As the primary active substance in tobacco, nicotine affects the activity of the central nervous system, and its effects are sex-dependent. There are complex interactions between the gut and brain, and the gut microbiome can influence neuronal activity and host behavior, with diverse chemical signaling being involved. However, it is unclear whether nicotine can affect the normal gut microbiome and associated chemical signaling of the gut–brain axis. Sex is an important factor that shapes the gut microbiome, but the role of sex in the interaction among nicotine, gut bacteria, and related metabolites remains unknown. In this study, we applied high-throughput sequencing and gas chromatography–mass spectrometry (GC–MS) to explore how nicotine exposure affects the gut microbiome and its metabolism in female and male C57BL/6J mice, with a focus on the chemical signaling involved in gut–brain interactions. 16S sequencing results indicated that the community composition of the gut microbiome was differentially perturbed by nicotine in females and males. Differential alterations of bacterial carbohydrate metabolic pathways are consistent with lower body weight gain in nicotine-treated males. Oxidative stress response and DNA repair genes were also specifically enriched in the nicotine-treated male gut microbiome. The fecal metabolome indicated that multiple neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), and glycine, were differentially altered in female and male mice. Some neuroactive metabolites, including leucine and uric acid, were also changed. This study demonstrates a sex-dependent effect of nicotine on gut microbiome community composition, functional bacterial genes, and the fecal metabolome.

中文翻译：

---

尼古丁以特定性别的方式改变肠道微生物组和肠道与大脑相互作用的代谢产物。

尼古丁作为烟草中的主要活性物质，会影响中枢神经系统的活动，其作用与性别有关。肠道和大脑之间存在复杂的相互作用，肠道微生物组可以影响神经元活动和宿主行为，并涉及多种化学信号。然而，目前尚不清楚尼古丁是否会影响正常的肠道微生物组以及肠脑轴相关的化学信号。性别是影响肠道微生物组的重要因素，但性别在尼古丁，肠道细菌和相关代谢产物之间的相互作用中的作用仍然未知。在这项研究中，我们应用高通量测序和气相色谱-质谱（GC-MS）来研究尼古丁暴露如何影响雌性和雄性C57BL / 6J小鼠的肠道微生物组及其代谢，重点研究肠脑相互作用中涉及的化学信号传递。16S测序结果表明，在男性和女性中，尼古丁对肠道微生物组的群落组成有不同的扰动。在尼古丁治疗的男性中，细菌碳水化合物代谢途径的差异性改变与较低的体重增加相一致。氧化应激反应和DNA修复基因也特别富集在尼古丁治疗的雄性肠道微生物组中。粪便代谢物组表明，雌性和雄性小鼠中谷氨酸，γ-氨基丁酸（GABA）和甘氨酸等多种神经递质发生差异性改变。一些神经活性代谢物，包括亮氨酸和尿酸，也发生了变化。这项研究表明尼古丁对肠道微生物组群落组成具有性别依赖性，