Nature

评语：

我们知道肠道微生物通过分解产生的代谢物通过神经内分泌途径或肠-脑神经投射对大脑的发育和动物行为有重要的影响，但是其机制还没有得到明确的阐释。本文结合传统神经生物学技术和小动物影像技术对肠道微生物代谢产生的分子影响行为的神经机理展开研究，揭示了自闭症谱系障碍患者血液中异常的代谢物4EPS通过血脑屏障影响少突胶质细胞功能，损伤髓鞘形成，改变功能连接从而引起焦虑行为的机制，为神经发育障碍的情绪问题提供脑肠轴干预策略和机制研究。

Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota and gut-derived metabolites are disseminated to all organs, including the brain. In mice, the gut microbiota impacts behaviour, modulates neurotransmitter production in the gut and brain, and influences brain development and myelination patterns. The mechanisms that mediate the gut–brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte–neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

Nature neuroscience

评语：

领域内很早就发现动物会对可代谢性糖产生比人工甜味剂更强的偏好，甚至可以通过学习形成代谢驱动的糖偏好记忆。之前报道的机制解释为糖和人工甜味剂引起边缘系统不同亚区的多巴胺释放，此外也有研究揭示糖在摄入后胃肠道产生的代谢信号通过肠脑轴传到大脑从而形成对糖的偏好。本文发现了能够直接区别糖与人工甜味剂的迷走神经通路，提供了糖偏好形成的新机制。此外本文发展出肠道神经操控策略，弥补了传统光遗传硅光纤材料在肠道中易引起损伤的缺陷，打破了传统光遗传学在内脏器官使用的局限性。

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.

Molecular Psychiatry

进食是非常复杂且保守的行为，受到能量平衡和奖赏信号整合后动态信息的调控。在可口、高热量食物普遍易得的今天，食物的奖赏效应成为塑造饮食习惯的重要因素。暴食症（binge eating）就是由食物奖励功能障碍引起的摄食不受控制的疾病，但是具体的生理和分子机制并不明确。本文作者构建了新型的由可口食物引发的暴食症小鼠模型，并确定了其摄食和代谢表型。作者进一步研究发现暴食模型小鼠产生的摄食适应性由外周的内源性大麻素信号（endocannabinoids, eCBs）所介导，并且依赖于迷走神经的完整。利用选择性的外周CB1受体拮抗剂会抑制奖赏诱导暴食症的发生，改变代谢效率，并且抑制边缘系统多巴胺环路的活动。本文揭示了eCBs信号通过控制迷走神经活动，上行控制代谢稳态和奖赏环路的神经反应从而调控奖赏驱动摄食行为的机制，提示eCBs可能是干预能量平衡和食物奖赏疾病的新靶点。

评语：

目前常用的暴食症造模方式是禁食结合提供高脂食物，这与临床上暴食症的产生方式相差较远，而本文作者所采用的行为范式是限时提供高度美味的、加糖加脂的牛奶混合物，来促进食物的奖赏作用，但不限制普通饲料的摄入。这种造模方式更加符合自然条件下人类暴食症的形成过程。此外本文还揭示了食物奖赏效应通过迷走神经将肠道信息传达大脑，引起大脑活动变化从而调控摄食行为的生理机制，丰富了我们对于肠脑轴沟通塑造饮食习惯的分子机制的认知。

The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.