() infection causes growth retardation and indigestion of silkworms (). The digestive tract is the primary infection route; thereby, in this study, we comprehensively investigated the disturbances of the digestive tract upon infection. Electron microscopy demonstrated the structure and integrity impairments of the peritrophic membrane and midgut after infection. A quantitative proteomic approach identified approximately 2,893 dysregulated proteins in the midgut after infection. Next, 16S rRNA and ITS analysis of the digestive juice and stool samples revealed that the gut microbiome profiles were significantly disturbed, such as bacterial genus , as well as eukaryotic , and so on. In addition, various digestive enzyme expressions were also disturbed upon infection. More interestingly, we found that chitin deacetylase BmCDA8, one of the top dysregulated host proteins, functioned as the key protective enzyme against since knocking down BmCDA8 leads to increased barrier permeability and higher loads. We also identified 24 . proteins that would potentially interact with BmCDA8. Taken together, our investigation will help to fully elucidate the impairing effects of on host and to identify novel pathogen control targets.IMPORTANCEThe digestive tract is the major infection route of many pathogens. A comprehensive view of the impairing effects of on 's digestive tract integrity, microbiome, and enzyme compositions is greatly needed. Therefore, we applied electron microscopy, quantitative proteomics, and microbiome analysis to clearly demonstrate that infections did impair host intestinal integrity, changed the gut microbiome composition, and dysregulated digestive enzymes. Interestingly, we found that the chitin deacetylase of exerts an essential protective role, and effector proteins may interact directly with it to facilitate the impairing effects. Our findings provide a comprehensive view and decode the phenomena of silkworm indigestion and growth retardation after infection and will provide potential targets for disease prevention and control.