Both immunosuppressants and antibiotics (ABX) are indispensable for transplant patients.However,the former increases the risk of new-onset diabetes,whereas the latter impacts intestinal microbiota (IM).It is still unclear whether and how the interaction between immunosuppressants and ABX alters the IM and thus leads to glucose metabolism disorders.This study examined the alterations of glucose and lipid metabolism and IM in mice exposed to tacrolimus (TAC) with or without ABX.We found that ABX further aggravated TAC-induced glucose tolerance and increased insulin secretion.Combined treatment resulted in exacerbated lipid accumulation in the liver.TAC-altered microbial community was further amplified by ABX administration,as characterized by reductions in phylum Firmicutes,family Lachnospiraceae,and genus Coprococcus.Analyses based on the metagenomic profiles revealed that ABX augmented the effect of TAC on microbial metabolic function mostly related to lipid metabolism.The altered components of gut microbiome and predicted microbial functional profiles showed significant correlation with hepatic lipid accumulation and glucose disorders.In conclusion,ABX aggravated the effect of TAC on the microbiome and its metabolic capacities,which might contribute to hepatic lipid accumulation and glucose disorders.These findings suggest that the ABX-altered microbiome can amplify the diabetogenic effect of TAC and could be a novel therapeutic target for patients.