结直肠癌(CRC)的发展和结果受到可改变的危险因素的影响,包括心理压力。肠道微生物群也被证明与心理因素有关。这里,我们在多个CRC模型中发现了慢性应激的显著恶化效应,包括化学诱导(AOM/DSS),基因工程(APCmin/+),和异种移植肿瘤小鼠模型。来自结肠组织的RNA-seq数据显示,在应激CRC组中,干性相关基因的表达通过激活的β-catenin信号上调,通过离体类器官分析以及体外和体内细胞致瘤性测定的结果进一步证实了这一点。肠道微生物群的16SrRNA测序显示,慢性应激破坏了肠道微生物,抗生素治疗和粪便微生物移植消除了慢性应激对CRC进展的刺激作用。强调的CRC小鼠显示出约氏乳杆菌(L.约翰逊)丰富,与肿瘤负荷呈负相关。此外,根据代谢组测序和LC-MS/MS分析,原儿茶酸(PCA)被鉴定为由L.johnsonii产生的有益代谢产物。约氏乳杆菌或PCA的补充通过降低β-catenin表达来阻断慢性应激诱导的CRC进展。此外,PCA激活了cGMP通路,cGMP激动剂西地那非消除了慢性应激对CRC的影响。总之,这些数据表明,应激影响肠道微生物组以支持CRC进展.
Colorectal cancer development and outcome are impacted by modifiable risk factors, including psychologic stress. The gut microbiota has also been shown to be linked to psychologic factors. Here, we found a marked deteriorative effect of chronic stress in multiple colorectal cancer models, including chemically induced (AOM/DSS), genetically engineered (APCmin/+), and xenograft tumor mouse models. RNA sequencing data from colon tissues revealed that expression of stemness-related genes was upregulated in the stressed colorectal cancer group by activated β-catenin signaling, which was further confirmed by results from ex vivo organoid analyses as well as in vitro and in vivo cell tumorigenicity assays. 16S rRNA sequencing of the gut microbiota showed that chronic stress disrupted gut microbes, and antibiotic treatment and fecal microbiota transplantation abolished the stimulatory effects of chronic stress on colorectal cancer progression. Stressed colorectal cancer mice displayed a significant decrease in Lactobacillus johnsonii (L. johnsonii) abundance, which was inversely correlated with tumor load. Moreover, protocatechuic acid (PCA) was identified as a beneficial metabolite produced by L. johnsonii based on metabolome sequencing and LC/MS-MS analysis. Replenishment of L. johnsonii or PCA blocked chronic stress-induced colorectal cancer progression by decreasing β-catenin expression. Furthermore, PCA activated the cGMP pathway, and the cGMP agonist sildenafil abolished the effects of chronic stress on colorectal cancer. Altogether, these data identify that stress impacts the gut microbiome to support colorectal cancer progression.
Chronic stress stimulates cancer stemness by reducing the intestinal abundance of L. johnsonii and its metabolite PCA to enhance β-catenin signaling, forming a basis for potential strategies to circumvent stress-induced cancer aggressiveness. See related commentary by McCollum and Shah, p. 645.