The influence of structural violence and individual behavior and health on the gut microbiome and colorectal cancer risk

项目总结 在所有种族/民族中，非裔美国人(AAs)表现出最高的结直肠癌(CRC)发病率 和死亡率，其原因仍然鲜为人知。肠道微生物组正在成为一种重要的 宿主健康和疾病的贡献者。社会决定因素如何与个人因素相互作用 肠道微生物群的影响可能是了解结直肠癌种族/民族差异的关键。 这项研究将 确定是否暴露于 结构性暴力增加了心理社会和身体上的脆弱性(例如， 焦虑/压力)，再加上一个人的行为(例如，饮食)，它以某种方式与肠道微生物群相互作用 这导致了儿童权利公约在城市地区的健康不平等。结构性暴力指的是社会、 经济和政治制度使特定人口面临风险和脆弱性，导致 发病率和死亡率。美国人更有可能生活在城市贫困地区，这些地区充满了结构性的 暴力。长期暴露在这些社会压力下会引起不良的神经内分泌和免疫反应。 改变肠道微生物群的反应。在目标1中，我们将利用我们正在进行的200个城市AA和非 西班牙裔白人(NHW)成人(R01 CA204808)对CRC进行高风险和低风险评估：暴露于结构性 社区和个人层面的暴力；心理社会和身体健康、饮食行为、 神经内分泌和免疫标记物，以及结肠粘膜炎症。从大便和粘膜、肠道 微生物分类结构、目标微生物及其功能基因的丰度 将确定宏基因组学和目标粪便微生物代谢物。我们会确定：(1)如果 这些暴露和微生物标志物在AAS和NHW之间的分布不同；(2)如果 暴露于结构性暴力与大便及结肠粘膜微生物群和大便有关 代谢产物；以及(3)如果暴露于结构性暴力、微生物数据、神经内分泌/免疫标记物，以及 使用先进计算技术，个体饮食/健康可预测结肠炎和腺瘤 接近了。在目标2中，使用APC驱动的结肠息肉的小鼠模型，我们将在控制下模拟 在城市AA社区观察到的饮食类型和结构性暴力造成的压力。老鼠会成为 暴露于三种饮食(低动物蛋白/低饱和脂肪、高动物蛋白/低饱和脂肪)之一，或 高动物蛋白/高饱和脂肪)，有或没有暴露于间歇性攻击(模仿结构性攻击 暴力)。结肠息肉的频率、大小和严重程度，目标肠道微生物及其数量的丰度 将评估功能基因、神经内分泌/免疫标记物和结肠炎 与每个动物群体相关联。 这项研究的成功得到了一个多学科团队的支持 在微生物学、社会科学、CRC小鼠模型、胃肠病学、生物信息学、 和营养。因为肠道微生物群可以通过饮食和其他因素来重塑，从而获得 了解社会决定因素、行为和生物对肠道微生物群的复杂相互作用 有希望导致新的战略，以减少儿童权利委员会的种族差距。

PROJECT SUMMARY Among all racial/ethnic groups, African Americans (AAs) exhibit the highest colorectal cancer (CRC) incidence and mortality, for reasons that remain poorly understood. The gut microbiome is emerging as a significant contributor to host health and disease. How social determinants interacting with individual factors influence the gut microbiome may be key to understanding racial/ethnic variation in CRC. This study will establish if exposure to structural violence increases psychosocial and physical vulnerability (e.g., anxiety/stress), compounded by one's behavior (e.g., diet), which interacts with the gut microbiome in ways that result in CRC health inequality in urban AAs. Structural violence refers to the multiple ways in which social, economic, and political systems expose particular populations to risks and vulnerabilities leading to increased morbidity and mortality. AAs are more likely to live in urban poverty areas that are fraught with structural violence. Chronic exposure to these societal pressures can elicit adverse neuroendocrine and immune responses that alter the gut microbiome. In Aim 1, we will leverage our ongoing trial of 200 urban AA and non- Hispanic white (NHW) adults (R01 CA204808) at high and low risk for CRC to evaluate: exposure to structural violence at the community and individual level; psychosocial and physical health, dietary behavior, neuroendocrine and immune markers, and colonic mucosa inflammation. From stool and mucosa, gut microbial taxonomic structure, abundance of targeted microbes and their functional genes, shotgun metagenomics, and targeted stool microbial metabolites will be determined. We will ascertain: (1) if the distribution of these exposures and microbial markers differ between AAs and NHWs; (2) if the level of exposure to structural violence is associated with the stool and colonic mucosa microbiomes and stool metabolites; and (3) if exposure to structural violence, microbial data, neuroendocrine/immune markers, and individual diet/health are predictive of colonic inflammation and adenoma using advanced computing approaches. In Aim 2, using a mouse model of APC-driven colon polyps, we will mimic under controlled conditions the type of diet and stress from structural violence observed in urban AA communities. Mice will be exposed to one of three diets (low animal protein/low saturated fat, high animal protein/low saturated fat, or high animal protein/high saturated fat), with or without exposure to episodic aggression (mimicking structural violence). Frequency, size, and severity of colon polyps, abundance of targeted gut microbes and their functional genes, neuroendocrine/immune markers, and colonic inflammation will be assessed and correlated to each animal cohort. The success of this research is supported by a multidisciplinary team of scientists with expertise in microbiology, social science, CRC mouse models, gastroenterology, bioinformatics, and nutrition. Because the gut microbiome can be reshaped by diet and other factors, gaining an understanding of the complex interaction of social determinants, behavior, and biology on the gut microbiome has promise to lead to novel strategies to reduce racial disparities in CRC.