肠道微生物组影响多种宿主生理功能，包括胃肠道功能，代谢，免疫稳态，神经活性，以及宿主行为。许多微生物对宿主的影响由微生物组和免疫系统双向交互作用所调节。该双向交互作用稳态失调能够导致免疫功能异常和免疫介导的包括大脑的远端器官出现状况。稳态失衡的肠道微生物组和失调的神经免疫响应是神经发育、神经精神病和神经紊乱的共同的合并症状，这些凸显了肠道微生物组-神经免疫轴作为对中枢神经系统稳态调节因子的重要作用。这篇综述系统的讨论了在健康和疾病中肠道微生物组对调控神经免疫图谱起作用的最新证据。

评语： 

本文系统地综述了肠道微生物组-神经免疫轴对中枢神经系统稳态的调控作用及其对宿主健康的影响，对刚进入该领域或者想较为全面了解该领域最新进展的科研人员来说是一篇经典综述。

关键词： 

gut microbiome, neuroimmune landscape, central nervous system, neurodevelopment, neuropsychiatric, and neurological disorders

文章链接：

https://www.annualreviews.org/doi/pdf/10.1146/annurev-immunol-101320-014237

Abstract

The gut microbiome influences many host physiologies, spanning gastrointestinal function, metabolism, immune homeostasis, neuroactivity, and behavior. Many microbial effects on the host are orchestrated by bidirectional interactions between the microbiome and immune system. Imbalances in this dialogue can lead to immune dysfunction and immune-mediated conditions in distal organs including the brain. Dysbiosis of the gut microbiome and dysregulated neuroimmune responses are common comorbidities of neurodevelopmental, neuropsychiatric, and neurological disorders, highlighting the importance of the gut microbiome-neuroimmune axis as a regulator of central nervous system homeostasis. In this review, we discuss recent evidence supporting a role for the gut microbiome in regulating the neuroimmune landscape in health and disease.

自闭症儿童经常表现出下调的免疫反应和相关的胃肠道症状，但与该症状相关的作用机制尚不清楚。Kim 等提出子代表现出自闭症样表型的小鼠，如果出生前暴露在母体内的炎症环境下，与出生后人工炎症干预的小鼠相比，更加容易发生肠道炎症。而在神经发育表型中，与子代小鼠在出生前这一因素相反的是，通过母体肠道微生物组的变化产生的子代IL-17A 诱导的免疫记忆（immune-primed）表型，导致子代出生后初始 CD4+ T 细胞的染色质图谱（chromatin landscape） 的改变。将IL-17A表达升高的怀孕母鼠的粪菌转移给无菌鼠，同样在子代产生了immune-primed表型。该研究从机制上解释了为什么子宫中暴露于高度炎症环境下的婴儿，除了有更高的风险导致神经发育异常外，也可能会有更高的风险发生炎症性疾病。

评语：

子宫里的健康环境对胎儿的发育十分重要。本文证明了母体里存在的炎症表型可以继承给子代，并且可能会损伤子代的神经发育和诱发炎症相关的疾病，对孕妇的健康管理有启示意义。

关键词： 

pregnancy, maternal immune activation, interleukin-17A, gut microbiota, inflammatory bowel diseases, neurodevelopmental disorders, autism spectrum disorder, colitis, Citrobacter

文章链接：

https://www.cell.com/immunity/pdf/S1074-7613(21)00496-9.pdf

Abstract

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

为了满足大脑不同发育阶段的需求，小胶质细胞不断在形态学上，表型上，以及功能上进行重新编程。He等研究了细胞代谢是否在神经发育阶段调节小胶质细胞的功能。对小胶质细胞的转录组学分析和代谢组学分析发现，IL-33信号通路被激活并伴随着吞噬活性 (phagocytic activity)。通过基因手段干扰IL-33和它的受体ST2能够导致小胶质细胞营养不良，突触功能损伤以及行为功能异常。在星形胶质细胞里条件敲除IL-33或者IL1rl1，以及在小胶质细胞里表达ST2能够增加对癫痫（Seizures）的易感性。机制上，IL-33以一种AKT依赖的方式促进了线粒体活性和吞噬活性。因此，通过IL-33-ST2-AKT信号轴介导的小胶质细胞-星形胶质细胞支持了小胶质细胞早期发育的代谢适应性和吞噬功能。这些发现对神经发育或者神经精神异常有潜在的应用价值。

To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.