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。

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.