Researchers have noted that organ-organ communication between bone and intestine has significant effects on bone health and its related diseases. In this study, we collected colonic epithelial tissue from dexamethasone-induced osteoporotic rats and Astragalus polysaccharide (APS)-alleviated osteoporotic rats and employed transcriptome sequencing to investigate the functional changes that occurred in the intestine. Principal component analysis showed that both dexamethasone (inducer of osteoporosis) and APS reprogrammed the gene expression profile of the intestine. Further analysis identified 496 and 291 differentially expressed genes (DEGs) in osteoporotic and APS-treated osteoporotic rats, respectively. KEGG enrichment analysis of these DEGs demonstrated osteoporosis-induced intestinal dysfunctions that were further modified by APS treatment. Further analysis demonstrated that APS could restore intestinal functions by reversing the expression of 53 DEGs in osteoporotic rats. Recovery of osteoclast differentiation and the calcium signalling pathway might contribute to the improvement of osteoporosis. Moreover, utilizing methylC-capture sequencing (MCC-Seq), we studied the changes in DNA methylation and performed epigenetic analysis of dexamethasone- and APS-induced gene expression changes. In this study, osteoporosis was observed to cause intestinal dysfunction, which is a complication of this disease. More importantly, APS was determined to reprogram intestinal functions to alleviate osteoporosis via the gut-bone axis. Our results support the existence of a gut-bone axis and suggest new therapeutic opportunities for the treatment of osteoporosis via the gut-bone axis.