Saenz Carmen, Fang Qing, Gnanasekaran Thiyagarajan, Trammell Samuel Addison Jack, Buijink Jesse Arnold, Pisano Paola, Wierer Michael, Moens Frédéric, Lengger Bettina, Brejnrod Asker, Arumugam Manimozhiyan
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark.
Department of Biomedical Sciences, University of Copenhagen , Copenhagen, Denmark.
Microbiol Spectr. 2023 Sep 26;11(5):e0393322. doi: 10.1128/spectrum.03933-22.
infection (CDI) is a major health concern and one of the leading causes of hospital-acquired diarrhea in many countries. infection is challenging to treat as is resistant to multiple antibiotics. Alternative solutions are needed as conventional treatment with broad-spectrum antibiotics often leads to recurrent CDI. Recent studies have shown that specific microbiota-based therapeutics such as bile acids (BAs) are promising approaches to treat CDI. encodes the bile acid-induced () operon that carries out 7-alpha-dehydroxylation of liver-derived primary BAs to secondary BAs. This biotransformation is thought to increase the antibacterial effects of BAs on . Here, we used an automated multistage fermentor to study the antibacterial actions of and BAs on in the presence/absence of a gut microbial community derived from healthy human donor fecal microbiota. We observed that inhibited growth when the medium was supplemented with primary BAs. Transcriptomic analysis indicated upregulation of operon and suppressed expression of exotoxins that mediate CDI. We also observed BA-independent antibacterial activity of the secretome from s cultured overnight in a medium without supplementary primary BAs, which suppressed growth and exotoxin expression in mono-culture. Further investigation of the molecular basis of our observation could lead to a more specific treatment for CDI than current approaches. IMPORTANCE There is an urgent need for new approaches to replace the available treatment options against infection (CDI). Our novel work reports a bile acid-independent reduction of growth and virulence gene expression by the secretome of . This potential treatment combined with other antimicrobial strategies could facilitate the development of alternative therapies in anticipation of CDI and in turn reduce the risk of antimicrobial resistance.
艰难梭菌感染(CDI)是一个重大的健康问题,也是许多国家医院获得性腹泻的主要原因之一。由于艰难梭菌对多种抗生素耐药,其感染治疗具有挑战性。由于使用广谱抗生素的传统治疗常常导致CDI复发,因此需要替代解决方案。最近的研究表明,基于特定微生物群的疗法,如胆汁酸(BAs),是治疗CDI的有前景的方法。艰难梭菌编码胆汁酸诱导的()操纵子,该操纵子将肝脏来源的初级胆汁酸进行7-α-脱羟基化转化为次级胆汁酸。这种生物转化被认为会增加胆汁酸对艰难梭菌的抗菌作用。在这里,我们使用自动多级发酵罐,研究了在存在/不存在源自健康人类供体粪便微生物群的肠道微生物群落的情况下,艰难梭菌和胆汁酸对艰难梭菌的抗菌作用。我们观察到,当培养基中添加初级胆汁酸时,艰难梭菌抑制了艰难梭菌的生长。转录组分析表明,()操纵子上调,介导CDI的毒素外毒素表达受到抑制。我们还观察到,在没有补充初级胆汁酸的培养基中过夜培养的艰难梭菌分泌组具有不依赖胆汁酸的抗菌活性,这抑制了艰难梭菌单培养中的生长和外毒素表达。对我们观察结果的分子基础进行进一步研究,可能会带来比目前方法更具针对性的CDI治疗方法。重要性迫切需要新的方法来替代现有的针对艰难梭菌感染(CDI)的治疗选择。我们的新研究报告了艰难梭菌分泌组对艰难梭菌生长和毒力基因表达的不依赖胆汁酸的降低作用。这种潜在的治疗方法与其他抗菌策略相结合,可能有助于开发针对CDI的替代疗法,进而降低抗菌耐药性的风险。