Bidirectional regulation of the gut microbiome-immune axis in the immune microenvironment of colorectal cancer and targeted interventions

Table 2 Conceptual framework of the microbiota-immune axis in colorectal cancer

Level	Key elements	Regulatory mechanisms	Intervention strategies	Translational indicators
Input layer	Microbiome	Pro-carcinogenic bacteria (e.g., Fusobacterium) activate TLR4/β-catenin - Protective bacteria (e.g., Faecalibacterium) produce NaB to strengthen barrier	Microbiome profiling (qPCR/metagenomics)	Fecal α-diversity; Fn/Fp ratio
	Host factors	Genetic mutations (e.g., APC), diet (high-fiber/high-fat), antibiotic exposure history	Risk stratification questionnaire + genetic testing	Patient subtype classification (inflammatory/metabolic)
Core interaction layer	Metabolite-immune crosstalk	SCFAs → HDAC inhibition → Treg induction - Secondary bile acids → FXR → IL-23/Th17 activation	NaB formulations; FXR antagonists	Serum NaB levels; IL-17A in colon tissue
	Cellular network	Microbial antigens → CD103+ DCs → CD8+ T cell activation - PD-1↑ → dysbiosis → MDSC recruitment	Engineered bacteria delivering DC activators (e.g., FLT3 L)	Tumor-infiltrating CD8+ T cell density; circulating MDSC levels
Effector layer	Immune phenotype	Inflamed type (high CD8+, TLS+) - Immune-desert (fibrosis, Treg-dominant)	Spatial multi-omics (CODEX/mIHC)	Immunoscore®, CT-based immune features
	Therapeutic response	Fusobacterium → oxaliplatin resistance via ABCB1 upregulation - B. fragilis → anti-PD-1 sensitization via polysaccharide-CTLA-4 interaction	Microbiome-guided personalized therapy	PFS, ORR
Intervention layer	Microbiome modulation	FMT for microbiota rebalancing - Phage therapy targeting pathogens	Donor-recipient matching; phage cocktail therapy	Post-FMT colonization rate; pathogen load reduction
	Immuno-metabolic combo	AhR inhibitors (e.g., IK-175) block IDO1-Kyn - STING agonists (e.g., ADU-S100) activate CD103+ DCs	Optimization of combination regimens (timing/dosing)	IFN-γ in tumor tissue; CXCL10 in blood
Output layer	Clinical benefit	Improved OS; reduced chemo toxicity (e.g., diarrhea)	QoL scales; CTC monitoring	5-year survival rate; grade ≥ 3 adverse event rate
	Biomarkers	Microbial signature (e.g., Clostridium cluster XIVa abundance); immune dynamics (CD8+/FoxP3+ ratio)	Liquid biopsy (ctDNA + microbial DNA)	AUC of predictive models; longitudinal consistency

Fn: Fusobacterium nucleatum; Fp: Faecalibacterium; TLR4: Toll-like receptor 4; SCFAs: Short-chain fatty acids; HDAC: Histone deacetylase; Treg: Regulatory T cells; FXR: Farnesoid X receptor; IL-23: Interleukin 23; Th17: T helper 17 cells; DCs: Dendritic cells; CD: Cluster of differentiation; PD-1: Programmed cell death protein 1; MDSCs: Myeloid-derived suppressor cells; FLT3 L: Fms-like tyrosine kinase 3 Ligand; TLS: Tertiary lymphoid structures; ABCB1: ATP-binding cassette sub-family B member 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; FMT: Fecal microbiota transplantation; AhR: Aryl hydrocarbon receptor; IDO1: Indoleamine 2:3-dioxygenase 1; Kyn: Kynurenine; STING: Stimulator of interferon genes; IFN-γ: Interferon gamma; CXCL10: C-X-C motif chemokine ligand 10; OS: Overall survival; QoL: Quality of life; CTC: Circulating tumor cells; ctDNA: Circulating tumor DNA; AUC: Area under the curve; NaB: Butyrate.