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

Abstract

Aging is a complex biological process regulated by multiple factors. Its characteristics include shortening of telomere length, DNA damage, abnormal secretion of cytokines, and cellular oxidative damage. These changes eventually lead to the formation of tumor cells and the remodeling of the intestinal microenvironment. The brain-gut axis is a complex bidirectional communication network connecting the intestine and the central nervous system, composed of the nervous system, immune system, microbiota and their metabolites. It allows for information exchange between the intestine and the brain, influencing the function of the digestive system and brain activity. The remodeling of the brain-gut axis function caused by aging is an important catalyst promoting the development of gastrointestinal tumors. In aging, the dysbiosis of the intestinal microbiota, abnormal release of neurotransmitters, and neuroendocrine disorders will directly affect tumor occurrence through the brain-gut axis. In addition, aging can put the gastrointestinal tract in an inflammaging state, causing dysregulation of cancer immune. At the same time, the disruption of the circadian rhythm can affect the homeostasis of the gastrointestinal tract and promote tumor development. This review will specifically explore the factors that induce gastrointestinal tumors in aging through the components of the brain-gut axis and propose new therapeutic perspectives targeting the intestinal microbiota, neurotransmitters, immune conditions, and clock rhythm.

Key Words: Brain-gut axis; Aging; Gastrointestinal tumors; Gut microbiota; Central nervous system

Core Tip: Aging remodels the brain-gut axis, creating a catalyst for gastrointestinal tumors. Key mechanisms include gut microbiota dysbiosis, neurotransmitter imbalance (e.g., 5-hydroxytryptamine, norepinephrine), neuroendocrine dysregulation, inflammaging, and circadian rhythm disruption. These factors remodel the tumor microenvironment, promote chronic inflammation, and drive tumorigenesis. Targeting the gut microbiota, neurotransmitter pathways, and circadian clocks offers emerging therapeutic strategies for aging-related gastrointestinal cancers.

INTRODUCTION

Aging is a complex process influenced by numerous factors, characterized by alterations in telomere length, DNA damage, aberrant cytokine secretion, and oxidative stress. These changes can result in the abnormal expression of cellular genetic material and the activation of senescence-associated secretory phenotype (SASP) proteins, ultimately facilitating the development of tumor cells and the remodeling of the tumor immune microenvironment[1]. Gastrointestinal cancer is a primary threat to the health of the elderly, with its onset closely linked to the aging process. For instance, gene sets associated with aging exhibit a significantly activated state in colon cancer compared to normal tissues[2]. Furthermore, chronic inflammation and immunosuppression resulting from aging may contribute to the dysfunctional gut-associated lymphoid tissue. It leads to improper recruitment of T cells in the digestive tract and the formation of the tumor immune microenvironment, thereby elevating the risk of gastrointestinal cancers[3,4].

Gastrointestinal cancers are those that occur in the digestive tract, encompassing esophageal, gastric, small intestine, and colon cancer, among others. These cancers may be associated with factors such as a high-fat diet, the composition and function of the intestinal microbiota, and host genes. For example, research has indicated that a high-fat diet can promote the development of pancreatic and hepatocellular carcinoma[5]. Changes in the intestinal microbiota are linked to host gene variations, which can impact the composition and function of the host microbiota and, consequently, the incidence of cancer[5]. Worldwide, gastrointestinal cancers account for over a quarter of all cancer cases and one-third of cancer-related deaths. Recent studies have demonstrated that the nervous system and immune system are crucial in the development, growth, apoptosis, and metastasis of cancers[6]. In recent years, research has shed light on the relationship between aging and gastrointestinal tumors, emphasizing the critical role of the brain-gut axis mechanism. Preliminary clinical studies have confirmed that the brain, gut, and microbiota engage in bidirectional interactions, collectively known as the brain-gut axis[7]. The brain-gut axis establishes a bidirectional information exchange network between brain and gut, encompassing neural communication pathways, neuroendocrine and neuroimmune pathways, as well as the gut microbiota. This interaction involves multiple mechanisms, including neural signaling, immune modulation, and the release of hormones and neurotransmitters, all of which influence human health and disease states[8-10]. Through complex neural and endocrine pathways, as well as the actions of neurotransmitters such as gamma-aminobutyric acid (GABA) and brain-derived neurotrophic factor (BDNF), the brain-gut axis plays a significant role in the proliferation, invasion, apoptosis, autophagy, and metastasis of gastrointestinal tumors[6].

