Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial

Background: Chemotherapy-related cognitive impairment (CRCI) is highly preva-lent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the pre-ventive effects of probiotics on CRCI development and underlying mechanisms.Methods: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTRINQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats.Results: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8dien-7-ol in rats. Administration 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.Conclusion: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8dien-7-ol. Trial registration: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www. chictr.org.cn/showproj.aspx?projZ24294].(c) 2021 Elsevier Ltd. All rights reserved.