Lacticaseibacillus rhamnosus Probio-M9 enhanced the antitumor response to anti-PD-1 therapy by modulating intestinal metabolites

鼠李糖乳杆菌 免疫系统 肠道菌群 免疫疗法 益生菌 动物双歧杆菌 肿瘤微环境 生物 细胞毒性T细胞 结直肠癌 代谢组 免疫 癌症免疫疗法 癌症研究 免疫学 癌症 双歧杆菌 医学 微生物学 代谢组学 乳酸菌 体外 细菌 生物信息学 生物化学 遗传学
作者
Guangqi Gao,Siyuan Shen,Tao Zhang,Jiachao Zhang,Shi Huang,Zhihong Sun,Heping Zhang
出处
期刊:EBioMedicine [Elsevier]
卷期号:91: 104533-104533 被引量:30
标识
DOI:10.1016/j.ebiom.2023.104533
摘要

Probiotics have been increasingly proposed for enhancing immune checkpoint blockade (ICB) treatments against cancer. However, its causal relationship with immunotherapeutic efficacy remains unclear, which promoted us to explore if and how probiotic Lacticaseibacillus rhamnosus Probio-M9 manipulates gut microbiome for expected outcomes.We evaluated the effects of Probio-M9 on the anti-PD-1 treatment against colorectal cancer in mice via a multi-omics approach. We defined the mechanisms of Probio-M9-mediated antitumor immunity by comprehensive analyses of metagenome and metabolites of commensal gut microbes as well as the immunologic factors and serum metabolome of the host.The results indicated that Probio-M9 intervention strengthened the anti-PD-1-based tumor inhibition. Both prophylactic and therapeutic administration of Probio-M9 showed conspicuous performance in controlling tumor growth with ICB treatment. The supplement of Probio-M9 modulated enhanced immunotherapy response through promoting beneficial microbes (e.g., Lactobacillus and Bifidobacterium animalis), producing beneficial metabolites including butyric acids in the gut, and accumulating blood-derived α-ketoglutaric acid, N-acetyl-l-glutamic acid and pyridoxine in particular, which promoted the infiltration and activation of cytotoxic T lymphocytes (CTLs) and suppressing the function of regulatory T cells (Tregs) in the tumor microenvironment (TME). Subsequently, we found that enhanced immunotherapeutic response was transmissible by transplanting either post-probiotic-treatment gut microbes or intestinal metabolites to new tumor-bearing mice.This study offered valuable insight into the causal role of Probio-M9 in correcting the defects in gut microbiota that compromised anti-PD-1 therapeutic efficacy, which can be used as an alternative synergetic agent with ICB for clinical cancer treatment.This research was supported by Research Fund for the National Key R&D Program of China (2022YFD2100702), Inner Mongolia Science and Technology Major Projects (2021ZD0014), and China Agriculture Research System of MOF and MARA.
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