Chronic kidney disease (CKD) can cause gut microbiota dysbiosis and decreasing production of short-chain fatty acids (SCFAs), which aggravate the injury of kidney. It has been found that a variety of Chinese medicine polysaccharides can regulate gut microbiota, especially probiotics, and have beneficial effects on human health. Astragalus polysaccharide (APS) is a major component of . The aim of this study was to investigate whether APS can regulate gut microbiota-SCFAs to slow the progression of CKD. Adenine-induced CKD mice (Ade) were established and APS was treated. The renal protection of APS on CKD mice was evaluated by renal function and pathological staining of renal tissues. Feces samples were collected for 16SrRNA sequence and LC-MS/MS analysis. Kidney G protein-coupled receptor (GPR) levels were also detected in renal tissue. APS supplementation can reduce serum creatinine and urea nitrogen levels in mice model (Ade) and attenuate renal tubular interstitial injury and renal fibrosis. Further application of 16SrRNA sequencing showed that the abundance of SCFA producing bacteria, such as , , , , and , was upregulated after APS treatment. Fecal LC-MS/MS detection showed that the levels of acetate, propionate and butyrate in Ade mice increased after APS supplementation. The detection of renal GPRs showed that APS supplementing could significantly increase the levels of renal GPR41 and GPR43, and also partially increase the levels of GPR109a in Ade mice. Our research confirms that APS supplementation can upregulate the abundance of SCFA producing bacteria and increase SCFA levels to attenuate renal tubular interstitial injury and fibrosis via GPRs.