Bridge of imbalance: How does the brain-gut axis act as a catalyst for gastrointestinal tumors in aging

Table 1 The influence of the neural and endocrine pathways on gastrointestinal cancers[121,122,137,209-212]

Species	Cancer	Models	Mechanism	Marker	Consequence	Ref.
GABA	Colon cancer	Sleep deprivation mouse model	Sleep deprivation can promote the expression of miR-223-3p in colon cancer cells through GABA, leading to downregulation of the E3 ligase CBLB and inhibition of c-Myc ubiquitination	GAD1, VGAT, GAT1, c-Myc protein	Sleep deprivation promote the occurrence and development of colon cancer via GABA release	Bao et al[122]
Ach	Gastric cancer	Human gastric cancer cells	Ach promotes cell proliferation and stimulates phosphorylation of ERK and AKT in gastric cancer cells	ERK, AKT, IC50	Ach acts through M3 muscarinic receptor to activate the EGFR signaling and promote gastric cancer cell proliferation	Yu et al[209]
5-HT	Colorectal cancer	Apcmin (min: Multiple intestinal neoplasia)/+ mice	5-HT promotes the occurrence and development of colorectal cancer by binding to 5-HT receptor and activating Wnt/β-catenin signaling pathway	β-catenin, TPH1, TPH2	Neurotransmitter 5-HT drives the self-renewal of colorectal CSCs and tumorigenesis	Zhu et al[121]
Norepinephrine	Gastric cancer	Chronic stress mouse model	Sympathetic neurotransmitters promote the malignant biological behaviour of GC cells by activating ADRB2	ADRB1, ADRB2	Activation of β2-adrenergic signals can promote the growth of gastric cancer xenografts under chronic stress	Zhang et al[210]
SP/NK1R	Colorectal cancer	SW480 cells model	SP exerts its oncogenic effects through NK1R activation, functioning as a critical driver of proliferation	MMP-2, MMP-9	The SP/NKR1 signaling pathway improved the colon cancer metastatic and angiogenic properties	Golestaneh et al[211]
Hypothalamic oxytocin	Colitis-associated cancer	AOM/DSS-induced CAC mouse model	Activation of OxtPVN neurons suppressed colitis-associated colorectal cancer progression through inhibition of CG-SMG neuronal activity	PCNA	Depletion of Oxt neurons promotes colorectal cancer progression	Pan et al[137]
Neurotrophin-3	HCC	HCC cells (Huh-7 and HCCLM3)	NTF3 acts as a ligand and binds to the p75NTR receptor and promotes apoptosis through the JNK and P38 MAPK pathways	NTF3, E-cadherin, N-cadherin, Ki67, p75NTR	NTF3 overexpression suppresses the proliferation of HCC cells, reduces their migration and invasion ability, increases apoptosis, and induces cycle arrest	Yang et al[212]

GABA: Gamma-aminobutyric acid; Ach: Acetylcholine; 5-HT: 5-hydroxytryptamine; SP: Substance P; NK1R: Neurokinin-1 receptor; HCC: Hepatocellular carcinoma; AOM: Azoxymethane; DSS: Dextran sulfate sodium; CAC: Colitis-associated colorectal cancer; ERK: Extracellular signal-regulated kinase; AKT: Protein kinase B; GC: Gastric cancer; Oxt: Hypothalamic oxytocin; PVN: Paraventricular nucleus; CG-SMG: Celiac-superior mesenteric ganglia; NTF3: Neurotrophin-3; JNK: C-Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; EGFR: Epidermal growth factor receptor; CSC: Cancer stem cells; GAD1: Glutamate decarboxylase 1; VGAT: Vesicular gamma-aminobutyric acid transporter; GAT1: Gamma-aminobutyric acid transporter 1; IC₅₀: Half maximal inhibitory concentration; TPH1: Tryptophan hydroxylase 1; TPH2: Tryptophan hydroxylase 2; ADRB1: Adrenergic receptor beta 1; ADRB2: Adrenergic receptor beta 2; MMP-2: Matrix metalloproteinase-2; MMP-9: Matrix metalloproteinase-9; NTF3: Neurotrophin 3; PCNA: Proliferating cell nuclear antigen; p75NTR: P75 neurotrophin receptor.

