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Microbial bile acid metabolites modulate gut ROR gamma(+) regulatory T cell homeostasis 期刊论文
NATURE, 2020, 577 (7790) : 410-+
作者:  Bhargava, Manjul
收藏  |  浏览/下载:18/0  |  提交时间:2020/07/03

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules(1). Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins(2). Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors(3,4). These receptors have pivotal roles in shaping host innate immune responses(1,5). However, the effect of this host-microorganism biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic FOXP3(+) regulatory T (T-reg) cells expressing the transcription factor ROR gamma. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this T-reg cell population. Restoration of the intestinal BA pool increases colonic ROR gamma(+) T-reg cell counts and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunological homeostasis via the resulting metabolites.


  
A metabolic pathway for bile acid dehydroxylation by the gut microbiome 期刊论文
NATURE, 2020
作者:  Zhong, Miao;  Tran, Kevin;  Min, Yimeng;  Wang, Chuanhao;  Wang, Ziyun;  Dinh, Cao-Thang;  De Luna, Phil;  Yu, Zongqian;  Rasouli, Armin Sedighian;  Brodersen, Peter;  Sun, Song;  Voznyy, Oleksandr;  Tan, Chih-Shan;  Askerka, Mikhail;  Che, Fanglin;  Liu, Min;  Seifitokaldani, Ali;  Pang, Yuanjie;  Lo, Shen-Chuan;  Ip, Alexander;  Ulissi, Zachary;  Sargent, Edward H.
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/03

The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice-an important proof-of-principle for the engineering of gut microbial pathways.


The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 mu M and are known to block the growth ofClostridium difficile(1), promote hepatocellular carcinoma(2)and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref.(3)). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids(4)  the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway intoClostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool.


  
Silicon dioxide nanoparticles have contrasting effects on the temporal dynamics of sulfonamide and beta-lactam resistance genes in soils amended with antibiotics 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2020, 15 (3)
作者:  Zhang, Xiujuan;  Li, Junjian;  Li, Dale;  Zhang, Hong;  Hu, Hangwei
收藏  |  浏览/下载:5/0  |  提交时间:2020/07/02
SiO2 nanoparticles  antibiotic resistance genes  mobile genetic element  bacterial composition  
Long-term nitrogen fertilization decreases bacterial diversity and favors the growth of Actinobacteria and Proteobacteria in agro-ecosystems across the globe 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (8) : 3452-3461
作者:  Dai, Zhongmin;  Su, Weiqin;  Chen, Huaihai;  Barberan, Albert;  Zhao, Haochun;  Yu, Mengjie;  Yu, Lu;  Brookes, Philip C.;  Schadt, Christopher W.;  Chang, Scott X.;  Xu, Jianming
收藏  |  浏览/下载:15/0  |  提交时间:2019/04/09
Actinobacteria  agro-ecosystems  bacterial diversity  community composition  microbial biomass  N fertilization