Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts

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 CST-KO mice to microbiota-depleted wild-type mice induced transcriptional and physiological features characteristic of a distorted colon in the recipient animals, including alterations 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 junctions morphology and altered fatty acid metabolism in recipient CST-KO mice. This study provides a comprehensive overview of mouse metabolic- and immune-related cellular pathways and processes that were 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 suggests 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.

为此，我们在野生型小鼠（wild-type mice）与嗜铬粒蛋白A（chromogranin-A）基因编码卡特斯塔汀（catestatin）的区域敲除小鼠（以下简称CST-KO小鼠）中开展了互惠性粪便微生物移植（reciprocal fecal microbial transplantation）实验。本研究采用了联合微生物组系统发育谱系分析（combined microbiota phylogenetic profiling）、RNA测序（RNA sequencing）以及透射电子显微镜（transmission electron microscopy）技术。将CST-KO小鼠的粪便微生物移植至菌群耗竭（microbiota-depleted）的野生型小鼠体内，可诱导受体小鼠出现结肠结构畸变的转录组与生理学特征，包括紧密连接（tight junctions）改变，以及提示结肠纤维化（colonic fibrosis）的胶原面积占比升高。与之相反，将野生型小鼠的粪便微生物移植至菌群耗竭的CST-KO小鼠体内，则可降低受体小鼠的胶原纤维化面积，修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（fatty acid metabolism）过程。本研究全面梳理了受粪便微生物移植共同调控的小鼠代谢与免疫相关细胞通路及生物学过程，证实肠道菌群在小鼠缺失卡特斯塔汀所介导的结肠结构异常中扮演关键角色。综上，本研究数据提示，肠道菌群或在肠道炎症与代谢紊乱的特征性发生过程中发挥因果作用——此类疾病已被证实与卡特斯塔汀水平异常相关，因此肠道菌群有望成为此类疾病防治中可干预的靶向靶点。