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

虽然饮食模式可以帮助人们获得/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。由于感觉疼痛对于个人适应环境和避免伤害是必不可少的，我们想要了解我们吃的东西是否(以及如何)影响我们的感觉。我们提出了一个具有长期目标的研究计划，以调查饮食产品对生理伤害性反应的影响。*盐是许多类型细胞正常运作所必需的营养物质，但它具有促炎特性。西化社会日常生活中的高盐饮食(HSD)也是扰乱肠道微生物区系的潜在候选者。在这项为期5年的研究计划中，我们将用HSD(4%的食盐和1%的水)喂养健康的C57BL/6雄性和雌性小鼠3个月，以观察HSD对生理伤害性反应的影响。我们将针对肠道和神经系统中的巨噬细胞(Ms)来剖析潜在的机制。我们的假设是，HSD将肠道ms极化为促炎状态，促进全身炎症的发展，进而促进疼痛传递途径中ms/小胶质细胞的激活。*目标1：通过分析肠道中的ms和痛觉传导途径上的ms/小胶质细胞的特征，揭示饮食对M特性的调节*目标2：通过执行一系列行为学测试，揭示HSD是否改变了对各种刺激的伤害性反应*目标3：通过以下方式剖析HSD导致痛敏改变的潜在机制：*3.1耗尽MS/小胶质细胞以了解HSD是否需要MS的参与*3.2将HSD应用于CCD2/-小鼠以了解肠道代谢综合征在饮食诱导的免疫系统和伤害性感受改变中的作用。由于成年期的肠道MS完全来自CCR2介导的募集，而CCR2-/-小鼠的肠道MS有相当大的缺陷。*3.3使用广谱抗生素扰乱HSD下小鼠的肠道微生物区系，以揭示HSD诱导的M身份和疼痛敏感性变化对肠道微生物区系的要求。*这项研究不仅将极大地提高我们对饮食生活方式如何改变生理动态平衡和基本功能的认识，而且还将使我们能够率先将微生物区系参与到感觉行为中，这一过程还处于起步阶段。

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 (Ms) in the gut and in the nervous system to dissect underlying mechanisms. Our hypothesis is that HSD polarizes gut Ms into pro-inflammatory status, contributing to the development of systemic inflammation, which in turn promotes the activation of Ms/microglia along the pain transmission pathway, leading to enhanced pain sensitivity.***Aim 1: Uncover dietary modulation of M identity by analyzing the features of Ms in the gut and Ms/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 Ms/microglia to understand whether HSD-induced alteration in nociceptive pain behavior requires the participation of Ms.***3.2 Applying HSD to CCD2-/- mice to understand the role of gut Ms in diet-induced alteration of the immune system and nociception. Since gut Ms at adulthood are derived exclusively from CCR2-mediated recruitment and CCR2-/- mice have a considerable deficit in gut Ms.***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 M 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.