Departments of Psychiatry & Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
Nutrients. 2023 Jul 6;15(13):3048. doi: 10.3390/nu15133048.
The serotonin transporter (SERT), highly expressed in the gut and brain, is implicated in metabolic processes. A genetic variant of the upstream regulatory region of the gene encoding SERT, the so-called short (s) allele, in comparison with the long (l) allele, results in the decreased function of this transporter, altered serotonergic regulation, an increased risk of psychiatric pathology and type-2 diabetes and obesity, especially in older women. Aged female mice with the complete (: KO) or partial (: HET) loss of SERT exhibit more pronounced negative effects following their exposure to a Western diet in comparison to wild-type (: WT) animals. We hypothesized that these effects might be mediated by an altered gut microbiota, which has been shown to influence serotonin metabolism. We performed V4 16S rRNA sequencing of the gut microbiota in 12-month-old WT, KO and HET female mice that were housed on a control or Western diet for three weeks. The relative abundance of 11 genera was increased, and the abundance of 6 genera was decreased in the Western-diet-housed mice compared to the controls. There were correlations between the abundance of and and the expression of the pro-inflammatory marker Toll-like-Receptor 4 () in the dorsal raphe, as well as the expression of the mitochondrial activity marker perixome-proliferator-activated-receptor-cofactor-1b () in the prefrontal cortex. Although there was no significant impact of genotype on the microbiota in animals fed with the Control diet, there were significant interactions between diet and genotype. Following FDR correction, the Western diet increased the relative abundance of and in the KO animals, which was not observed in the other groups. abundance was increased by the Western diet in the WT group but not in HET or KO animals. The enhanced effects of a challenge with a Western diet in SERT-deficient mice include the altered representation of several gut genera, such as , and , which are also implicated in serotonergic and lipid metabolism. The manipulation of these genera may prove useful in individuals with the short SERT allele.
血清素转运体（SERT）在肠道和大脑中高度表达，与代谢过程有关。编码 SERT 的基因上游调控区的一个遗传变异，即所谓的短（s）等位基因，与长（l）等位基因相比，导致该转运体功能降低、血清素能调节改变、精神病理学和 2 型糖尿病和肥胖的风险增加，尤其是在老年女性中。与野生型（WT）动物相比，完全缺失（KO）或部分缺失（HET）SERT 的老年雌性小鼠在暴露于西方饮食后表现出更明显的负面效应。我们假设这些影响可能是由肠道微生物群的改变介导的，肠道微生物群已被证明会影响血清素代谢。我们对 12 个月大的 WT、KO 和 HET 雌性小鼠进行了肠道微生物群的 V4 16S rRNA 测序，这些小鼠被安置在对照或西方饮食中 3 周。与对照组相比，在西方饮食饲养的小鼠中，有 11 个属的相对丰度增加，有 6 个属的丰度减少。与背侧中缝核中的促炎标志物 Toll 样受体 4（）的表达以及前额叶皮质中的线粒体活性标志物过氧化物酶体增殖物激活受体共激活因子 1b（）的表达呈正相关。尽管基因型对控制饮食喂养的动物的微生物群没有显著影响，但饮食和基因型之间存在显著的相互作用。在 FDR 校正后，西方饮食增加了 KO 动物中 和 的相对丰度，但在其他组中没有观察到。西方饮食增加了 WT 组中的丰度，但在 HET 或 KO 动物中没有增加。SERT 缺失小鼠对西方饮食挑战的增强效应包括几种肠道属的改变，如、和，它们也与血清素能和脂代谢有关。这些属的操纵可能对携带短 SERT 等位基因的个体有用。
