Introduction Coronavirus 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. Methods HCoV-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. Results MK-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. Conclusion By 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.
Feng et al. (Wed,) studied this question.