Gut L-Histidine Metabolism and Histamine Signaling in Colonic Neoplasia

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内的先天和适应性免疫反应，抑制炎症可能会改变癌症，特别是结肠直肠癌的易感性。微生物组中的细菌基因编码酶，将膳食氨基酸进行生化转化为各种微生物代谢物。我们提出来自人类微生物组的氨基酸代谢物通过抑制粘膜炎症和细胞增殖来抑制肿瘤的发生。根据最近的发现，肠道细菌可以将氨基酸（如l -组氨酸）转化为生物胺，如组胺，通过阻碍MAP激酶信号传导抑制促炎细胞因子的产生。一些l -组氨酸代谢物已显示出免疫调节作用，并提出肠道微生物的肠道转化可能是饮食介导的癌症预防的重要策略。总体假设是肠道微生物产生的l -组氨酸代谢物，包括但不限于组胺，通过调节Stat3和MAP激酶信号通路抑制慢性肠道炎症和炎症相关的结肠肿瘤。在Aim 1中，将探索人类肠道微生物组的l -组氨酸代谢物对急性肠道炎症的抑制作用。具有有效免疫调节和组氨酸代谢活性的细菌菌株已经从人类微生物组中分离出来。l -组氨酸途径和代谢物将通过肠道乳酸菌的基因表达和代谢组学研究来探索。在小鼠肠道微生物组中添加来自人类微生物组的组氨酸代谢和组胺生成基因，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Aims 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 -组氨酸将作为示踪剂用于探索肠道微生物组介导的体内氨基酸代谢。这些研究可能为更好地理解饮食和微生物群如何影响人类癌症风险指明了道路。

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.