Study Of The Preventive Effects And Underlying Mechanism Of Probiotics On Chemotherapy-related Cognitive Impairment

Objective:To investigate the preventive effects and underlying mechanism of probiotics on chemotherapy-related cognitive impairment（CRCI）among breast cancer patients.Methods:From May 1^st,2018 to Oct.8^th,2019,breast cancer（stage I-III）patients in the 3^rdXiangya Hospital,who needed adjuvant chemotherapy,were screened,enrolled,and randomly assigned to receive probiotics or placebo（three capsules,twice a day）during chemotherapy.The incidence of CRCI,anxiety and depression were assessed with neuropsychological test battery,self-rating anxiety scale and self-rating depression scale on the day before chemotherapy began and 21 days after the last cycle of chemotherapy.Their plasma biomarkers（blood routine,liver and kidney function,blood glucose,blood lipid）,inflammatory factors（IL-1α,IL-β,TNF-α）,blood insulin,cortisol,estradiol,metabolites,and faecal microbiota compositions were also measured before and after chemotherapy.In addition,the systemic effects of the metabolites found in the trial patients on long-term potentiation,synapse injury,oxidative stress,and glial activation were assessed in rats treated with chemotherapy drug.Results:（1）Enrollment:by screening 206 breast cancer patients,a total of 162 patients were included.159 patients completed the trial,3patients lost to follow-up.（2）General information of patients:no significant difference between the two groups was detected at age,height,weight,education,molecular subtypes,disease stages and cognitive function before chemotherapy（P>0.050,respectively）.（3）Effect on CRCI:compared with the placebo group,the incidence of CRCI in the probiotics group was significantly lower（28/80[35%]vs 64/79[81%],RR=0.43）.The allover cognitive functions significantly improved in the probiotics group including verbal（instantaneous:P=0.003;delayed:P=0.001）,visuospatial（instantaneous:P=0.001;delayed:P=0.003;interference:P<0.001）memory,visuospatial judgment（P=0.007）,and reaction ability（P<0.001）.The occurrence of CRCI was closely related to aged,low education,obesity,and the typicality of ultrasonographic features.No significant difference in the incidence of anxiety and depression between the two groups was detected（P>0.050）.（4）Effects on blood index:before chemotherapy,there was no significant difference between the two groups（P>0.050）.After chemotherapy,the blood glucose（P=0.021）and LDL（P=0.033）in the probiotic group were significantly lower than the placebo group,and no significant inter-group difference was detected in other hematological indicators（P>0.050）.（5）Effects on metabolites:during chemotherapy,the changes of p-mentha-1,8-dien-7-ol（P=0.006）,linoelaidyl carnitine（P=0.048）,1-aminocyclopropane-1-carboxylic acid（P=0.016）,1,3-diazinane-2,4-dione（P=0.022）,3,4,5-trimethoxyphenyl glucoside（P=0.007）,carnosol（P=0.009）,adamantan-1-amine（P=0.022）,phenylalanyl-tryptophan（P=0.030）,and glycylproline（P=0.012）were significantly different between the two groups.The change of linoelaidyl carnitine（P=0.012）,1-aminocyclopropane-1-carboxylic acid（P=0.033）,and p-mentha-1,8-dien-7-ol（P=0.043）were negatively correlated to the occurrence of CRCI.（6）Effects on inflammatory factors,estrogen,and glucocorticoids.There was no significant difference in the levels of plasma inflammatory factor,insulin,cortisol,and estradiol between the two groups before and after chemotherapy（P>0.050,respectively）.（7）Effects on gut microbiota:there was no significant difference on both phylum and genus level between the two groups before chemotherapy（P>0.050）.The ratio of Proteobacteria/Actinobacteria（P=0.045）,the abundance of Streptococcus（P=0.023）,Tyzzerella＿3（P=0.033）and Enterococcus（P<0.001）were significantly different between the two groups after chemotherapy.（8）Adverse events:no adverse events related to the experimental intervention were found in the two groups.（9）Animal experiment:Probiotics supplementation can prevent CRCI in rats,and increased plasma p-Mentha-1,8-dien-7-ol in rats and adminstration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment,synapse injury,oxidative stress,and glial activation in the hippocampus of rats.Conclusions:Probiotics supplement prevents the occurrence of CRCI in breast cancer patients via modulating plasma metabolites including p-Mentha-1,8-dien-7-ol.