Aging-induced functional remodeling of the brain-gut axis is a key factor contributing to the development of gastrointestinal tumors. Previous studies have confirmed that aging can lead to an imbalance of the gut microbiota, abnormal neuron-glia cell interaction, immune dysfunction, abnormal release of cytokines, and disruption of the gastrointestinal circadian rhythm[11-13]. Under the subsequent influence of factors leading to inflammatory senescence, oxidative stress, and abnormal cytokine secretion, intestinal microbiota, enteric nervous system (ENS) and central nervous system (CNS) becomes disordered, providing a foundation for the occurrence and development of tumors[6,14,15]. The gut microbiota is an important component of the brain-gut axis, undertaking multiple functions such as breaking down food components, synthesizing essential vitamins, activating and regulating the immune system, resisting pathogens, eliminating toxins and carcinogens, and maintaining intestinal health[3,16]. Increasing evidence indicates that many human physiological functions, including metabolism, inflammation, and immune responses, are influenced by microorganisms. For instance, gut microbiota can affect intestinal immunity through complex interactions with programmed death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade, suggesting that the gut microbiota and its metabolites are key factors in modulating the efficacy and toxicity of cancer immunotherapy[17]. Additionally, gut microbiota can produce or stimulate the production of neurotransmitters, including serotonin, dopamine, and GABA, indirectly regulating neuronal function. Moreover, gut metabolites can act on glial cells through the gut-brain axis, either directly or indirectly, influencing their function and activity[18,19]. These metabolites play significant roles in regulating neuroinflammation, intestinal barrier disruption, and neurodevelopmental disorders.

This review mainly focuses on how aging affects the brain-gut axis function and thereby becomes an important factor promoting the occurrence of gastrointestinal tumors. The imbalance of gut microbiota, the abnormal release of neurotransmitters and neurotrophic factors, and the connection between neuroendocrine and tumors will be explored. In addition, the relationship between the brain-gut axis and intestinal tumors will be deeply explained.

THE INEVITABLE LINK BETWEEN THE BRAIN-GUT AXIS AND GASTROINTESTINAL TUMORS

Composition and physiological functions of the brain-gut axis

The brain-gut axis is a complex bidirectional communication network that connects the gut and the CNS, composed of the autonomic nervous system (ANS), ENS, neuroendocrine system, hypothalamic-pituitary-adrenal (HPA) axis, immune system, and the microbiota and its metabolites[7,16]. This system enables information exchange between the gut and the brain, influencing the function of the digestive system and the activity of the brain. The intestinal barrier and the blood-brain barrier play crucial roles in the so-called “remote regulatory effect” of the brain-gut axis. The body maintains the integrity of the intestinal and blood-brain barriers to regulate the interaction between the gut microbiota and the host[17]. Gut microbiota and their metabolites can enter the bloodstream through the intestinal barrier and act on the CNS through a damaged blood-brain barrier[17,18]. Meanwhile, studies have shown that metabolites derived from the gut microbiota are important regulators of blood-brain barrier integrity. For instance, short chain fatty acids (SCFAs) or their metabolites and trimethylamine N-oxide (TMAO) can maintain the function of the blood-brain barrier by enhancing the expression of tight junction proteins, while TMAO precursor trimethylamine can damage the blood-brain barrier and the integrity of tight junctions[19]. A damaged blood-brain barrier can subsequently trigger the infiltration of peripheral immune cells and activate microglia and astrocytes, ultimately leading to the loss of synapses and neurons[20]. Additionally, studies have shown that the gut microbiota can trigger specific signaling pathways through SCFAs, arachidonic acid, and their metabolites, such as the activation of the CCAAT-enhancer-binding protein/asparagine endopeptidase pathway, thereby causing neuroinflammation[21]. Moreover, neuroinflammation caused by the gut microbiota can further lead to mental disorders, such as depression and cognitive impairment[21,22].

