Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production
Gut Microbe-Mediated Suppression of Inflammation-Associated Colon Carcinogenesis by Luminal Histamine Production
复制标题
DOI：
10.1016/j.ajpath.2017.06.011
复制
发表时间：
2017-10-01
影响因子：
6
通讯作者：
Versalovic, James
中科院分区：
文献类型：
--
作者：
Gao, Chunxu;Ganesh, Bhanu Priya;Versalovic, James
微生物组介导的致癌抑制可能为肿瘤治疗靶点的确定和预防策略开辟新的途径。组氨酸脱羧酶(HDC)缺乏通过聚集CD11b(+)Gr-1(+)未成熟髓系细胞促进炎症相关性结直肠癌的发生，表明组胺具有潜在的抗肿瘤作用。在这里，我们证明了在肠道中给予HDC(+)雷氏乳杆菌可以导致HDC(-/-)小鼠肠道内HDC基因的表达和组胺的产生。通过正电子发射断层扫描，这种产生组胺的益生菌减少了HDC(-/-)小鼠结肠肿瘤的数量和大小，并减少了对[F-18]-氟代脱氧葡萄糖的摄取。L能抑制大鼠结肠黏膜角质形成细胞趋化因子(KC)、1122、116、肿瘤坏死因子和白介素1α基因的表达，降低血浆中促炎性细胞因子、肿瘤相关细胞因子、角质形成细胞趋化因子、IL-22和IL-6的含量。组胺生成素还可减少小鼠脾CD11b(+)、Gr-1(+)未成熟髓系细胞的相对数量。此外，不能产生组胺的等位基因缺失的L突变株不能抑制致癌作用，表明组胺在抑制慢性肠炎和结直肠肿瘤发生中具有重要作用。这些发现与鲁米纳有关。肠道微生物将氨基酸转化为生物胺和益生菌介导的大肠肿瘤抑制。
Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation-associated colorectal cancer by accumulation of CD11b(+)Gr-1(+) immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc(+) Lactobacillus reuteri in the gut resulted in liminal hdc gene expression and histamine production in the intestines of Hdc(-/-) mice. This histamine-producing probiotic decreased the number and size of colon tumors and colonic uptake of [F-18]-fluorodeoxyglucose by positron emission tomography in Hdc(-/-) mice. Administration of L muted suppressed keratinocyte chemoattractant (KC), 1122, 116, Tnf, and IL1 alpha gene expression in the colonic mucosa and reduced the amounts of proinflammatory, cancer-associated cytokines, keratinocyte chemoattractant, IL-22, and IL-6, in plasma. Histamine-generating L. reuted also decreased the relative numbers of splenic CD11b(+)Gr-1(+) immature myeloid cells. Furthermore, an isogenic HDC-deficient L reuted mutant that was unable to generate histamine did not suppress carcinogenesis, indicating a significant role of the cometabolite, histamine, in suppression of chronic intestinal inflammation and colorectal tumorigenesis. These findings Link luminal. conversion of amino acids to biogenic amines by gut microbes and probiotic-mediated suppression of colorectal neoplasia.