Harnessing oral acetate supplementation to enhance anti-tumor immunity

行政副刊摘要(膳食补充剂办公室) 几千年来，哺乳动物和它们的微生物群在食物波动或有限的时期共同进化。 可用性。因此，限制饮食摄入可能会使我们的生理状态恢复到 与我们的进化史相容。与此一致，轻微或暂时的饮食限制(DR)可以改善 健康和衰老的许多方面。来自我们和其他人的新证据表明，博士也 优化免疫反应的发展和质量。因此，我们的工作有可能揭示 对促进最佳状态的生理因素和机制有独特的基本见解 免疫反应。我们的主要目标是在设计新型癌症时利用这些机制。 免疫疗法。 来自我的实验室的新数据(由父母R00基金资助)表明，增强的免疫功能和宿主 DR期间的保护依赖于肠道微生物区系。微生物区系由数万亿的 与哺乳动物共同进化并在调节宿主生理、行为、 和豁免权。这种影响可以由微生物区系衍生的代谢物介导，例如高度 免疫调节短链脂肪酸(SCFA)。其中包括醋酸盐，它已被证明可以调节 通过代谢和表观遗传机制的免疫反应。因此，肠道微生物区系衍生的代谢物提供 饮食摄入量和免疫调节之间的关键联系。我们的初步数据显示，醋酸盐由 肠道共生双歧杆菌在DR期间对优化免疫功能和宿主保护至关重要 这一发现使我们假设，单独补充醋酸盐可以增强抗黑色素瘤的免疫反应 通过代谢和表观遗传机制。接受膳食补充剂办公室的行政 补充助学金对我们解决这个问题至关重要，并将显著提高家长助学金。 在这项建议中，我们将使用新的体内系统来直接测试补充醋酸盐是否促进 免疫细胞功能的调节：1)线粒体氧化磷酸化和2)原蛋白的表达 炎症基因。此外，我们将利用醋酸盐补充剂来优化免疫疗法 已确诊的实体肿瘤。这里描述的初步资金是通过母公司赠款获得的，以及 新提出的研究目标仍在这一母基金的范围内。总之，这项提议 有潜力促进更多地了解膳食补充剂如何有益于健康和如何使用 预防和治疗疾病。

Abstract for Administrative Supplement (The Office of Dietary Supplements) Mammals and their microbiota have co-evolved for millennia through periods of fluctuating or limited food availability. As such, restricting dietary intake could have the potential to restore our physiological state to one compatible with our evolutionary history. Consistent with this, mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. Therefore, our work has the potential to reveal unique, fundamental insights into the physiological factors and mechanisms involved in promoting optimal immune responses. Our primary goal is to harness these mechanisms in the design of novel cancer immunotherapies. New data from my laboratory (funded by parent R00 grant) indicate that enhanced immune function and host protection during DR is dependent on the gut microbiota. The microbiota is comprised of trillions of microorganisms that co-evolved with mammals and play a critical role in regulating host physiology, behavior, and immunity. Such effects can be mediated by microbiota-derived metabolites, such as the highly immunomodulatory short-chain fatty acids (SCFA). These include acetate, which has been shown to regulate immune responses via metabolic and epigenetic mechanisms. Thus, gut microbiota-derived metabolites provide a key link between dietary intake and immunoregulation. Our preliminary data suggest that acetate produced by the gut commensal Bifidobacteria is critical for optimizing immune function and host protection during DR. This finding led us to hypothesize that acetate supplementation alone will enhance anti-melanoma immune responses via metabolic and epigenetic mechanisms. To receive an Office of Dietary Supplements administrative supplement grant will be essential for us to address this question, and will significantly enhance the parent grant. In this proposal, we will use novel in vivo systems to directly test whether acetate supplementation promotes immune cell function by regulating 1) mitochondrial oxidative phosphorylation and 2) the expression of pro- inflammatory genes. Further, we will 3) harness acetate supplementation to optimize immunotherapy against established, solid tumors. The preliminary described here was acquired via funding from the parent grant, and the new proposed research objectives remains within the scope of this parent grant. Altogether, this proposal has the potential to promote a greater understanding of how dietary supplements can benefit health and be used to prevent and treat disease.