Objective To investigate the effect of intestinal flora on the efficacy of polyethylene glycol losenatide(PEX168)in mice with type 2 diabetes mellitus(T2DM).Methods A total of 50 healthy male C57BL/6 mice were fed with a high-fat diet combined with STZ to establish a T2DM mouse model.Among them,40 were successfully modeled and divided into T2DM group(n=10)and PEX168 group(n=30).PEX168 group was further divided into two sub groups according to HbA1c:ideal group(IE subgroup,HbA1c≤6.5%,n=12)and unsatisfactory group(NE subgroup,HbA1c>6.5%,n=12).IE subgroup was fecal donor,NE subgroup was recipientand further divided into fecal bacteria transplantation subgroup(FMT,n=5)and Sham subgroup(Sham,n=5).Fecal bacteria transplantation(FMT)was used to transfer fecal bacteria from IE group to FMT group.Body weight,food intake and blood glucose were measured every 2 weeks in all the groups.FPG,FIns,HbA1c and insulin resistance index(HOMA-IR)were compared on the 7th day after 10 weeks of intervention in all the groups.Results FPG and body weight were lower at the 4th,6th,8th and 10th week(P<0.05),and food intake was lower in PEX168 group than in T2DM group at the 2nd,4th,6th,8th and 10th week(P<0.05).At the 4th,6th,8th and 10th week after administration,the FPG and body weight were lower in IE subgroup than in NE subgroup(P<0.05),and the food intake was lower at the 0th,4th,8th and 10th week after administration than in NE subgroup(P<0.05).The FBG,body weight and food intake were lower in FMT subgroup than in Sham subgroup at 4,6 and 8 weeks(P<0.05).The FPG,HbA1c,2 hPG,FIns and HOMA-IR were lowerin PEX168 group after treatment than in PEX168 group before treatment and T2DM group after treatment(P<0.05).FPG,HbA1c,FIns,2 hPG and HOMA-IR were lower in IE subgroup after treatment than in IE subgroup before treatment and NE subgroup after treatment(P<0.05).FPG,HbA1c,FIns,2 hPG and HOMA-IR were lower in FMT subgroup after treatment than in FMT subgroup before treatment and Sham subgroup after treatment(P<0.05).Conclusions Differences in intestinal flora between individuals affect the efficacy of PEX168.FMT treatment can improve the composition of intestinal flora and affect the efficacy of PEX168.