BACKGROUND: Hand-foot syndrome (HFS) and oral mucositis (OM) are common adverse events during cancer chemotherapy and can significantly decrease patients' quality of life and chemotherapy adaptation, however, prevention strategies of these complications yet to be established. METHODS: Patients with stages I-III breast cancer, who had surgery and needed pegylated liposomal doxorubicin (PLD)-based adjuvant chemotherapy were screened, recruited and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) treatment during the course of chemotherapy from November 2019 to August 2020. The incidence and severity of PLD related HFS and OM, and patients' quality of life were assessed. Their plasma biomarkers, metabolites and fecal microbiota compositions were measured. And the results were further verified in animal experiments. RESULTS: Probiotics supplement during PLD treatment significantly decreased the incidence and the severity of HFS and OM ( P <
0.001), improved patients' life quality ( P <
0.001), increased the relative abundance of intestinal Enterococcus ( P = 0.025) and mitigated the changes of seven plasma metabolites. Among these metabolites, the changes of p-Mentha-1,8-dien-7-ol (MDO) ( B = - 0.441, P = 0.02) and L-arginine ( B = - 0.586, P = 0.002) were negatively correlated with the occurrence of severe HFS and OM. MDO can partly reproduce the preventive effects of probiotics on PLD-related skin cell proliferating inhibition, DNA damage, and local inflammation in rats. CONCLUSION: Probiotics supplement during PLD-based chemotherapy prevents the incidence and severity of HFS and OM, which may be associated with modulating plasma metabolites including the MDO.