Probiotics and the microbiota-gut-brain axis

摘要 宿主-微生物相互作用对于维持人类宿主的正常生理至关重要，包括 大脑和行为。胃肠道（GI）细菌定植，GI粘膜屏障形成 功能和神经发生都发生在生命早期的关键发育窗口期。因此，暴露于 新生儿生活中的创伤，如压力，感染或炎症，可能会在精神上影响发育， 微生物群，肠道和大脑（MGB）轴。破坏MGB轴信号传导，包括生态失调、粘膜屏障 行为缺陷和/或改变，发生在多种疾病中，包括炎症性肠病（IBD）， 自闭症谱系障碍、重度抑郁症和肥胖症。 由于儿童对抗生素（Abx）的敏感性增加， 细菌病原体由于MGB轴在这一关键时期正在发展，因此Abx管理可能具有 持久的影响。益生菌生物体的施用可以改善许多病理，包括 生态失调、粘膜屏障功能障碍、炎症和行为缺陷。我们已经证明 含乳酸杆菌的益生菌可以预防感染后应激诱导的MGB轴缺陷。 细菌病原体我们假设给予特定的益生菌可以预防新生儿Abx- 在成人MGB轴诱导赤字。因此，我们的主要目标是解决新生儿的影响， 使用新生儿Abx给药模型，观察了MGB轴发育的生态失调。我们的总目标 是为了确定肠道生态失调是否破坏肠-脑轴，以及是否施用 益生菌有益地调节MGB轴。这一目标将通过以下具体措施实现： 目的：（1）新生儿生态失调破坏了发育中的MGB轴，（2）NOD样受体（NLR）是关键 选择性益生菌可通过NLR恢复MBG轴缺陷。 总之，这些拟议中的研究将证明新生儿生态失调是否会破坏 发展MGB轴，影响微生物群组成，改变NLR信号传导， 成年后的缺陷此外，我们将确定是否管理选择益生菌改善这些 部分地通过NLR信号传导，从而支持选择的益生菌菌株在治疗上用于改变 MGB轴。最后，我们的研究结果可能会促进益生菌的使用伴随着Abx管理，以防止 MGB轴缺陷，特别是在儿童和新生儿中。

ABSTRACT Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, and neurogenesis all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection or inflammation during neonatal life could detrimentally impact the developing microbiota, gut and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including inflammatory bowel disease (IBD), autism spectrum disorder, major depressive disorder, and obesity. Antibiotics (Abx) are administered to children more frequently than adults, due to increased susceptibility to bacterial pathogens. Since the MGB axis is developing during this critical time, Abx administration may have long-lasting effects. Administration of probiotic organisms can ameliorate numerous pathologies, including dysbiosis, mucosal barrier dysfunction, inflammation and behavioral defects. We have demonstrated that Lactobacillus-containing probiotics can prevent stress-induced MGB axis deficits following infection with a bacterial pathogen. We hypothesize that administration of specific probiotics can prevent neonatal Abx- induced deficits in the adult MGB axis. Therefore, our primary objective is to address the effects of neonatal dysbiosis on the development of the MGB axis using a model of neonatal Abx administration. Our overall goal is to determine whether intestinal dysbiosis disrupts the gut-brain axis, and whether administration of probiotics beneficially modulates the MGB axis. This goal will be accomplished by the following Specific Aims: (1) neonatal dysbiosis disrupts the developing MGB axis, (2) NOD-like receptors (NLR) are critical for MBG axis development; and (3) selective probiotics can restore MBG axis deficits via NLR. Taken together, these proposed studies will demonstrate whether neonatal dysbiosis disrupts the developing MGB axis, impacting the microbiota composition, altering NLR signaling, and causing behavioral deficits in adulthood. Furthermore, we will determine whether administering select probiotics ameliorates these effects, in part via NLR signaling and thereby support use of select probiotic strains therapeutically for altered MGB axis. Finally, our results may promote use of probiotics concomitantly with Abx administration to prevent development MGB axis deficits, particularly in children and neonates.