Toledo Míriam, Martínez-Martínez Sara, Van Hul Matthias, Laudo Berta, Eyre Elena, Pelicaen Rudy, Puel Anthony, Altirriba Jordi, Gómez-Valadés Alicia G, Inderhees Julica, Moreno-Indias Isabel, Pozo Macarena, Chivite Iñigo, Milà-Guasch Maria, Haddad-Tóvolli Roberta, Obri Arnaud, Fos-Domènech Júlia, Tahiri Iasim, Llana Sergio R, Ramírez Sara, Monelli Erika, Schwaninger Markus, Cani Patrice D, Nogueiras Rubén, Claret Marc
Neuronal Control of Metabolism Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Department of Physiology (CIMUS), School of Medicine-Instituto de Investigaciones Sanitarias (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain.
Nat Metab. 2025 Apr 22. doi: 10.1038/s42255-025-01280-3.
In recent years, the gut microbiota and derived metabolites have emerged as relevant players in modulating several brain functions, including energy balance control. 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. 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 (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.
近年来，肠道微生物群及其衍生代谢产物已成为调节多种脑功能（包括能量平衡控制）的相关因素。这种远距离通讯形式与代谢激素（如瘦素、胃饥饿素）类似，代谢激素通过对包括主要稳态中心下丘脑在内的不同脑区产生作用，来传递有关机体能量状态的信息。然而，下丘脑是否也能够影响肠道微生物群的组成仍然是个谜。在此，我们展示一项旨在解开这个具有挑战性问题的研究。为此，我们对雄性小鼠使用化学遗传学方法（选择性激活或抑制下丘脑促黑素细胞皮质激素或刺鼠相关肽神经元）或脑室内注射瘦素或胃饥饿素。随后，我们使用16S rRNA基因测序对整个肠道的微生物群组成进行分析。我们的结果表明，这些脑部干预措施以解剖学和短期（2 - 4小时）的方式显著改变了肠道微生物群。转录组分析表明，这些变化与十二指肠中神经元和突触通路的重新配置以及交感神经张力增加有关。有趣的是，饮食诱导的肥胖减弱了瘦素在肠道微生物群落中引发的脑介导变化以及交感神经激活。我们的研究结果揭示了一种先前未被预料到的脑 - 肠轴，它在快速时间尺度上急性调节微生物群组成，对餐间调整和全身能量平衡控制具有潜在影响。
