Bacteria sensory transduction from gut to brain to modulate behavior

从肠道到大脑的细菌感觉转导来调节行为

• 批准号: 10586158
• 负责人: Diego V Bohorquez
• 金额: $ 45.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586158
• 关键词: Acute; Animals; Bacteria; Behavior; Behavior Disorders; Biological Assay; Brain; Brain Stem; Calcium; Cells; Chemicals; Clinic; Colon; Communication; Data; Desire for food; Diet; Disease; Dissociation; Eating; Electrophysiology (science); Epithelial Cells; Epithelium; Fiber; Flagellin; Foundations; Germ-Free; Goals; Human; Hyperphagia; Immune signaling; Knock-out; Knowledge; Label; Laboratories; Learning; Ligands; Link; Metabolic; Metabolic Diseases; Microbe; Modeling; Molecular; Mus; Nervous System; Neurons; Nutrient; Obesity; Organoids; Pain; Pathway interactions; Pattern; Perfusion; Positive Valence; Psyche structure; Rabies virus; Reporter; Research Project Grants; Rewards; Role; Route; Sensory; Signal Transduction; Small Intestines; Stimulus; Sweetening Agents; Synapses; System; TLR5 gene; Testing; Therapeutic; Time; Transducers; Translating; Transplantation; Vagus nerve structure; Viral; Well in self; Work; absorption; conditioned place preference; design; detection of nutrient; dietary approach; food consumption; gastrointestinal; gut bacteria; gut health; gut microbes; gut microbiota; improved; in vivo; microbial; millisecond; neural; neural circuit; neurotransmission; optogenetics; preference; rational design; receptor; reinforced behavior; response; sensory mechanism; sugar; therapeutic target

SUMMARY Gut microbes are associated with disorders of behavior, including those related to food intake and appetite. Obesity and hyperphagia can be transferred from donor to germ-free recipient mice, simply by microbial transplants. However, the correlative effects seen in mice have yet to be translated to the clinic. There is a critical need to determine how microbial signals alter host behaviors. Specifically, it is unknown how a microbial stimulus arising in the GI lumen is converted into a neural signal reinforces behavior. This gap in our knowledge is a significant problem because knowing how microbial ligands and GI sensory function interact will allow for rational design of gut-based therapies to treat disorders of food intake and promote emotional well-being. Our laboratory recently discovered a neural circuit linking the gut lumen with the brain stem in one synapse. Formed between neuropod cells and vagal neurons, this neural circuit transduces luminal stimuli to the brain in milliseconds (Kaelberer et al., 2018). Moreover, in the proximal small intestine where nutrients are abundant, this neural circuit is necessary for an animal to distinguish sugar from sweeteners (Buchanan et al., 2020). On this basis, our hypothesis is that colonic neuropod cells synapse with vagal neurons to communicate reward from bacterial stimuli. The objectives for this proposal are to define if colonic neuropod cells sense bacterial ligands, transduce bacterial signals onto vagal neurons, and modulate reward behavior. Our rationale is that by elucidating the mechanisms of bacterial sensory transduction from gut to brain, gut microbial therapeutics could be developed to treat disorders of food intake linked to diet and gut microbes.

总结 肠道微生物与行为障碍有关，包括与食物摄入和食欲有关的行为障碍。 肥胖和暴食症可以从供体转移到无菌受体小鼠，简单地通过微生物 移植然而，在小鼠中观察到的相关效应尚未转化为临床。有一个 迫切需要确定微生物信号如何改变宿主行为。具体来说，不知道一个 在胃肠道腔中产生的微生物刺激被转化为神经信号，从而加强行为。我们之间的差距 知识是一个重要的问题，因为了解微生物配体和GI感觉功能如何相互作用 将允许合理设计以肠道为基础的治疗方法，以治疗食物摄入障碍， well-being. 我们的实验室最近在一个突触中发现了连接肠腔和脑干的神经回路。 该神经回路形成于神经足细胞和迷走神经元之间，将腔刺激传递到大脑， 毫秒（Kaelberer等人，2018年）。此外，在营养丰富的近端小肠中， 该神经回路对于动物区分糖和甜味剂是必需的（Buchanan等人，2020年）。对 在此基础上，我们的假设是结肠神经足细胞与迷走神经元突触传递奖赏 细菌刺激。这项提议的目的是确定结肠神经足细胞是否能感知细菌， 配体，将细菌信号传递到迷走神经元，并调节奖励行为。 我们的理论基础是，通过阐明细菌从肠道到大脑的感觉传导机制，肠道 微生物疗法可以被开发用于治疗与饮食和肠道微生物有关的食物摄入紊乱。