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Physiology and Biochemistry

Dietary switch to Western diet induces hypothalamic adaptation associated with gut microbiota dysbiosis in rats

International Journal of Obesity volume 45, pages 1271–1283 (2021)Cite this article

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Abstract

Background

Early hyperphagia and hypothalamic inflammation encountered after Western diet (WD) are linked to rodent propensity to obesity. Inflammation in several brain structures has been associated with gut dysbiosis. Since gut microbiota is highly sensitive to dietary changes, we hypothesised that immediate gut microbiota adaptation to WD in rats is involved in inflammation-related hypothalamic modifications.

Methods

We evaluated short-term impact of WD consumption (2 h, 1, 2 and 4 days) on hypothalamic metabolome and caecal microbiota composition and metabolome. Data integration analyses were performed to uncover potential relationships among these three datasets. Finally, changes in hypothalamic gene expression in absence of gut microbiota were evaluated in germ-free rats fed WD for 2 days.

Results

WD quickly and profoundly affected the levels of several hypothalamic metabolites, especially oxidative stress markers. In parallel, WD consumption reduced caecal microbiota diversity, modified its composition towards pro-inflammatory profile and changed caecal metabolome. Data integration identified strong correlations between gut microbiota sub-networks, unidentified caecal metabolites and hypothalamic oxidative stress metabolites. Germ-free rats displayed reduced energy intake and no changes in redox homoeostasis machinery expression or pro-inflammatory cytokines after 2 days of WD, in contrast to conventional rats, which exhibited increased SOD2, GLRX and IL-6 mRNA levels.

Conclusion

A potentially pro-inflammatory gut microbiota and an early hypothalamic oxidative stress appear shortly after WD introduction. Tripartite data integration highlighted putative links between gut microbiota sub-networks and hypothalamic oxidative stress. Together with the absence of hypothalamic modifications in germ-free rats, this strongly suggests the involvement of the microbiota-hypothalamus axis in rat adaptation to WD introduction and in energy homoeostasis regulation.

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Fig. 1: First week energy intake after WD introduction is correlated to 6-week obesity phenotype.
Fig. 2: Hypothalamic metabolome evolution during adaptation to WD in conventional rats.
Fig. 3: Evolution of caecal microbiota diversity and composition during early adaptation to WD in conventional rats.
Fig. 4: Tripartite network showing links between caecal microbiota, caecal metabolome and hypothalamic oxidative stress.
Fig. 5: Germ-free and conventional rat response to 2 days of WD consumption.

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Data availability

R code and raw metabolomic data used in this study are available upon request to the corresponding author. Raw microbiota sequences are available at Sequence Read Archive (BioProject ID 602836).

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Acknowledgements

We thank Mathilde Guerville and Annaëlle Sinquin as well as Helen Raybould. We thank Isabelle Nogret for her technical help. Caecal Metabolomic analysis were performed within the metaboHUB French infrastructure (ANR-INBS-0010). This work was partly funded by a grant from INRAE AlimH division.

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Author notes

  1. These authors contributed equally: Véronique Douard, Gaëlle Boudry

Authors and Affiliations

  1. Institut Numecan, INRAE, INSERM, Univ Rennes, Rennes, France

    Mélanie Fouesnard & Gaëlle Boudry

  2. TENS U1235, INSERM, Nantes, France

    Johanna Zoppi

  3. Clermont Auvergne University, INRAE, UNH, Plateforme d’Exploration du Métabolisme, MetaboHUB Clermont, Clermont-Ferrand, France

    Mélanie Petera, Carole Migné & Stéphanie Durand

  4. Institut MICALIS, INRAE, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France

    Léa Le Gleau, Fabienne Devime & Véronique Douard

  5. Centre des Sciences du Goût et de l’Alimentation, Unité Mixte de Recherche 6265—Centre National de la Recherche Scientifique 13241—Institut National de la Recherche pour l’Agriculture, l’Alimentation et l’Environnement, Université de Bourgogne, Dijon, France

    Alexandre Benani

  6. Université de Nantes, CNRS (UMR6004), LS2N, Nantes, France

    Samuel Chaffron

  7. Research Federation (FR2022) Tara Oceans GO-SEE, Paris, France

    Samuel Chaffron

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  1. Mélanie Fouesnard
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Fouesnard, M., Zoppi, J., Petera, M. et al. Dietary switch to Western diet induces hypothalamic adaptation associated with gut microbiota dysbiosis in rats. Int J Obes 45, 1271–1283 (2021). https://doi.org/10.1038/s41366-021-00796-4

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