Table 1_Microbiota-derived succinic acid boosts antiviral activity of AKT targeting in coronaviruses.xlsx

IntroductionCoronavirus infection in humans may cause not only pulmonary infection but also secondary intestinal infection. The AKT inhibitors have a significant inhibitory effect on various coronavirus infections, and they can effectively alleviate the intestinal barrier damage induced by the SARS-CoV-2. However, it is unknown how the AKT inhibitors exert their anti-viral effects through the intestinal tract.
MethodsHCoV-OC43-infected mice were treated with MK-2206 or vehicle control via oral gavage. The body weight, viral load in the lungs, and pathological changes in the lung-intestine tissues were measured. Fecal samples were collected for 16S rRNA gene sequencing and non-targeted GC/LC-MS/MS metabolic profiling to determine the characteristics of the intestinal microbiota and metabolic profile.
ResultsMK-2206 treatment significantly reduced the viral load in the lungs of infected mice and the damage to the lung-intestinal tissues. The analysis of the intestinal microbiota showed that MK-2206 treatment restored the levels of the Firmicutes and Actinobacteria phyla, increased the abundance of probiotic bacteria such as Lactobacillus, and decreased the abundance of Acinetobacter and Desulfobacter. Metabolomics analysis revealed an increase in the abundance of succinic acid, and the combination of succinic acid and MK-2206 exhibited a stronger antiviral effect.
ConclusionBy integrating multi-omics methods, we discovered that succinic acid can enhance the antiviral efficacy of MK-2206, and clarified the related interactions between the intestinal microbiota and metabolites, revealing the crucial role of the intestinal microenvironment in the host’s response to MK-2206 treatment for coronavirus infection.

引言
人类冠状病毒感染不仅可引发肺部感染，还可继发肠道感染。AKT抑制剂(AKT inhibitors)对多种冠状病毒感染均具有显著抑制作用，可有效缓解新型冠状病毒（SARS-CoV-2）诱导的肠道屏障损伤。然而，AKT抑制剂如何通过肠道发挥抗病毒作用，目前尚不明确。

方法
将感染HCoV-OC43的小鼠通过灌胃给予MK-2206或赋形剂对照。记录小鼠体重，检测肺部病毒载量以及肺-肠组织的病理变化。收集粪便样本进行16S rRNA基因测序以及非靶向气相色谱/液相色谱-串联质谱（GC/LC-MS/MS）代谢组学分析，以解析肠道菌群与代谢谱特征。

结果
MK-2206处理可显著降低感染小鼠的肺部病毒载量，并减轻肺-肠组织损伤。肠道菌群分析结果显示，MK-2206处理可恢复厚壁菌门（Firmicutes）与放线菌门（Actinobacteria）的丰度水平，增加乳杆菌属（Lactobacillus）等益生菌的丰度，同时降低不动杆菌属（Acinetobacter）与脱硫杆菌属（Desulfobacter）的丰度。代谢组学分析发现，琥珀酸（succinic acid）的丰度升高；且琥珀酸与MK-2206联合使用时，展现出更强的抗病毒效果。

结论
本研究通过整合多组学方法，发现琥珀酸可增强MK-2206的抗病毒效力，并阐明了肠道菌群与代谢物之间的相关互作机制，揭示了肠道微环境在宿主应对MK-2206治疗冠状病毒感染过程中的关键作用。