To explore the effects of anti‐programmed death‐1 (PD‐1) therapy on advanced colorectal cancer (CRC) based on the intestinal microecology. Ninety‐two patients with advanced CRC were selected. Patients were treated with Apatinib alone or anti PD‐1 treatment combined with Apatinib. The lactulose/mannitol (L/M) value of the urine was detected by high performance liquid chromatography. The changes of intestinal microflora were determined by real‐time fluorescence quantitative PCR. The risk factors were analyzed through multivariate logistic regression analysis. The curative effect of anti PD‐1 treatment combined with the Apatinib treatment (82.61%) was much higher than that of the Apatinib treatment alone (63.04%, p < 0.05). After treatment, the contents of Bifidobacterium, Lactobacillus, and Enterococcus faecalis were higher with lower levels of Escherichia coli in the observation group than the control (p < 0.05). The level of D‐lactic acid and urinary L/M value of the urine in the observation group was lower than that in control after treatment (p < 0.001). The patients had a 3‐year survival rate of 91.30%. Age >60 years old, histological types of mucinous adenocarcinoma and signet ring cell carcinoma, vascular tumor thrombus, nerve invasion, TNM stage of Ⅲ−Ⅳ were independent risk factors, and anti PD‐1 treatment was the protective factor (p < 0.05). In advanced CRC patients receiving anti PD‐1 treatment combined with the Apatinib treatment, the progression of advanced CRC was effectively controlled by maintaining the intestinal microflora balance. Anti PD‐1 therapy can improve the living quality of CRC patients.
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