Chronic stress dampens Lactobacillus johnsonii-mediated tumor suppression to enhance colorectal cancer progression.

Colorectal cancer (CRC) development and outcome are impacted by modifiable risk factors, including psychological stress. The gut microbiota has also been shown to be linked to psychological factors. Here, we found a marked deteriorative effect of chronic stress in multiple CRC models, including chemically-induced (AOM/DSS), genetically engineered (APCmin/+), and xenograft tumor mouse models. RNA-seq data from colon tissues revealed that expression of stemness-related genes was upregulated in the stressed CRC 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 CRC progression. Stressed CRC 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 CRC progression by decreasing β-catenin expression. Furthermore, PCA activated the cGMP pathway, and the cGMP agonist sildenafil abolished the effects of chronic stress on CRC. Altogether, these data identify that stress impacts the gut microbiome to support CRC progression.