The core communication framework of the brain-gut axis is constituted by the ANS, ENS, and CNS through a complex neuroendocrine network[7]. The ANS serves as a bridge connecting the CNS and the gastrointestinal tract. Its sympathetic nerve branches transmit inhibitory signals (such as norepinephrine) through the spinal cord to regulate gastrointestinal blood flow and barrier function, while the parasympathetic nerve releases neurotransmitters such as acetylcholine (Ach). These neural signal directly activating ENS neurons and regulating intestinal motility, secretion, and immune responses[23]. The ENS independently regulates local digestive tract functions, such as intestinal mucosal permeability, smooth muscle contraction, and forms a bidirectional loop with the CNS through the vagus nerve and spinal cord afferent/efferent fibers. They permit the emotional states of the CNS, such as anxiety and stress, to influence gastrointestinal activity in real time[7,24]. The CNS integrates signals through the HPA axis and limbic system to regulate autonomic nerve activity and thereby shape the local microenvironment driven by the ENS[25,26]. The three systems work together to maintain gastrointestinal homeostasis through neurotransmitters, metabolic products, and epigenetic modifications mediated by the microbiota-gut-brain axis. In the field of ANS research, the vagus nerve has attracted much attention due to its role in hunger, satiety, and stress responses, and it also plays a key role in regulating inflammatory responses[27]. Additionally, some vagus nerve fibers are connected to the ENS through synapses, thereby expanding the range of information transmission[28,29]. These research results collectively reveal the possibility of communication between the gut and the brain through neural interaction, thereby influencing cognition and behavior.

The endocrine system also constitutes a key channel for communication between the gut and the CNS. There exists a complex bidirectional interaction between the gut microbiota and the neuroendocrine system, which may be achieved through multiple direct and indirect pathways, including humoral and immune pathways[25]. The connection between the brain-gut axis and the endocrine system is mainly realized through the HPA axis and enteroendocrine cells (EECs) for bidirectional regulation[30]. Metabolic products of the gut microbiota, such as SCFAs and secondary bile acids, can directly act on EECs to promote the secretion of neuropeptides (such as glucagon-like peptide-1, peptide YY) and hormones (such as serotonin)[31]. These substances influence the metabolic regulation and emotional responses of the brain through the blood circulation[31,32]. Additionally, the brain regulates intestinal function by secreting hormones such as corticotropin-releasing hormone (CRH), leading to dysbiosis of the gut microbiota, increased oxidative damage in the colon, and triggering immune responses involving mast cells, neutrophils, and monocytes[33]. Moreover, the metabolic products of the gut microbiota can regulate the expression of CRH receptors, further affecting endocrine homeostasis[34]. This complex interaction network plays a crucial role in the occurrence of metabolic diseases and tumors (Figure 1).

Figure 1 Mechanisms of bidirectional regulation of the brain-gut axis. The brain-gut axis is a bidirectional signal regulation system formed between the central nervous system and the gut through neural, endocrine and immune pathways. The gut transmits signals to the brain through the vagus nerve, metabolites such as short-chain fatty acids and hormones, while the brain regulates the intestinal function through the autonomic nervous system and hypothalamic-pituitary-adrenal axis. Both of them are involved in the regulation of appetite, mood, metabolism and immunity. In this process, intestinal flora plays a crucial role through its metabolites and immune regulation. Its imbalance is closely related to a variety of diseases, including neurodegenerative diseases, obesity, and inflammatory bowel diseases. SCFA: Short-chain fatty acid.

The remodeled brain-gut axis in aging

Aging refers to the spontaneous and inevitable degenerative process of living organisms over time, characterized by the decline of tissue structure, physiological function, adaptability and resistance, and ultimately leading to death as a natural phenomenon[35]. Its core mechanism involves the combined effect of genetic and environmental factors. In aging, the structure and function of the brain-gut axis undergo a series of changes. Firstly, the intestinal barrier function declines, which is related to the dysbiosis of the intestinal microbiota, increased inflammatory response, altered metabolic function, and decreased systemic health[35]. The intestinal mucosal layer becomes thinner, and the mucus layer becomes discontinuous, reducing the barrier effect on the intestinal epithelial cells and allowing microorganisms to come into direct contact with the epithelial cells more easily. Secondly, the disrupted intestinal barrier leads to the easy translocation of pathogen-associated molecular patterns such as lipopolysaccharide (LPS) produced by microorganisms into the circulatory system, causing chronic inflammation and dysbiosis[36,37]. Then the inflammatory signals from the intestine enter the brain through the vagus nerve or blood circulation, activating microglia and enhancing the toll-like receptor 2 (TLR2)/4 signaling pathway in the hippocampus and prefrontal cortex, exacerbating neuroinflammation and neuronal damage[38,39]. Additionally, as the repair ability of intestinal epithelial cells weakens, the functions of T cells and macrophages also decline, making it difficult to effectively eliminate invading pathogens or toxins. This results in low-level chronic inflammation accompanying the aging process and is interrelated with changes in the microbiota[37,40]. Moreover, aging is accompanied by a series of imbalances in the intestinal microbiota. In the elderly, the alpha diversity of the intestinal microbiota significantly decreases, with a reduction in beneficial bacteria (such as Bifidobacterium and Lactobacillus) and an increase in the proportion of potential pathogenic bacteria (such as Enterobacteriaceae and Clostridium)[36]. The imbalance of the intestinal microbiota leads to the overgrowth of Fusobacterium nucleatum and Enterobacter, which produce endotoxins and carcinogenic metabolites, inducing chronic intestinal inflammation. In the end, the long-term stimulation can activate the inflammatory system and induce cell gene mutations.

