Gut L-Histidine Metabolism and Histamine Signaling in Colonic Neoplasia

结肠肿瘤中的肠道 L-组氨酸代谢和组胺信号传导

基本信息

批准号：
8711382
负责人：
James Versalovic
金额：
$ 59.71万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711382
关键词：
Acute Acute Myelocytic Leukemia Affect Allergic Amino Acids Anti-Inflammatory Agents Anti-inflammatory Bacteria Bacterial Genes Bifidobacterium Biochemical Biogenic Amines Biological Biology Cell Proliferation Chemicals Chronic Colitis Colorectal Colorectal Cancer Colorectal Neoplasms Decarboxylation Development Diet Disease Disease model Disease susceptibility Elemental Diets Endowment Enzymes Gene Expression Gene Expression Profiling Generations Genes Genetic Histamine Histamine Receptor Histidine Histidine Decarboxylase Histidine Metabolism Pathway Human Human Microbiome Human body Immune response Immune system Immunity Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestinal Neoplasms Intestines Label Lactobacillus Lead Life Link MAP Kinase Signaling Pathways Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Metabolic Metabolic Pathway Metabolism Microbe Mitogen-Activated Protein Kinases Modeling Mucositis Mucous Membrane Mus Mutant Strains Mice Neoplasms Nuclear Magnetic Resonance Pathway interactions Patients Physiology Population Predisposition Production Publications Relative (related person)Risk Role Signal Pathway Signal Transduction System Testing Tracer base cancer prevention cancer risk cytokine gastrointestinal immunoregulation improved in vivo lifetime risk metabolomics microbial microbiome mouse model prevent public health relevance research study small molecule stable isotope transcriptomics tumor tumor metabolism tumor progression

项目摘要

DESCRIPTION (provided by applicant): The gastrointestinal microbiome forms a "bridge" between diet, mammalian metabolism, and immunity. Gut microbes can modulate innate and adaptive immune responses in the gut via different signaling pathways, and suppression of inflammation may alter predisposition to cancer, specifically colorectal neoplasms. Bacterial genes in the microbiome encode for enzymes that perform biochemical conversion of dietary amino acids into various microbial metabolites. We propose that amino acid metabolites derived from the human microbiome suppress neoplasia by inhibiting mucosal inflammation and cell proliferation. Based on recent findings, intestinal bacteria can convert amino acids, such as L-histidine, into biogenic amines, such as histamine, that suppress pro-inflammatory cytokine production by impeding MAP kinase signaling. Several L-histidine metabolites have demonstrated immunomodulatory effects and raise the possibility that luminal conversion by gut microbes may be an important strategy for diet-mediated cancer prevention. The overall hypothesis is that L-histidine metabolites produced by gut microbes, including but not limited to histamine, suppress chronic intestinal inflammation and inflammation-associated colonic neoplasia by regulating Stat3 and MAP kinase signaling pathways. In Aim 1, suppression of acute intestinal inflammation by L-histidine metabolites of the human gut microbiome will be explored. Bacterial strains with potent immunomodulatory and histidine-metabolizing activities have been isolated from the human microbiome. L-histidine pathways and metabolites will be explored by gene expression and metabolomics studies of gut lactobacilli. Endowment of the mouse gut microbiome with histidine-metabolizing, histamine-generating genes from the human microbiome will facilitate studies of the interplay between diet and the intestinal microbiome in vivo. In Aims 2 and 3, two different mouse models (DSS-ApcMin/+ and Hdc-/-) will be used to explore the importance of L-histidine metabolism and histamine generation in the biology of chronic intestinal inflammation and colorectal cancer. Isotopically labeled L-histidine will be deployed as a tracer to explore gut microbiome- mediated amino acid metabolism in vivo. These studies may point the way towards an improved understanding of how diet and the microbiome affect cancer risk in human populations.

描述（由申请人提供）：胃肠道微生物组在饮食，哺乳动物代谢和免疫力之间形成“桥”。肠道微生物可以通过不同的信号通路来调节肠道中的先天和适应性免疫反应，炎症的抑制可能会改变对癌症的易感性，特别是结直肠肿瘤。微生物组中的细菌基因编码将饮食氨基酸进行生化转化为各种微生物代谢产物的酶。我们提出，源自人类微生物组的氨基酸代谢产物通过抑制粘膜炎症和细胞增殖来抑制肿瘤。根据最近的发现，肠道细菌可以将氨基酸（例如L-抗二胺）转化为诸如组胺等生物胺，从而通过阻碍MAP激酶信号传导抑制促炎细胞因子的产生。几种L-杀手代谢物已表现出免疫调节作用，并提高了肠道微生物的管腔转化可能是饮食介导的预防癌症的重要策略。总体假设是，肠道微生物产生的L---------包括但不限于组胺，可通过调节STAT3和MAP激酶信号通路来抑制慢性肠炎和与炎症相关的结肠肿瘤。在AIM 1中，将探索通过L-histidine代谢物对人肠道微生物组的急性肠道炎症的抑制。具有有效的免疫调节性和组氨酸 - 代谢活性的细菌菌株已从人类微生物组中分离出来。 lut乳糖杆菌的基因表达和代谢组学研究将探索l-杀菌素途径和代谢产物。小鼠肠道微生物组的赋与人类微生物组的组胺生成基因的组氨酸生成基因将有助于研究饮食与体内肠道微生物组之间的相互作用。在目标2和3中，将使用两种不同的小鼠模型（DSS-APCMIN/+和HDC - / - ）来探索L-抗二碱代谢和组胺产生在慢性肠道炎症和结直肠癌生物学中的重要性。在体内探索肠道微生物组介导的氨基酸代谢的示踪剂将部署为l-齐丁定代谢。这些研究可能会指向人们对饮食和微生物组如何影响人群癌症风险的理解的道路。