ABSTRACT

The gut microbiota is in continuous interaction with the intestinal mucosa via metabolic, neuro-immunological, and neuroendocrine pathways. Disruption in levels of antimicrobial peptides produced by the enteroendocrine cells, such as catestatin, has been associated with changes in the gut microbiota and imbalance in intestinal homeostasis. However, whether the changes in the gut microbiota have a causational role in intestinal dyshomeostasis has remained elusive. To this end, we performed reciprocal fecal microbial transplantation in wild-type mice and mice with a knockout in the catestatin coding region of the chromogranin-A gene (CST-KO mice). Combined microbiota phylogenetic profiling, RNA sequencing, and transmission electron microscopy were employed. Fecal microbiota transplantation from mice deficient in catestatin (CST-KO) to microbiota-depleted wild-type mice induced transcriptional and physiological features characteristic of a distorted colon in the recipient animals, including impairment in tight junctions, as well as an increased collagen area fraction indicating colonic fibrosis. In contrast, fecal microbiota transplantation from wild-type mice to microbiota-depleted CST-KO mice reduced collagen fibrotic area, restored disrupted tight junction morphology, and altered fatty acid metabolism in recipient CST-KO mice. This study provides a comprehensive overview of the murine metabolic- and immune-related cellular pathways and processes that are co-mediated by the fecal microbiota transplantation and supports a prominent role for the gut microbiota in the colonic distortion associated with the lack of catestatin in mice. Overall, the data show that the gut microbiota may play a causal role in the development of features of intestinal inflammation and metabolic disorders, known to be associated with altered levels of catestatin and may, thus, provide a tractable target in the treatment and prevention of these disorders.

摘要

肠道微生物群通过代谢、神经免疫和神经内分泌途径与肠粘膜持续相互作用。肠内分泌细胞产生的抗菌肽（例如儿茶素）水平的破坏与肠道微生物群的变化和肠道稳态​​失衡有关。然而，肠道微生物群的变化是否与肠道稳态失衡具有因果关系仍不清楚。为此，我们在野生型小鼠和嗜铬粒蛋白-A 基因的儿茶素编码区敲除小鼠（CST-KO 小鼠）中进行了相互粪便微生物移植。采用了微生物群系统发育分析、RNA 测序和透射电子显微镜相结合的方法。将缺乏儿联蛋白 (CST-KO) 的小鼠的粪便微生物群移植到微生物群耗尽的野生型小鼠中，可诱导受体动物出现结肠扭曲的转录和生理特征，包括紧密连接受损以及胶原蛋白面积分数增加提示结肠纤维化。相比之下，将野生型小鼠的粪便微生物移植到微生物群耗尽的 CST-KO 小鼠中，可以减少胶原纤维化面积，恢复受损的紧密连接形态，并改变受体 CST-KO 小鼠的脂肪酸代谢。这项研究全面概述了由粪便微生物群移植共同介导的小鼠代谢和免疫相关细胞途径和过程，并支持肠道微生物群在与小鼠缺乏儿联蛋白相关的结肠变形中的重要作用。 。总体而言，数据表明肠道微生物群可能在肠道炎症和代谢紊乱特征的发展中发挥因果作用，已知这些特征与儿茶素水平的改变有关，因此可能为治疗和预防肠道炎症和代谢紊乱提供了一个易于处理的目标。这些疾病。