Data from Chronic Stress Dampens <i>Lactobacillus Johnsonii</i>–Mediated Tumor Suppression to Enhance Colorectal Cancer Progression

• DOI: 10.1158/0008-5472.c.7104548.v1
• Publication Date: 2024-03-04T22:24:11Z
• Authors: Qiuhua Cao; Mingrui Zhao; Yali Su; Siliang Liu; Yanting Lin; Huijuan Da; Chongxiu Yue; Yiming Liu; Dongquan Jing; Qixiang Zhao; Ning Liu; Juan Du; Zhanjie Zuo; Yao Fu; Anqi Chen; Lutz Birnbaumer; Yong Yang; Beiying Dai; Xinghua Gao

<div>Abstract<p>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 (APC^min/+), 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 <i>ex vivo</i> organoid analyses as well as <i>in vitro</i> and <i>in vivo</i> 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 <i>Lactobacillus johnsonii</i> (<i>L. johnsonii</i>) abundance, which was inversely correlated with tumor load. Moreover, protocatechuic acid (PCA) was identified as a beneficial metabolite produced by <i>L. johnsonii</i> based on metabolome sequencing and LC/MS-MS analysis. Replenishment of <i>L. johnsonii</i> 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.</p>Significance:<p>Chronic stress stimulates cancer stemness by reducing the intestinal abundance of <i>L. johnsonii</i> and its metabolite PCA to enhance β-catenin signaling, forming a basis for potential strategies to circumvent stress-induced cancer aggressiveness.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-3871" target="_blank">See related commentary by McCollum and Shah, p. 645</a></i></p></div>