Hornung Franziska, SureshKumar Harini K, Klement Laura, Reisser Yasmina, Wernike Christoph, Nischang Vivien, Jordan Paul M, Werz Oliver, Hoffmann Carsten, Löffler Bettina, Deinhardt-Emmer Stefanie
Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, Jena, Germany.
Institute of Molecular Cell biology, CMB- Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany.
Cell Commun Signal. 2025 Jul 31;23(1):359. doi: 10.1186/s12964-025-02367-w.
Alterations in the gut microbiom can significantly impact various regions in the human body, including the pulmonary tract. This study investigates alterations in the gut microbiome during a high-fat diet (HFD), particularly short-chain fatty acids (SCFAs), and how these metabolites affect lung infection caused by Influenza A virus (IAV).
We used a HFD-mouse model to evaluate gut microbiota composition, SCFA levels, and pulmonary outcomes following IAV infection. Microbial changes were analyzed via taxonomic and functional profiling and SCFA levels were measured from non-obese and obese serum donors. Ultimately, acetate's effects were tested ex vivo in human precision-cut lung slices (PCLS) and in vitro in pulmonary epithelial cells. Mechanistic studies investigated the involvement of the SCFA receptor free fatty acid receptor 2 (FFAR2) and intracellular antiviral pathways.
Our data indicates an increased Firmicutes/Bacteroidetes ratio of the gut microbiome and an altered carbohydrate metabolism, leading to reduced SCFA production. Infected HFD mice showed increased IAV titers and sustained microbial alterations. Interestingly, acetate demonstrated antiviral effects in both the human PCLS model and pulmonary cells with an reduced viral replication. These effects depended on FFAR2, which also acts as an IAV co-receptor, as acetate treatment led to FFAR2 internalization and influenced host cell metabolism in our in vitro data.
HFD alters the SCFA production, reducing acetate levels in the gut microbiome. This reduction may lead to higher viral loads and worsened disease in HFD mice infected with IAV. Our findings indicate that acetate has antiviral effects during IAV infection in both a human ex vivo lung model and pulmonary epithelial cells. Here, acetate prevents viral entry and affects the cellular metabolic state and antiviral response. Understanding these mechanisms could provide new targets for preventing and treating viral infections in individuals with diet-related health issues.
肠道微生物群的改变会对人体的各个部位产生重大影响，包括呼吸道。本研究调查了高脂饮食（HFD）期间肠道微生物群的变化，特别是短链脂肪酸（SCFA），以及这些代谢产物如何影响甲型流感病毒（IAV）引起的肺部感染。
我们使用高脂饮食小鼠模型来评估肠道微生物群组成、SCFA水平以及IAV感染后的肺部结局。通过分类学和功能分析来分析微生物变化，并从非肥胖和肥胖血清供体中测量SCFA水平。最终，在人精密切割肺切片（PCLS）中进行体外测试乙酸盐的作用，并在肺上皮细胞中进行体外测试。机制研究调查了SCFA受体游离脂肪酸受体2（FFAR2）和细胞内抗病毒途径的参与情况。
我们的数据表明，肠道微生物群的厚壁菌门与拟杆菌门的比例增加，碳水化合物代谢改变，导致SCFA产生减少。感染HFD的小鼠显示出IAV滴度增加和持续的微生物变化。有趣的是，乙酸盐在人PCLS模型和肺细胞中均显示出抗病毒作用，病毒复制减少。这些作用依赖于FFAR2，FFAR2也作为IAV的共受体，因为乙酸盐处理导致FFAR2内化，并在我们的体外数据中影响宿主细胞代谢。
高脂饮食会改变SCFA的产生，降低肠道微生物群中的乙酸盐水平。这种降低可能导致感染IAV的HFD小鼠的病毒载量更高，疾病更严重。我们的研究结果表明，乙酸盐在人离体肺模型和肺上皮细胞的IAV感染期间具有抗病毒作用。在这里，乙酸盐可防止病毒进入，并影响细胞代谢状态和抗病毒反应。了解这些机制可为预防和治疗患有饮食相关健康问题的个体的病毒感染提供新的靶点。
