Dietary modulation of macrophage identity: potential impact on nociceptive sensory response

虽然饮食模式可以帮助人们达到/保持良好的健康，但人们对饮食如何影响基本的细胞功能和生理能力知之甚少。由于感知疼痛对于个体适应环境和避免伤害是必不可少的，我们想了解我们吃的东西是否（以及如何）影响我们的感觉。我们提出了一项长期研究计划，以调查饮食产品对生理伤害反应的影响。***盐是多种细胞正常运作所必需的营养物质，但它具有促炎特性。在西化社会的日常生活中看到的高盐饮食（HSD）也是扰乱肠道微生物群的潜在候选人。在这项为期5年的研究计划中，我们将给健康的C57BL/6雄性和雌性小鼠喂食HSD （4% NaCl的饲料和1% NaCl的水）3个月，以研究HSD如何影响生理伤害性反应。我们将针对肠道和神经系统中的巨噬细胞（MØs）来剖析潜在的机制。我们的假设是HSD极化肠道MØs进入促炎状态，促进全身性炎症的发展，进而促进沿疼痛传递途径MØs/小胶质细胞的激活，导致疼痛敏感性增强。***目的1：通过分析肠道中MØs和MØs/小胶质细胞在疼痛传递通路上的特征，揭示饮食对MØ身份的调节***目的2：通过一系列行为测试，揭示HSD是否会改变对各种刺激的伤害性反应***目的3：***3.1消耗MØs/小胶质细胞，了解HSD诱导的痛觉性疼痛行为改变是否需要MØs的参与。***3.2将HSD应用于CCD2-/-小鼠，了解肠道MØs在饮食诱导的免疫系统和痛觉改变中的作用。由于成年期的肠道MØs完全来自CCR2介导的募集，CCR2-/-小鼠在肠道中存在相当大的缺陷MØs.***3.3用广谱抗生素破坏HSD小鼠的肠道微生物群，揭示HSD诱导的MØ身份和疼痛敏感性变化对肠道微生物群的要求。***这项研究不仅将大大提高我们对饮食生活方式如何改变生理稳态和基本功能的认识，而且还将使我们能够开拓微生物群参与感觉行为的早期阶段。

While eating patterns can help people to achieve/maintain good health, not much is known about how diet affects basic cellular function and physiological ability. As sensing pain is essential for an individual to adapt to its environment and to avoid damage, we want to understand whether (and how) what we eat affects how we feel. We propose a research program with long term objectives to investigate the impact of dietary products on physiological nociceptive response. ***Salt is an essential nutrient required for normal functioning of many types of cells, but it has pro-inflammatory properties. High salt diet (HSD) seen in daily life in westernized society is also a potential candidate disturbing the gut microbiota. In this 5-year research proposal, we will feed healthy C57BL/6 male and female mice with HSD (4% NaCl in chow and 1% NaCl in water) for 3 months to investigate how HSD affects physiological nociceptive response. We will target macrophages (MØs) in the gut and in the nervous system to dissect underlying mechanisms. Our hypothesis is that HSD polarizes gut MØs into pro-inflammatory status, contributing to the development of systemic inflammation, which in turn promotes the activation of MØs/microglia along the pain transmission pathway, leading to enhanced pain sensitivity.***Aim 1: Uncover dietary modulation of MØ identity by analyzing the features of MØs in the gut and MØs/microglia along the pain transmission pathway ***Aim 2: Reveal whether HSD alters nociceptive response to various stimuli by performing a series of behavioral tests ***Aim 3: Dissect underlying mechanisms of HSD-induced alteration in pain sensitivity by:***3.1 Depleting MØs/microglia to understand whether HSD-induced alteration in nociceptive pain behavior requires the participation of MØs.***3.2 Applying HSD to CCD2-/- mice to understand the role of gut MØs in diet-induced alteration of the immune system and nociception. Since gut MØs at adulthood are derived exclusively from CCR2-mediated recruitment and CCR2-/- mice have a considerable deficit in gut MØs.***3.3 Disrupting gut microbiota in mice under HSD with broad spectrum antibiotics to unveil the requirement of gut microbiota in HSD-induced changes in MØ identity and pain sensitivity. ***This research will not only advance significantly our knowledge on how dietary lifestyle alters physiological homeostasis and fundamental functions, but also allow us to pioneer the involvement of microbiota in sensory behavior which is at its very beginning stage.