IntroductionSerotonin (5-HT) is critical for neurodevelopment and the serotonin transporter (SERT) modulates serotonin levels. Perturbed prenatal and postnatal dietary exposures affect the developing offspring predisposing to neurobehavioral disorders in the adult. We hypothesized that the postnatal brain 5-HT-SERT imbalance associated with gut dysbiosis forms the contributing gut-brain axis dependent mechanism responsible for such ultimate phenotypes.MethodsEmploying maternal diet restricted (IUGR, n=8) and high fat+high fructose (HFhf, n=6) dietary modifications, rodent brain serotonin was assessed temporally by ELISA and SERT by quantitative Western blot analysis. Simultaneously, colonic microbiome studies were performed.ResultsAt early postnatal (P) day 2 no changes in the IUGR, but a ~24% reduction in serotonin (p = 0.00005) in the HFhf group occurred, particularly in the males (p = 0.000007) revealing a male versus female difference (p = 0.006). No such changes in SERT concentrations emerged. At late P21 the IUGR group reared on HFhf (IUGR/HFhf, (n = 4) diet revealed increased serotonin by ~53% in males (p = 0.0001) and 36% in females (p = 0.023). While only females demonstrated a ~40% decrease in serotonin (p = 0.010), the males only trended lower without a significant change within the HFhf group (p = 0.146). SERT on the other hand was no different in HFhf or IUGR/RC, with only the female IUGR/HFhf revealing a 28% decrease (p = 0.036). In colonic microbiome studies, serotonin-producing Bacteriodes increased with decreased Lactobacillus at P2, while the serotonin-producing Streptococcus species increased in IUGR/HFhf at P21. Sex-specific changes emerged in association with brain serotonin or SERT in the case of Alistipase, Anaeroplasma, Blautia, Doria, Lactococcus, Proteus, and Roseburia genera.DiscussionWe conclude that an imbalanced 5-HT-SERT axis during postnatal brain development is sex-specific and induced by maternal dietary modifications related to postnatal gut dysbiosis. We speculate that these early changes albeit transient may permanently alter critical neural maturational processes affecting circuitry formation, thereby perturbing the neuropsychiatric equipoise.

中文翻译：

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雄性和雌性产后大鼠后代的脑血清素和血清素转运蛋白表达对生命早期饮食暴露干扰的反应

简介血清素 (5-HT) 对于神经发育至关重要，而血清素转运蛋白 (SERT) 可调节血清素水平。产前和产后饮食暴露的干扰会影响发育中的后代，导致成人出现神经行为障碍。我们假设与肠道菌群失调相关的产后大脑 5-HT-SERT 失衡形成了导致这种最终表型的肠脑轴依赖性机制。方法采用母亲饮食限制（IUGR，n = 8）和高脂肪+高果糖（HFhf） , n=6) 饮食改变，通过 ELISA 和 SERT 通过定量蛋白质印迹分析暂时评估啮齿动物脑血清素。同时进行了结肠微生物组研究。结果在出生后第 2 天早期 (P)，IUGR 没有变化，但血清素减少了约 24%（p= 0.00005) 在 HFhf 组中发生，特别是在男性中（p= 0.000007）揭示了男性与女性的差异（p= 0.006）。 SERT 浓度没有出现此类变化。在 P21 后期，IUGR 群体在 HFhf 上饲养（IUGR/HFhf，（n= 4) 饮食显示男性血清素增加约 53%（p= 0.0001），女性为 36%（p= 0.023）。虽然只有女性的血清素水平下降了约 40%（p= 0.010），HFhf 组中男性仅呈下降趋势，没有显着变化（p= 0.146）。另一方面，SERT 在 HFhf 或 IUGR/RC 中没有什么不同，只有女性 IUGR/HFhf 下降了 28%（p= 0.036）。在结肠微生物组研究中，在 P2 时，产生血清素的拟杆菌随着乳酸杆菌的减少而增加，而在 P21 的 IUGR/HFhf 中，产生血清素的链球菌种类则增加。性别特异性变化与大脑血清素或 SERT 相关阿利斯脂酶、厌氧原体、Blautia、Doria、乳球菌、变形杆菌和罗斯伯利亚属讨论我们得出的结论是，产后大脑发育过程中 5-HT-SERT 轴的不平衡具有性别特异性，并且是由与产后肠道菌群失调相关的母亲饮食改变引起的。我们推测，这些早期变化虽然短暂，但可能会永久改变影响电路形成的关键神经成熟过程，从而扰乱神经精神平衡。