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

项目摘要 在所有种族/族裔群体中，非裔美国人（AA）的结直肠癌（CRC）发病率最高 和死亡率，原因仍然知之甚少。肠道微生物组正在成为一个重要的 促进宿主健康和疾病。社会决定因素如何与个人因素相互作用 影响肠道微生物组可能是理解CRC种族/民族差异的关键。 本研究将 确定是否暴露于 结构性暴力增加了心理和身体的脆弱性（例如， 焦虑/压力），由一个人的行为（例如，饮食），它与肠道微生物组相互作用， 这导致了城市AA中CRC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群面临风险和脆弱性， 发病率和死亡率。AA更有可能生活在充满结构性问题的城市贫困地区。 暴力长期暴露于这些社会压力会引起不良的神经内分泌和免疫反应。 改变肠道微生物组的反应。在目标1中，我们将利用我们正在进行的200个城市AA和非AA的试验， 评价CRC高风险和低风险的西班牙裔白色（NHW）成人（R 01 CA 204808）：暴露于结构性 社区和个人层面的暴力;心理和身体健康，饮食行为， 神经内分泌和免疫标志物以及结肠粘膜炎症。从粪便和粘膜，肠道 微生物分类结构，目标微生物及其功能基因的丰度，鸟枪法 宏基因组学和靶向粪便微生物代谢物将被确定。我们将确定：（1）如果 这些暴露和微生物标志物的分布在AA和NHW之间不同;（2）如果 暴露于结构暴力与粪便和结肠粘膜微生物组和粪便 代谢物;和（3）如果暴露于结构暴力，微生物数据，神经内分泌/免疫标志物，和 使用先进计算，个人饮食/健康可预测结肠炎症和腺瘤 接近。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社区观察到的结构性暴力造成的饮食和压力的类型。小鼠将被 暴露于三种饮食之一（低动物蛋白/低饱和脂肪，高动物蛋白/低饱和脂肪，或 高动物蛋白/高饱和脂肪），有或没有暴露于偶发性攻击（模仿结构性 暴力）。结肠息肉的频率、大小和严重程度，目标肠道微生物的丰度及其 将评估功能基因、神经内分泌/免疫标志物和结肠炎症， 与每个动物队列相关。 这项研究的成功得到了多学科团队的支持， 具有微生物学、社会科学、CRC小鼠模型、胃肠病学、生物信息学专业知识的科学家， 和营养。因为肠道微生物组可以通过饮食和其他因素重塑， 了解社会决定因素，行为和生物学对肠道微生物组的复杂相互作用 有希望导致新的战略，以减少种族差异的CRC。

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.