产生抗炎性次级胆汁酸的肠道细菌联合体对结肠炎的改善作用
Amelioration of Colitis by a Gut Bacterial Consortium Producing Anti-Inflammatory Secondary Bile Acids.
作者信息
Zhou Chunhua, Wang Ying, Li Cun, Xie Zhiyong, Dai Lei
机构信息
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus, Sun Yat-sen University, Shenzhen, China.
CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China.
出版信息
Microbiol Spectr. 2023 Mar 21;11(2):e0333022. doi: 10.1128/spectrum.03330-22.
The Integrative Human Microbiome Project and other cohort studies have indicated that inflammatory bowel disease is accompanied by dysbiosis of gut microbiota, decreased production of secondary bile acids, and increased levels of primary bile acids. Secondary bile acids, such as ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. In this study, we screened human gut bacterial strains for bile acid metabolism and designed a consortium of three species, including AP sp000509125, Bacteroides ovatus, and Eubacterium limosum, and named it BAC (bile acid consortium). We showed that the three-strain gut bacterial consortium BAC is capable of converting conjugated primary bile acids taurochenodeoxycholic acid and glycochenodeoxycholic acid to secondary bile acids UDCA and LCA . Oral gavage treatment with BAC in mice resulted in protective effects against dextran sulfate sodium (DSS)-induced colitis, including reduced weight loss and increased colon length. Furthermore, BAC treatment increased the fecal level of bile acids, including UDCA and LCA. BAC treatment enhanced intestinal barrier function, which may be attributed to the increased activation of the bile acid receptor TGR5 by secondary bile acids. Finally, we examined the remodeling of gut microbiota by BAC treatment. Taken together, the three-strain gut bacterial consortium BAC restored the dysregulated bile acid metabolism and alleviated DSS-induced colitis. Our study provides a proof-of-concept demonstration that a rationally designed bacterial consortium can reshape the metabolism of the gut microbiome to treat diseases. Secondary bile acids have been reported to be anti-inflammatory, yet it remains to be studied whether introducing selected bacteria strains to restore bile acid metabolism of the gut microbiome can alleviate intestinal inflammation. To address this gap, we designed a consortium of human gut bacterial strains based on their metabolic capacity to produce secondary bile acids UDCA and LCA, and we evaluated the efficacy of single bacterial strains and the bacterial consortium in treating the murine colitis model. We found that oral gavage of the bacterial consortium to mice restored secondary bile acid metabolism to increase levels of UDCA and LCA, which induced the activation of TGR5 to improve gut-barrier integrity and reduced the inflammation in murine colitis. Overall, our study demonstrates that rationally designed bacterial consortia can reshape the metabolism of the gut microbiome and provides novel insights into the application of live biotherapeutics for treating IBD.
综合人类微生物组计划和其他队列研究表明,炎症性肠病伴随着肠道微生物群失调、次级胆汁酸产生减少以及初级胆汁酸水平升高。据报道,次级胆汁酸,如熊去氧胆酸(UDCA)和石胆酸(LCA)具有抗炎作用,但引入特定细菌菌株以恢复肠道微生物群的胆汁酸代谢是否能减轻肠道炎症仍有待研究。在本研究中,我们筛选了用于胆汁酸代谢的人类肠道细菌菌株,并设计了一个由三种菌株组成的联合体,包括AP sp000509125、卵形拟杆菌和黏液真杆菌,并将其命名为BAC(胆汁酸联合体)。我们发现,三菌株肠道细菌联合体BAC能够将结合型初级胆汁酸牛磺鹅去氧胆酸和甘氨胆酸转化为次级胆汁酸UDCA和LCA。用BAC对小鼠进行灌胃治疗对葡聚糖硫酸钠(DSS)诱导的结肠炎产生了保护作用,包括减轻体重减轻和增加结肠长度。此外,BAC治疗增加了粪便中胆汁酸的水平,包括UDCA和LCA。BAC治疗增强了肠道屏障功能,这可能归因于次级胆汁酸对胆汁酸受体TGR5的激活增加。最后,我们研究了BAC治疗对肠道微生物群的重塑作用。综上所述,三菌株肠道细菌联合体BAC恢复了失调的胆汁酸代谢并减轻了DSS诱导的结肠炎。我们的研究提供了一个概念验证,即合理设计的细菌联合体可以重塑肠道微生物群的代谢以治疗疾病。据报道,次级胆汁酸具有抗炎作用,但引入特定细菌菌株以恢复肠道微生物群的胆汁酸代谢是否能减轻肠道炎症仍有待研究。为了填补这一空白,我们根据其产生次级胆汁酸UDCA和LCA的代谢能力设计了一个人类肠道细菌菌株联合体,并评估了单一细菌菌株和细菌联合体在治疗小鼠结肠炎模型中的疗效。我们发现,对小鼠灌胃细菌联合体可恢复次级胆汁酸代谢,增加UDCA和LCA的水平,从而激活TGR5以改善肠道屏障完整性并减轻小鼠结肠炎中的炎症。总体而言,我们的研究表明,合理设计的细菌联合体可以重塑肠道微生物群的代谢,并为活生物疗法治疗炎症性肠病的应用提供了新的见解。