Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, PR China; Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, PR China.
Center for Experimental Medicine, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, PR China; Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410013, PR China.
Eur J Cancer. 2022 Jan;161:10-22. doi: 10.1016/j.ejca.2021.11.006. Epub 2021 Dec 9.
Chemotherapy-related cognitive impairment (CRCI) is highly prevalent 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 preventive effects of probiotics on CRCI development and underlying mechanisms.
We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-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.
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-1,8-dien-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.
Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8-dien-7-ol.
Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www.chictr.org.cn/showproj.aspx?proj=24294].
化疗相关认知障碍（CRCI）在癌症患者中极为普遍，与不良结局和生活质量有关。迄今为止，CRCI 的管理仍然是一个临床挑战。在此，我们旨在确定益生菌对 CRCI 发展的预防作用及其潜在机制。
我们对 159 例乳腺癌患者进行了一项随机、双盲、安慰剂对照试验（ChiCTR-INQ-17014181），并在临床前环境中进一步研究了其潜在机制。2018 年至 2019 年，筛选并招募需要辅助化疗的乳腺癌患者（I-III 期），并在化疗期间接受益生菌或安慰剂（每天三次，每次三粒）治疗。使用成熟的检测方法评估他们的认知、焦虑和抑郁；测量他们的血浆生物标志物、代谢物和粪便微生物群组成。此外，还在大鼠中评估了临床试验中发现的代谢物对长时程增强、突触损伤、氧化应激和神经胶质激活的系统影响。
益生菌补充剂显著降低了 CRCI 的发生率，改善了整体认知功能，改变了肠道微生物组成，并调节了 9 种血浆代谢物的变化。在这些代谢物中，p-薄荷-1,8-二烯-7-醇、亚油酰肉碱和 1-氨基环丙烷-1-羧酸与 CRCI 的发生呈负相关。此外，益生菌补充剂增加了大鼠血浆中的 p-薄荷-1,8-二烯-7-醇。给予外源性 p-薄荷-1,8-二烯-7-醇可显著减轻化疗引起的大鼠海马长时程增强损伤、突触损伤、氧化应激和神经胶质激活。
我们的数据表明，益生菌补充剂通过调节包括 p-薄荷-1,8-二烯-7-醇在内的血浆代谢物来预防乳腺癌患者发生 CRCI。
中国临床试验注册中心（ChiCTR-INQ-17014181）[http://www.chictr.org.cn/showproj.aspx?proj=24294]。
