Exploring the effects of time-restricted feeding on the immune function of obese individuals: a multi-omic approach

与营养处理不平衡相关的病理状况，如肥胖，与不适应的免疫反应相关，导致对致病性感染的易感性增加。肥胖受试者的免疫系统无法对病原体做出充分反应的确切机制尚不清楚，但伴随肥胖状况的脂肪性低度慢性炎症似乎起了相关作用。值得注意的是，基于严格热量限制的饮食干预已被证明对健康产生有益影响，包括改善免疫功能。然而，长期的基于卡路里限制的干预措施通常由于依从性差而失败，这突出表明需要对患者更具吸引力但在健康益处方面同样有效的替代营养干预措施。尽管有证据支持限时喂养（TRF）饮食对肥胖个体代谢适应性的有效性，但其对免疫功能的影响仍未被探索。鉴于肥胖、营养和免疫功能之间的相互作用，勾勒出宿主对病原体的反应，OBESIMM项目的主要目标是精确定义TRF对人类肥胖个体免疫功能的影响及其如何影响其免疫能力。为此，我们将在接受TRF饮食的肥胖人群中进行一项介入性研究，并探索这种干预如何重新编程他们的免疫系统，以增强他们抵御感染性病原体的能力。我们将采用多学科方法，结合细胞学、转录组学、代谢组学、宏基因组学和系统生物学，以揭示TRF调节免疫和改善脂肪间炎症的潜在机制。我们的人体研究将与临床前肥胖模型的使用相辅相成，以直接评估TRF对宿主对脂多糖的反应的影响。此外，随着营养保健品作为改善健康习惯和增强免疫系统的补充策略的出现，肥胖的临床前模型也将用于研究基于三种具有免疫调节特性的生物活性化合物（紫光芪、b -谷甾醇和泛醇）的高可溶性和生物可利用性共晶体的多成分对宿主反应的影响。

Pathological conditions associated with unbalanced nutrient handling, such as obesity, are associated with maladapted immune responses that lead to increased susceptibility to pathogenic infections. The precise mechanisms by which the immune system of obese subjects fails to adequately respond to pathogens remain unclear, but the adipose low-grade chronic inflammation that accompanies the obese condition seems to play a relevant role. Remarkably, dietary interventions based on severe caloric restriction have proven to exert beneficial effects on health, including the improvement of the immune function. However, chronic calorie restriction-based interventions usually fail due to poor adherence, highlighting the need for alternative nutritional interventions more appealing to patients but equally effective in terms of health benefits. Despite evidence supporting the effectiveness of time-restricted feeding (TRF) diets on the metabolic fitness of obese individuals, their impact on the immune function remains unexplored. On the view of the interplay observed between obesity, nutrition and immune function that outlines the host response to pathogens, the main goal of the OBESIMM project is to precisely define the effect that TRF exerts on the immune function of human obese individuals and how it impacts their immunocompetence. For this, we will conduct an interventional study in obese human individuals who will be subjected to a TRF diet and explore how this intervention reprograms their immune system to enhance their capacity to defend from infectious pathogens. We will use a multidisciplinary approach that combines cytomics, transcriptomics, metabolomics, metagenomics and systems biology, in order to unravel potential mechanisms involved in the modulation of immunity and theimprovement of adipose meta-inflammation by TRF. Our study in humans will be complemented with the use of preclinical models of obesity to directly assess the impact that TRF has on host's response to lipopolysaccharide. In addition, in line with the emerging use of nutraceuticals as complementary strategies to improve healthy habits and boost immune system, the preclinical model of obesity will be used also to study the effects of a multi-ingredient based on high soluble and bioavailable co-crystals ofthree bioactive compounds with immunomodulatory properties (pterostilbene, B-sitosterol and ubiquinol) on the host's response.