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

Table 1 Comparative impact of gut microbiota interventions on immune regulation and colorectal cancer therapy outcomes

Intervention	Key microbes	Mechanism of action	Impact on CRC treatment
Prognostic Biomarker	Fn/Fp ratio	Fn promotes inflammation and tumorigenesis, while Fp has anti-inflammatory and protective effects; Fn/Fp ratio reflects tumor microenvironment status	Higher Fn abundance correlates with poor prognosis, while higher Fp levels associate with better outcomes; Fn/Fp ratio aids in early screening and prognosis assessment
Enhance Chemosensitivity	NaB-producing bacteria (e.g., Faecalibacterium) and NaB	NaB strengthens gut barrier function, modulates immune activity, and induces tumor cell apoptosis while inhibiting proliferation, migration, and invasion	Improves efficacy of OXA and other chemotherapies while reducing side effects
Modulate Immunotherapy Response	B. fragilis (polysaccharides), Fn (succinic acid)	(1) B. fragilis polysaccharides synergize with CTLA-4 inhibitors to activate T cells; and (2) Fn-derived succinate inhibits the cGAS-interferon-β pathway, reducing CD8+ Tcells infiltration	(1) Enhances immune checkpoint inhibitor efficacy; and (2) High Fn abundance causes anti-PD-1 resistance, reversible via antibiotics or microbiota modulation

CRC: Colorectal cancer; Fn: Fusobacterium nucleatum; Fp: Faecalibacterium; OXA: Oxaliplatin; NaB: Butyrate; CD: Cluster of differentiation; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; cGAS Cyclic: GMP-AMP synthase; PD-1: Programmed cell death protein 1; B. fragilis: Bacteroides fragilis.

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.