Rapid modulation of gut microbiota composition by hypothalamic circuits in mice

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control<sup>1-3</sup>. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism's energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus<sup>4</sup>. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics<sup>5</sup> (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2-4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain-gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.

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Publication Details

Journal
Nature Metabolism
Published
2025-04-22
DOI
https://doi.org/10.1038/s42255-025-01280-3
Citations
23
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
18.54

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article

Rapid modulation of gut microbiota composition by hypothalamic circuits in mice

Isabel Moreno‐Indias, Markus Schwaninger, Arnaud Obri, Elena Eyre et al.
23 citations
Nature Metabolism
Gut microbiota and health
18.54
article

Rapid modulation of gut microbiota composition by hypothalamic circuits in mice

Isabel Moreno‐Indias, Markus Schwaninger, Arnaud Obri, Elena Eyre, Iasim Tahiri, Rubén Nogueiras, Rudy Pelicaen, Maria Milà‐Guasch, Alícia G. Gómez-Valadés, Erika Monelli, Matthias Van Hul, Júlia Fos-Domènech, Jordi Altirriba, Anthony Puel, Macarena Pozo, Míriam Toledo, Berta Laudo, Marc Claret, Patrice D. Cani, Roberta Haddad-Tóvolli, Íñigo Chivite, Julica Inderhees, Sara Ramírez, Sara Martínez-Martínez, Sergio R. Llana
article en
23 citations

Abstract

In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control<sup>1-3</sup>. This form of distant communication mirrors that of metabolic hormones (for example, leptin, ghrelin), which convey information about the organism's energy status by exerting effects on diverse brain regions, including the master homeostatic centre, the hypothalamus<sup>4</sup>. However, whether the hypothalamus is also able to influence gut microbiota composition remains enigmatic. Here we present a study designed to unravel this challenging question. To this aim, we used chemogenetics<sup>5</sup> (to selectively activate or inhibit hypothalamic pro-opiomelanocortin or agouti-related peptide neurons) or centrally administered leptin or ghrelin to male mice. Subsequently, we conducted microbiota composition analysis throughout the gut using 16S rRNA gene sequencing. Our results showed that these brain interventions significantly changed the gut microbiota in an anatomical and short-term (2-4 h) fashion. Transcriptomic analysis indicated that these changes were associated with the reconfiguration of neuronal and synaptic pathways in the duodenum concomitant with increased sympathetic tone. Interestingly, diet-induced obesity attenuated the brain-mediated changes triggered by leptin in gut microbiota communities and sympathetic activation. Our findings reveal a previously unanticipated brain-gut axis that acutely attunes microbiota composition on fast timescales, with potential implications for meal-to-meal adjustments and systemic energy balance control.

Nature MetabolismVol. 7(6)
University of Geneva (CH), Universidade de Santiago de Compostela (ES), Xunta de Galicia (ES), Instituto de Salud Carlos III (ES), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES), Centro de Investigación Biomédica en Red (ES), German Centre for Cardiovascular Research (DE), Walloon Excellence in Lifesciences and Biotechnology (BE), Instituto de Investigación Sanitaria de Santiago (ES), Andalusian Centre for Nanomedicine and Biotechnology (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación Biomédica de Málaga (ES), Universitat de Barcelona (ES), University of Lübeck (DE), UCLouvain (BE)
“la Caixa” Foundation, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, Walloon excellence in life sciences and biotechnology, Instituto de Salud Carlos III
Zero hunger
Openalex Percentile: Top 0%
Gut microbiota and health
18.54
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