Table_1_Battling Enteropathogenic Clostridia: Phage Therapy for Clostridioides difficile and Clostridium perfringens.pdf

The pathogenic Clostridioides difficile and Clostridium perfringens are responsible for many health care-associated infections as well as systemic and enteric diseases. Therefore, they represent a major health threat to both humans and animals. Concerns regarding increasing antibiotic resistance (related to C. difficile and C. perfringens) have caused a surge in the pursual of novel strategies that effectively combat pathogenic infections, including those caused by both pathogenic species. The ban on antibiotic growth promoters in the poultry industry has added to the urgency of finding novel antimicrobial therapeutics for C. perfringens. These efforts have resulted in various therapeutics, of which bacteriophages (in short, phages) show much promise, as evidenced by the Eliava Phage Therapy Center in Tbilisi, Georgia (https://eptc.ge/). Bacteriophages are a type of virus that infect bacteria. In this review, the (clinical) impact of clostridium infections in intestinal diseases is recapitulated, followed by an analysis of the current knowledge and applicability of bacteriophages and phage-derived endolysins in this disease indication. Limitations of phage and phage endolysin therapy were identified and require considerations. These include phage stability in the gastrointestinal tract, influence on gut microbiota structure/function, phage resistance development, limited host range for specific pathogenic strains, phage involvement in horizontal gene transfer, and—for phage endolysins—endolysin resistance, -safety, and -immunogenicity. Methods to optimize features of these therapeutic modalities, such as mutagenesis and fusion proteins, are also addressed. The future success of phage and endolysin therapies require reliable clinical trial data for phage(-derived) products. Meanwhile, additional research efforts are essential to expand the potential of exploiting phages and their endolysins for mitigating the severe diseases caused by C. difficile and C. perfringens.

致病性艰难梭菌（Clostridioides difficile）与产气荚膜梭菌（Clostridium perfringens）可引发多种医疗相关感染，以及全身性与肠道疾病。因此，这两类病原菌对人类与动物均构成重大健康威胁。随着这两类病原菌的抗生素耐药性持续攀升，相关担忧促使学界大力探寻可有效对抗致病性感染（包括这两种病原菌引发的感染）的新型防控策略。家禽养殖业禁止使用抗生素生长促进剂的政策，进一步加剧了为产气荚膜梭菌研发新型抗菌治疗手段的紧迫性。相关研究已催生多种治疗方案，其中噬菌体（bacteriophages，简称phages）展现出极大应用前景，格鲁吉亚第比利斯的埃利亚瓦噬菌体治疗中心（Eliava Phage Therapy Center，https://eptc.ge/）便是其可行性的有力佐证。噬菌体是一类感染细菌的病毒。本综述首先概述了梭菌感染在肠道疾病中的（临床）影响，随后分析了当前学界对噬菌体及其衍生的内溶素（phage-derived endolysins）的认知水平与在该疾病适应症中的应用潜力。目前已明确噬菌体及噬菌体内溶素治疗存在若干局限，需予以重视，具体包括：噬菌体在胃肠道中的稳定性、对肠道微生物群结构/功能的影响、病原菌对噬菌体耐药性的产生、针对特定致病菌株的宿主范围受限、噬菌体参与水平基因转移（horizontal gene transfer），以及针对噬菌体内溶素而言的内溶素耐药性、安全性与免疫原性（immunogenicity）。本文还探讨了优化这类治疗手段特性的方法，例如诱变技术与融合蛋白（fusion proteins）策略。噬菌体与内溶素治疗未来的成功落地，有赖于噬菌体（衍生）产品的可靠临床试验数据支撑。与此同时，仍需开展更多研究，以充分挖掘噬菌体及其内溶素在缓解艰难梭菌与产气荚膜梭菌引发的重症疾病方面的应用潜力。