Table 1_Lactobacillus reuteri-derived HDCA suppresses PEDV replication while alleviating virus-triggered inflammation in piglets.xlsx

BackgroundPorcine epidemic diarrhea virus (PEDV) causes severe diarrhea, vomiting, and high mortality in neonatal piglets, but no fully effective treatments or vaccines are currently available. Although gut microbiota transplantation can alleviate post infection symptoms, the specific protective bacterial strains or metabolites involved, along with their underlying mechanisms of action against PEDV, remain unclear.
ResultsOral administration of L. reuteri GZ-1 or its metabolite hyodeoxycholic acid (HDCA) to three-day-old piglets significantly mitigated clinical symptoms and improved survival outcomes following PEDV challenge. This protection was achieved through five-day pretreatment preceding viral exposure. Both interventions substantially preserved the intestinal architecture, maintaining normal villus height and goblet cell density while markedly reducing PEDV loads in jejunal tissue. Metabolomic profiling established HDCA—a secondary bile acid derivative of L. reuteri metabolism—as the core protective mediator. The direct antiviral activity of HDCA against PEDV was subsequently confirmed through complementary in vitro and in vivo experimental validation. Integrated transcriptomic and proteomic analyses revealed a dual mechanistic pathway underlying HDCA efficacy: (1) suppression of NF-κB-driven inflammatory cascades and (2) activation of interferon-stimulated gene 15 (ISG15)-dependent antiviral pathways.
ConclusionThis study establishes the L. reuteri-HDCA-TGR5-IFNβ-ISG15 metabolic axis as a novel antiviral pathway. This study identified microbial-derived HDCA as a key effector metabolite that mediates protection against PEDV through the coordinated suppression of inflammation and enhancement of antiviral defenses. These findings highlight microbial-metabolic crosstalk as a promising therapeutic strategy against enteric coronaviruses and provide foundational evidence for commensal-derived interventions to manage porcine epidemic diarrhea.

研究背景：猪流行性腹泻病毒（Porcine epidemic diarrhea virus, PEDV）可引发新生仔猪严重腹泻、呕吐及高死亡率，但目前尚无完全有效的治疗方案或疫苗。尽管肠道菌群移植可缓解病毒感染后的临床症状，但其所介导保护性作用的特异性菌株、代谢产物，以及抗PEDV的潜在作用机制仍未明确。研究结果：对3日龄仔猪灌服罗伊氏乳杆菌（Lactobacillus reuteri, L. reuteri）GZ-1及其代谢产物猪去氧胆酸（hyodeoxycholic acid, HDCA），可显著减轻PEDV攻毒后的临床症状并改善存活结局，且该保护效应需在病毒暴露前5天进行预处理方可实现。两种干预手段均能有效维持肠道结构完整性，保持正常的肠绒毛高度与杯状细胞密度，同时显著降低空肠组织内的PEDV载量。代谢组学分析证实，HDCA作为罗伊氏乳杆菌代谢产生的次级胆汁酸衍生物，是核心的保护性介质。后续通过体外与体内互补实验验证，进一步确认了HDCA对PEDV的直接抗病毒活性。整合转录组学与蛋白质组学分析揭示了HDCA发挥功效的双重机制通路：（1）抑制核因子κB（NF-κB）介导的炎症级联反应；（2）激活干扰素刺激基因15（interferon-stimulated gene 15, ISG15）依赖的抗病毒通路。研究结论：本研究确立了罗伊氏乳杆菌-HDCA-TGR5-IFNβ-ISG15代谢轴作为一条新型抗病毒通路。本研究鉴定出微生物来源的HDCA为关键效应代谢物，其可通过协同抑制炎症反应与增强抗病毒防御功能，介导针对PEDV的保护性作用。上述研究结果凸显了微生物-代谢串扰作为抗击肠道冠状病毒的潜在治疗策略的价值，并为利用共生菌衍生干预手段防控猪流行性腹泻提供了基础性实验证据。