Aging not only affects multiple systems of the body but also may lead to the disorder of neurotransmitters and brain-gut axis signaling. During the aging process, changes in the ENS are particularly significant, manifested as a reduction in the size of ganglia, the density of neurons, and an increase in the proportion of ganglionic cavities[41]. For instance, in the colon of mice, the nerve cell bodies of 24-month-old mice are approximately 20% larger than those of 3-month-old mice[42]. In the enteric plexus of the mouse colon, the density of nerve fibers increased significantly with age. Even after correction for intestinal growth and traction, there was swelling of nerve fibers within the ganglion, bundles of nerve fibers between the interganglia, areas adjacent to the ganglion, and nerve fibers between the ganglion plane[43]. In addition, swelling and degenerative changes in tyrosine hydroxylase or calcitonin gene-related peptide (CGRP)-positive axons and terminals are observed in the ileum of aged mice[44]. Additionally, aging reduces the synthesis capacity of 5-hydroxytryptamine (5-HT) in the intestine and disrupts the function of the vagus nerve-HPA axis[45]. At the same time, the reduction of SCFAs and other microbial metabolites weakens their regulatory effects on enterochromaffin cells and CNS, ultimately leading to fragmented sleep, cognitive decline, and mood disorders[9,37]. These neurotransmitter imbalances caused by aging can activate 5-HT receptors in the intestinal mucosa and stimulate abnormal proliferation of epithelial cells[8,46]. For example, patients with colon cancer often have overexpression of nerve growth factor (NGF) released by enteric glial cells, which accelerates cancer invasion[47].

In aging, the instantaneous communication between the gut and the brain may be disrupted, which is often accompanied by dysregulation of the HPA axis and abnormal stress responses, as well as reduced efficiency of vagus nerve signal transmission[38]. Studies have shown that the increased permeability of the blood-brain barrier due to aging allows inflammatory factors to penetrate into the hippocampus and prefrontal cortex. It not only inhibits neurogenesis but also promotes the activation of microglia, ultimately leading to the decline of spatial memory and cognitive dysfunction[38,42]. Meanwhile, the reduction of metabolites produced by intestinal microbiota further weakens the energy supply of neurons and the plasticity of synapses. This can lead to an imbalance of neurotransmitters in the gastrointestinal tract, such as serotonin synthesis, which can exacerbate mood disorders and sleep disturbances, creating a vicious cycle that accelerates aging[30,32]. Recent studies have also revealed that this dysregulation of the microbiota-gut-brain axis affects the occurrence of gastrointestinal tumors through mechanisms such as the loss of autophagy function, abnormal intercellular communication, and disruption of circadian rhythms (Figure 2).

Figure 2 Pathological changes of the brain-gut axis in aging. Aging can lead to alterations in the homeostasis of the gastrointestinal tract. For instance, aging can cause impaired intestinal barrier function, dysbiosis, and weakened immune surveillance, resulting in the entry of bacterial endotoxins into the bloodstream, systemic inflammatory responses, and oxidative stress. At the local level in the intestine, abnormal proliferation of epithelial cells accompanied by weakened repair capacity, along with a reduction in the number and density of neurons in the enteric nervous system, collectively form the pathological basis for the imbalance of intestinal homeostasis. Additionally, there is abnormal function of immune cells in the gastrointestinal tract and a decline in the immune surveillance function of the intestinal epithelium. These changes are mediated through the immune-neuro-endocrine network and are closely associated with various diseases. ENS: Enteric nervous system.

