Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Key Laboratory of Respiratory Diseases Research and Medical Transformation of Anhui Province, Hefei, China.
J Transl Med. 2024 Jun 15;22(1):570. doi: 10.1186/s12967-024-05376-4.
Gut microbiota (GM) have been implicated as important regulators of gastrointestinal symptom which is commonly occurred along with respiratory influenza A virus (IAV) infection, suggesting the involvement of the gut-to-lung axis in a host's response to IAV. IAV primarily destroys airway epithelium tight junctions (TJs) and consequently causes acute respiratory disease syndrome. It is known that GM and their metabolism produce an anti-influenza effect, but their role in IAV-induced airway epithelial integrity remains unknown.
A mouse model of IAV infection was established. GM were analyzed using 16S rRNA gene sequencing, and short-chain fatty acids (SCFAs) levels were measured. GM depletion and fecal microbiota transplantation (FMT) were conducted to validate the role of GM in IAV infection. A pair-feeding experiment was conducted to reveal whether IAV-induced GM dysbiosis is attributed to impaired food intake. Furthermore, human bronchial epithelial (HBE) cells were cocultured with IAV in the presence or absence of acetate. TJs function was analyzed by paracellular permeability and transepithelial electronic resistance (TEER). The mechanism of how acetate affects TJs integrity was evaluated in HBE cells transfected with G protein-coupled receptor 43 (GPR43) short hairpin RNA (shRNA).
IAV-infected mice exhibited lower relative abundance of acetate-producing bacteria (Bacteroides, Bifidobacterium, and Akkermansia) and decreased acetate levels in gut and serum. These changes were partly caused by a decrease in food consumption (due to anorexia). GM depletion exacerbated and FMT restored IAV-induced lung inflammatory injury. IAV infection suppressed expressions of TJs (occludin, ZO-1) leading to disrupted airway epithelial barrier function as evidenced by decreased TEER and increased permeability. Acetate pretreatment activated GPR43, partially restored IAV-induced airway epithelial barrier function, and reduced inflammatory cytokines levels (TNF-α, IL-6, and IL-1β). Such protective effects of acetate were absent in HBE cells transfected with GPR43 shRNA. Acetate and GPR43 improved TJs in an AMP-activated protein kinase (AMPK)-dependent manner.
Collectively, our results demonstrated that GM protected airway TJs by modulating GPR43-AMPK signaling in IAV-induced lung injury. Therefore, improving GM dysbiosis may be a potential therapeutic target for patients with IAV infection.
肠道微生物群（GM）已被认为是胃肠道症状的重要调节因子，这些症状通常与呼吸道流感 A 病毒（IAV）感染同时发生，这表明肠道-肺部轴在宿主对 IAV 的反应中起作用。IAV 主要破坏气道上皮紧密连接（TJ），从而导致急性呼吸窘迫综合征。已知 GM 及其代谢产物具有抗流感作用，但它们在 IAV 诱导的气道上皮完整性中的作用尚不清楚。
建立了 IAV 感染的小鼠模型。使用 16S rRNA 基因测序分析 GM，测量短链脂肪酸（SCFAs）水平。进行 GM 耗竭和粪便微生物群移植（FMT）以验证 GM 在 IAV 感染中的作用。进行了配对喂养实验以揭示 IAV 诱导的 GM 失调是否归因于食物摄入减少。此外，在存在或不存在乙酸的情况下，将人支气管上皮（HBE）细胞与 IAV 共培养。通过旁通透性和跨上皮电阻（TEER）分析 TJ 功能。在转染 G 蛋白偶联受体 43（GPR43）短发夹 RNA（shRNA）的 HBE 细胞中评估了乙酸影响 TJ 完整性的机制。
IAV 感染的小鼠表现出产乙酸菌（拟杆菌、双歧杆菌和阿克曼氏菌）相对丰度降低和肠道及血清中乙酸水平降低。这些变化部分是由于食欲下降导致食物摄入量减少所致。GM 耗竭加剧了并通过 FMT 恢复了 IAV 诱导的肺部炎症损伤。IAV 感染抑制 TJ 的表达（occludin，ZO-1），导致气道上皮屏障功能受损，表现为 TEER 降低和通透性增加。乙酸预处理激活 GPR43，部分恢复 IAV 诱导的气道上皮屏障功能，并降低炎症细胞因子水平（TNF-α、IL-6 和 IL-1β）。在转染了 GPR43 shRNA 的 HBE 细胞中，乙酸没有这种保护作用。乙酸和 GPR43 通过 AMP 激活蛋白激酶（AMPK）依赖性方式改善 TJ。
总的来说，我们的研究结果表明，GM 通过调节 IAV 诱导的肺损伤中的 GPR43-AMPK 信号通路来保护气道 TJ。因此，改善 GM 失调可能是 IAV 感染患者的潜在治疗靶点。
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