血清素信号调节肠道微生物组成影响肠道免疫反应和结肠炎易感性。
Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis.
机构信息
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
出版信息
Cell Mol Gastroenterol Hepatol. 2019;7(4):709-728. doi: 10.1016/j.jcmgh.2019.01.004. Epub 2019 Feb 1.
BACKGROUND & AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggests the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigated the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis.
METHODS
Gut microbiota of Tph1 and Tph1 mice were investigated by deep sequencing. Direct influence of 5-HT on bacteria was assessed by using in vitro system of isolated commensals. The indirect influence of 5-HT on microbiota was assessed by measuring antimicrobial peptides, specifically β-defensins, in the colon of mice and HT-29 colonic epithelial cells. The impact of gut microbiota on the development of dextran sulfate sodium-induced colitis was assessed by transferring gut microbiota from Tph1 mice to Tph1 littermates and vice versa, as well as in germ-free mice.
RESULTS
A significant difference in microbial composition between Tph1 and Tph1 littermates was observed. 5-HT directly stimulated and inhibited the growth of commensal bacteria in vitro, exhibiting a concentration-dependent and species-specific effect. 5-HT also inhibited β-defensin production by HT-29 cells. Microbial transfer from Tph1 to Tph1 littermates and vice versa altered colitis severity, with microbiota from Tph1 mice mediating the protective effects. Furthermore, germ-free mice colonized with microbiota from Tph1 mice exhibited less severe dextran sulfate sodium-induced colitis.
CONCLUSIONS
These findings demonstrate a novel role of gut-derived 5-HT in shaping gut microbiota composition in relation to susceptibility to colitis, identifying 5-HT-microbiota axis as a potential new therapeutic target in intestinal inflammatory disorders.
背景与目的
血清素（5-羟色胺[5-HT]）主要在肠道中的肠嗜铬细胞（EC）中合成，色氨酸羟化酶 1（Tph1）是 EC 细胞中 5-HT 合成的限速酶。越来越多的证据表明肠道微生物群在肠道炎症中很重要。考虑到 EC 细胞与微生物之间的紧密接近，我们研究了肠道来源的 5-HT 对微生物群和结肠炎易感性的影响。
方法
通过深度测序研究 Tph1 和 Tph1 小鼠的肠道微生物群。使用分离共生体的体外系统评估 5-HT 对细菌的直接影响。通过测量结肠中的抗菌肽（特别是β防御素）和 HT-29 结肠上皮细胞，评估 5-HT 对微生物群的间接影响。通过将 Tph1 小鼠的肠道微生物群转移到 Tph1 同窝仔鼠中以及反之，以及在无菌小鼠中，评估肠道微生物群对葡聚糖硫酸钠诱导的结肠炎发展的影响。
结果
观察到 Tph1 和 Tph1 同窝仔鼠之间微生物组成存在显著差异。5-HT 体外直接刺激和抑制共生菌的生长，表现出浓度依赖性和物种特异性的影响。5-HT 还抑制了 HT-29 细胞的β防御素产生。从 Tph1 到 Tph1 同窝仔鼠以及反之的微生物转移改变了结肠炎的严重程度，Tph1 小鼠的微生物群介导了保护作用。此外，用 Tph1 小鼠的微生物群定植无菌小鼠导致葡聚糖硫酸钠诱导的结肠炎减轻。
结论
这些发现表明肠道来源的 5-HT 在与结肠炎易感性相关的肠道微生物群组成中发挥了新的作用，确定了 5-HT-微生物群轴作为肠道炎症性疾病的潜在新治疗靶点。
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