Eggerthella lenta disrupts the gut vascular barrier to drive colorectal cancer liver metastasis.

Abstract

Distant metastasis is the leading cause of death in colorectal cancer (CRC), and the gut vascular barrier (GVB) is the first obstacle to hematogenous spread. To investigate whether GVB function is directly influenced by metastasis-associated bacteria, we analyzed two cohorts comprising 20 healthy controls, 82 non-metastatic CRC patients, and 65 patients with liver or lung metastases. Multi-omics approaches (metagenomic sequencing and single-cell RNA sequencing) and gnotobiotic mouse models were employed to examine gut microbes that are linked to GVB disruption and metastasis. Patients with CRC liver metastasis exhibited impaired GVB and bacterial colonization at metastatic sites. Eggerthella lenta was enriched in patients with elevated expression of plasmalemmal vesicle-associated protein-1 (PV-1), a GVB injury marker, and its abundance was correlated with metastasis and recurrence. In vitro and in vivo, E. lenta compromised endothelial tight junction and GVB integrity, enhancing CRC cell migration and liver metastasis. Mechanistically, E. lenta adhered to endothelial cells and activated endoplasmic reticulum (ER) stress via a TLR4-dependent pathway, promoting autophagy and apoptosis. The knockdown of PERK attenuated ER stress, prevented autophagy and apoptosis, and downregulated the expression of ZO-1 and Claudin-5 induced by E. lenta. These findings highlight the clinical potential of microbiota-targeted strategies and PERK inhibition in the treatment of E. lenta-associated CRC metastasis.