Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Gut Microbes. 2024 Jan-Dec;16(1):2355693. doi: 10.1080/19490976.2024.2355693. Epub 2024 May 23.
Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.
化疗仍然是治疗恶性肿瘤的主要方法，但由于细胞毒性药物的副作用，尤其是在老年人群中，标准剂量强度化疗的应用受到限制。细胞毒性的潜在机制和提高化疗安全性和耐受性的策略仍有待探索。本研究以氟尿嘧啶（5-FU）这一基石化疗药物为例，发现化疗后接受 AL 喂养的小鼠的主要死亡原因是化疗引起的肠道机会性病原体易位导致的感染。我们发现，化疗后肠道内这些机会性病原体大量增加，这与肠溶菌酶的丢失密切相关。值得注意的是，化疗前两周的饮食限制（DR）显著保护了溶菌酶的丢失，并增加了有益属的含量，从而显著抑制了肠道机会性病原体及其易位。DR 的这种挽救作用可以被溶菌酶或灌胃所模拟。本研究首次提供了证据，证明 DR 实现了对肠道物理、生物和化学屏障的全面保护，显著提高了接受 5-FU 治疗的小鼠的总生存率。重要的是，上述发现对老年小鼠更为显著。此外，我们发现，65 岁以上的患者肠道微生物群中富含机会性病原体，尤其是在接受基于 5-FU 的化疗后。本研究揭示了老年人群化疗耐受性差的重要机制，通过短期 DR 可以显著改善。本研究为通过提高恶性肿瘤患者的化疗耐受性和安全性来改善化疗预后提供了新的思路。
