Milhouse Wynne, Organski Anna Clapp, Sun Xun, Ai Derek, Zhou Baohua, Cross Tzu-Wen L, Ren Hongxia
Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Physiol Rep. 2025 May;13(10):e70373. doi: 10.14814/phy2.70373.
The gut microbiome (GMB) regulates digestion, metabolism, immunity, and energy homeostasis. This study investigates how gut microbiota integrate the regulation in the neuroendocrine and enteroendocrine systems, with a focus on G protein-coupled receptors (GPCRs) in the brain-gut axis and sex differences. Germ-free (GF) mice exhibited increased hypothalamic expression of the anorexigenic neuropeptide and decreased expression of the negative regulator of leptin signaling. GF males had significantly lower serum leptin levels compared to conventional (CON) males, highlighting a potential link between the microbiome and leptin resistance. In the gut, GF mice demonstrated heightened expression of anorexigenic gut hormones, including peptide YY (Pyy) and cholecystokinin (Cck), in addition to increased levels of G protein-coupled receptors (GPCRs) involved in gut hormone secretion and nutrient metabolism, particularly in females. While carbohydrate metabolism genes were upregulated in CON mice, lipid metabolism genes were predominantly higher in GF mice. These findings suggest that the gut microbiota downregulates genes involved in appetite suppression, modulates GPCRs linked to gut hormone secretion, and contributes to leptin resistance, particularly in males. This research underscores the importance of the gut microbiome in host metabolism and reveals potential molecular targets for novel treatments of metabolic diseases.
肠道微生物群（GMB）调节消化、代谢、免疫和能量稳态。本研究调查了肠道微生物群如何整合神经内分泌和肠内分泌系统中的调节，重点关注脑-肠轴中的G蛋白偶联受体（GPCRs）和性别差异。无菌（GF）小鼠下丘脑中食欲抑制神经肽的表达增加，瘦素信号负调节因子的表达降低。与常规（CON）雄性小鼠相比，GF雄性小鼠的血清瘦素水平显著降低，这突出了微生物群与瘦素抵抗之间的潜在联系。在肠道中，GF小鼠除了参与肠道激素分泌和营养代谢的G蛋白偶联受体（GPCRs）水平增加外，还表现出食欲抑制性肠道激素的表达升高，包括肽YY（Pyy）和胆囊收缩素（Cck），特别是在雌性小鼠中。虽然CON小鼠中碳水化合物代谢基因上调，但GF小鼠中脂质代谢基因的表达主要更高。这些发现表明，肠道微生物群下调参与食欲抑制的基因，调节与肠道激素分泌相关的GPCRs，并导致瘦素抵抗，特别是在雄性小鼠中。这项研究强调了肠道微生物群在宿主代谢中的重要性，并揭示了代谢疾病新治疗方法的潜在分子靶点。
