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

• 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
• 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

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之间形成“桥梁”。肠道微生物可以通过不同的信号通路调节肠道中的先天性和适应性免疫应答，并且抑制炎症可能改变癌症的易感性，特别是结肠直肠肿瘤。微生物组中的细菌基因编码将膳食氨基酸生化转化为各种微生物代谢物的酶。我们提出，来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形成。基于最近的发现，肠道细菌可以将氨基酸，如L-组氨酸，转化为生物胺，如组胺，其通过阻碍MAP激酶信号传导来抑制促炎细胞因子的产生。几种L-组氨酸代谢物已被证明具有免疫调节作用，并提出了肠道微生物的管腔转化可能是饮食介导的癌症预防的重要策略的可能性。总体假设是由肠道微生物产生的L-组氨酸代谢物，包括但不限于组胺，通过调节Stat 3和MAP激酶信号通路抑制慢性肠道炎症和炎症相关结肠肿瘤形成。在目标1中，将探索人肠道微生物组的L-组氨酸代谢物对急性肠道炎症的抑制。已从人体微生物组中分离出具有强效免疫调节和组氨酸代谢活性的细菌菌株。通过对肠道乳酸杆菌的基因表达和代谢组学研究，探索L-组氨酸的代谢途径和代谢产物。赋予小鼠肠道微生物组以来自人类微生物组的组氨酸代谢、组胺生成基因将有助于研究体内饮食与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-组氨酸代谢和组胺生成在慢性肠道炎症和结直肠癌生物学中的重要性。同位素标记的L-组氨酸将被部署为示踪剂，以探索体内肠道微生物组介导的氨基酸代谢。这些研究可能为更好地理解饮食和微生物组如何影响人类癌症风险指明了方向。