Fig. 2

The mechanisms by which the gut microbiota promotes CRC metastasis by targeting seeds. (1) Promote the EMT process: F. nucleatum induces the formation and release of NETs from neutrophils by activating TLR4-ROS signaling and NLR1/2, and with consequent reduced expression of E-cadherin as well as increased expression of N-cadherin and vimentin in CRC cells captured by NETs. F. nucleatum also activates the downstream effector kinases AKT and ERK via EGFR. Fn-Dps, a novel virulence molecule produced by F. nucleatum, stimulates macrophages to secrete CCL2/7, thereby regulating the expression of related factors involved in EMT. F. nucleatum upregulates EVADR levels, which guide the RNA-binding protein YBX1 to recruit Snail, Slug, and Zeb1, to polysomes. F. Nucleatum infection decreases the level of the miR-122-5p, resulting in the overexpression of FUT8 to activate TGF-β1/Smads signaling pathway, inducing a decrease in E-cadherin levels and an increase in N-cadherin, Vimentin, Snail and Slug levels. (2) Promote the self-renewal of CSCs to enhance the stemness: F. nucleatum binds to CEACAM-1 on CSCs via CbpF to cause the dissociation of CEACAM-1 from SHP-2, triggering Wnt/β-catenin signaling. The gut microbiota metabolite IVA inhibits the enrichment of the NuRD complex on the Tph2 promoter to initiate Tph2 transcription, leading to the synthesis of 5-HT in the gut, which subsequently promotes the interaction of HTR1B/1D/1F with Axin1 to activate Wnt/β-catenin signaling. (3) a few CTCs that undergo EMT can survive the blood circulation, and these CTC subpopulations have the CSCs phenotype. Of note, treatment with metronidazole significantly reduced F. nucleatum load and inhibiting mCRC, while vancomycin is ineffective against F. nucleatum and can even increase its proportion in the intestines of healthy people, destroying the original intestinal environment. The Figure was created with BioRender.com.

Abbreviations: 5-HT, 5-hydroxytryptamine; AKT, protein kinase B; CCL, C-C motif chemokine ligand; CEACAM-1; carcinoembryonic antigen-related cell adhesion molecule 1; CRC, colorectal cancer; EGFR, epidermal growth factor receptor; CSCs, cancer stem cells; CTCs, circulating tumour cells; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; EVADR, endogenous retroviral-associated adenocarcinoma long non-coding RNA; FUT8, α1,6-Fucosyltransferase; F. nucleatum, Fusobacterium nucleatum; HTR, 5-HT receptor; IVA, isovalerate; NETs, neutrophil extracellular traps; NLR, NOD-like receptor; NuRD, nucleosome-remodeling and deacetylase; ROS, oxygen species; TGF-β1, transforming growth factor-β1; TLR4, Toll-like receptor 4; Tph2, tryptophan hydroxylase 2; YBX1, Y-box binding protein 1