Table 2 A brain-gut axis based approach to the treatment of gastrointestinal cancer and precancerous lesions[121,213-220]

Treatment	Disease	Methods	Model	Therapies	Consequence	Mechanism	Ref.
FMT	Colorectal cancer	Mouse models of colorectal cancer were established by orthotopic, subcutaneous colorectal allotransplantation and xenotransplantation	Germ-free, CD34+ humanized mice	Stool samples for FMT were suspended in sterile PBS, given to mice by gavage	Enhance the efficacy of PD-1 therapy in colorectal cancer	Inhibit the expression of PD-1 in cancer cells, alleviate the exhaustion of CD8+ T cells, and promote the function of effector T cells	Wang et al[213]
Activate the sympathetic fibers	Colitis	DSS-induced colitis model	SPF mice	An optogenetic probe was inserted intra-rectally to transgenic mice expressing the optogenetic channel, ChR2 in TH expressing cells	Attenuate the clinical symptoms of the DSS-induced colitis and diminished immune cell abundance in the inflamed site	Reduce MAdCAM-1 expression on endothelial cells	Schiller et al[214]
ASAH1 inhibitor	Colorectal cancer	CT26 cells allogeneic transplantation-induced colorectal cancer mice model	NOD-SCID mice and BALB/c mice	Intraperitoneal injection	Compared to immunodeficient mice, silencing ASAH1 significantly reduced the final tumor volume and tumor weight	Enhance the infiltration of CD8+ T cells and M1 macrophages	Vijayan et al[215]
Oral surfactin	Colitis	DSS-induced colitis model	Kunming male mice	Mice treated with orally administered 80 mg/kg body weight surfactin per day	Oral surfactin ameliorate intestinal dysbiosis, colon and brain inflammation, and behavior disorders	Up-regulate the expression of tight junction proteins and inhibits inflammatory signaling pathways	Chen et al[216]
2’,4’-DHC	Colorectal cancer	CT26 cells allogeneic transplantation-induced colorectal cancer mice model	BALB/c mice	Mice are received 2’,4’-DHC gavage	Significantly inhibit growth of tumor	Inhibit NLRP3 inflammasome through the NF-κB pathway, increasing caspase-3/4/11 activation, enhance the anticancer immune response by regulating the infiltration and function of T cells and macrophages	Zhang et al[217]
FCT: A synbiotic combination of Lactobacillus gasseri 505 and Cudrania tricuspidata leaf extract	Colorectal cancer	AOM/DSS-induced colorectal cancer mice model	C57BL/6 mice	FCT is administered orally in the colorectal cancer mice	The FCT administration showed cancer-protective effects	Promote the expression of tight junction protein to repair colon barrier, up-regulate P53 and inhibit the apoptosis of cancer cells induced by Bcl-2	Oh et al[218]
Denervation	Gastric cancer	APC gene knockout	Apcmin (min: Multiple intestinal neoplasia)/+ k/o mice	Subdiaphragmatic vagotomy	Denervation reduce tumor incidence and progression	Inhibit the activation of the ERK1/2 signaling pathway, inflammation response, and cellular proliferation by reducing the activation of M3R and α7nAChR	Liu et al[219]
Denervation	Gastric cancer	Overexpression of gastrin produces spontaneous gastric cancer	INS-GAS mouse model	Subdiaphragmatic bilateral truncal vagotomy unilateral vagotomy, or Botox local injection	Denervation of the stomach markedly reduce tumor incidence and progression	Inhibit Wnt signaling and suppress stem cell expansion via M3 receptor	Zhao et al[220]
5-HT inhibitor	Colorectal cancer	Colorectal cancer model is established by injecting patient-derived CRC tumor cells	B-NSG mice	Mice are injected with 5-FU and methiothepin in tumor	Significantly inhibit tumor growth	Blocking 5-HT signaling pathway can inhibit the self-renewal and proliferation of colorectal cancer stem cells	Zhu et al[121]

DHC: Dihydroxychalcone; FMT: Fecal microbiota transplantation; FCT: Fimbrial cluster of type C; 5-HT: 5-hydroxytryptamine; AOM: Azoxymethane; DSS: Dextran sulfate sodium; CRC: Colorectal cancer; CD: Cluster of differentiation; SPF: Specific pathogen free; INS-GAS: Insulin-gastrin transgenic; PBS: Phosphate-buffered saline; ChR2: Channelrhodopsin-2; TH: Tyrosine hydroxylase; 5-FU: 5-Fluorouracil; PD-1: Programmed death receptor 1; MAdCAM-1: Mucosal vascular address in cell adhesion molecule-1; NF-κB: Nuclear factor kappa-B; ERK: Extracellular signal‑regulated kinase; M3R: Muscarinic acetylcholine receptor M3; α7nAChR: Alpha-7 nicotinic acetylcholine receptor.