chow diet) and after 1 week and 10 weeks of HFD (weeks 11 and 20 of age, respectively). Each sample was pooled from two mice. Female lab mice at baseline, n = 14; at week 1 of HFD, n = 12; at week 10 of HFD, n = 16; male lab mice at baseline, n = 14; at week 1 of HFD, n = 14; at week 10 of HFD, n = 14; female wildlings at baseline, n = 14; at week 1 on HFD, n = 16; at week 10 of HFD, n = 12; male wildlings at baseline, n = 14; at week 1 of HFD, n = 16; at week 10 of HFD, n = 12. a Heatmap displaying median value of each group presented as z-score. BDNF, brain derived neurotropic factor; BAFF, B-cell activating factor. The Mesoscale Mouse Metabolic Combo 1 multiplex assay was used. b-h Serum concentration of glucagon (b), peptide YY (PYY) (c, d), thyroid stimulating hormone (TSH) (e, f), and the inactive form of glucagon like peptide 1 (GLP1) (g, h) at the indicated time points on chow or HFD as determined by multiplex Mesoscale Mouse Metabolic Combo 1 multiplex assay (b, c, d, g, h) or ELISA (e, f). Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Two-sided Wilcoxon signed rank test (NS, not significant; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, exact p-values are shown in the Source Data).

Source data

Extended Data Fig. 8 Increased diversity of wildling microbiome with interspersed clustering of MM-lab mice.

Shotgun metagenomics analysis of cecal microbiome from 12-day-old lab (n = 6), MM-lab (n = 4) and wildling (n = 5) pups. MM-lab mice were generated by co-housing lab mice with antibiotic-treated wildlings for 2 weeks and then separating and breeding these lab mice. Their offspring (microbiome modified (MM)-lab) were used for these experiments. a, Heat map generated by unsupervised clustering, showing the most variant last known taxa (LKT) after filtering based on taxon genome completeness of >10% in at least 5% of samples and abundance of >250 parts per million in at least 15% of samples. Relative abundances are shown as z-scores. Letters in front of LKT describe taxonomy (s = species, f=family, g=genus, o=order, p=phylum). b-d, Alpha-diversity, measured as number of observed unique taxa (b), Simpson index (c) and Shannon index (d) based on LKT. Box plots show median (center line), 75th (upper limit of box) and 25th percentile (lower limit of box) and outliers (whiskers) if values do not exceed 1.5-times interquartile range. Two-sided Wilcoxon signed rank test (NS, not significant; * p < 0.05, ** p < 0.01, exact p-values are shown in the Source Data).

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Extended Data Fig. 9 Graphical Summary.

Exposure to a wildling microbiome resulting in increased brown adipose tissue activity that protects from diet-induced obesity later-on in life.

Supplementary information

Supplementary Information

Supplementary Table 1. Pathogen profile of wildling and lab mice.

Reporting Summary

Source data

Source Data Fig. 1

Exact P values for statistical results in Fig. 1.

Source Data Fig. 2

Exact P values for statistical results in Fig. 2.

Source Data Fig. 3

Exact P values for statistical results in Fig. 3.

Source Data Fig. 4

Exact P values for statistical results in Fig. 4.

Source Data Fig. 5

Exact P values for statistical results in Fig. 5.

Source Data Fig. 6

Exact P values for statistical results in Fig. 6.

Source Data Fig. 7

Exact P values for statistical results in Fig. 7.

Source Data Extended Data Fig. 1

Exact P values for statistical results in Extended Data Fig. 1.

Source Data Extended Data Fig. 2

Exact P values for statistical results in Extended Data Fig. 2.

Source Data Extended Data Fig. 3

Exact P values for statistical results in Extended Data Fig. 3.

Source Data Extended Data Fig. 5

Exact P values for statistical results in Extended Data Fig. 5.

Source Data Extended Data Fig. 6

Unprocessed western blots for data shown in Extended Data Fig. 6.

Source Data Extended Data Fig. 7

Exact P values for statistical results in Extended Data Fig. 7.

Source Data Extended Data Fig. 8

Exact P values for statistical results in Extended Data Fig. 8.

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Hild, B., Dreier, M.S., Oh, J.H. et al. Neonatal exposure to a wild-derived microbiome protects mice against diet-induced obesity. Nat Metab 3, 1042–1057 (2021). https://doi.org/10.1038/s42255-021-00439-y

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