The brain-gut axis is involved in the gastrointestinal tumor microenvironment

Gastrointestinal cancers, including esophageal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, and other epithelial tumors as well as non-epithelial malignant tumors originating in the digestive system. The combined incidence and mortality rates of these cancers have exceeded half of the total for all cancers, ranking first among malignant tumors. With the continuous deepening of research, it has been found that gastrointestinal tumors are related to multiple aspects of diseases in the immune system, endocrine system, and nervous system[48-50]. Studies have shown that patients with gastrointestinal tumors often develop concurrent depression, dementia, and neurological diseases after treatment. Firstly, gastrointestinal tumors affect the CNS through the brain-gut axis system, causing related neurological symptoms. For instance, a meta-analysis study found that the prevalence of depression among global and regional gastric cancer patients was significantly increased[51]. Additionally, the probability of developing dementia among gastric cancer and rectal cancer patients after treatment is significantly higher than that of the general population[52]. Although these symptoms may be related to the patients’ psychological state, side effects of chemotherapy drugs, or brain metastasis of the tumor, with the continuous exploration of the brain-gut axis concept, the interaction between gastrointestinal cancers and the brain-gut axis has been confirmed to be associated with the occurrence of these symptoms[53]. The brain-gut axis, through a bidirectional regulatory network composed of the CNS, ENS, ANS, and neuroendocrine components, dynamically interacts with microenvironmental elements such as the gut microbiota, immune cells, and intestinal epithelium, jointly driving the occurrence and development of gastrointestinal tumors. Firstly, the brain-gut axis mediates bidirectional signal transmission through anatomical neural pathways and neuroendocrine pathways, regulating key biological behaviors of tumors. The activation or inactivation of the central and gastrointestinal nervous systems, as well as the dynamic changes of neurotransmitters and neurotrophic factors, can directly promote the proliferation, migration, invasion, angiogenesis and apoptosis resistance of gastrointestinal cancer cells[6,54].

In the process, gastrointestinal cancer cells release neurotrophic factors that attract neurons to migrate towards the cancer tissue and enhance the uptake of neurotransmitters, thereby promoting cancer cells progression[55]. Additionally, the innervation of the vagus nerve promotes cancer progression through the muscarinic mechanism and regulates immune function[56]. The nervous system can also regulate downstream factors to indirectly modulate the intestinal microbiota and immune function, thereby promoting tumor progression. For instance, studies have shown that chronic stress leads to the activation of the HPA axis, releasing glucocorticoids, which promote regulatory T cell infiltration and suppress natural killer cell activity through glucocorticoid receptors, thereby exacerbating immune escape in liver cancers[54,57].

Additionally, the brain-gut axis regulates changes in the tumor microenvironment (TME). The TME primarily refers to the local environment surrounding tumor cells and plays a vital role in tumor development, progression, and treatment response. It is composed of three main cell types: Cancer-associated fibroblasts, vascular cells, and infiltrating immune cells, most of which express receptors for norepinephrine, Ach, and various neuropeptides[58,59]. Cancer-associated fibroblasts are key components of TME that provide structural support to epithelial cells and regulate cancer progression by either promoting or inhibiting tumor development based on the surrounding environment[60]. The latest research indicates that the nervous system and the endocrine system can interact dynamically with the gut microbiota, forming a multi-level and systematic regulatory network, which in turn affects the TME. Firstly, neurotransmitters influence the stress response through the brain-gut axis, thereby regulating the composition of the intestinal microbiota; their metabolic products, such as SCFAs, tryptophan, and bile acids, can enter the circulation and act on the brain, forming a feedback loop[61]. These gut microbiota-derived metabolites can also directly affect the differentiation and function of immune cells in the TME of gastrointestinal tumors, regulate immune escape, and influence an individual’s response to immune checkpoint inhibitors[62,63].

In addition, the neural signals mediated by the ANS can reshape the TME. The unique anatomical structure of the ENS promotes the interaction among neurons, immune cells, intestinal microbiota, and other components. These complex interactions jointly regulate the proliferation, survival, and invasion behaviors of gastrointestinal cancer cells. Further studies found that the dynamic interaction between cancer cells and TME not only alters the intestinal microenvironment, but also remodels the brain-gut axis. This alteration leads to the recruitment, activation, and reprogramming of immune cells and stromal cells in the extracellular space, creating favorable conditions for the growth of cancer cells[64,65]. It is generally believed that the immunosuppressive effect of the TME is achieved by directly inhibiting effector cells or increasing the number of regulatory T cells[66]. Granulocytes, lymphocytes, and macrophages are involved in various immune responses related to tumorigenesis, such as inflammation in tumor tissues, thereby promoting the survival of tumor cells[64]. In addition, studies have shown that sympathetic innervation in the ANS can promote the development of the TME, thereby driving cancer progression and being associated with stress-induced cancer behaviors[67]. The ANS regulates the TME through multiple pathways, influencing tumor growth, metastasis, and immune responses. For example, the β-adrenergic signaling pathway can prompt immune cells to secrete interleukin (IL)-6 and IL-8, enhance the recruitment of macrophages to the tumor parenchyma, while inhibiting the transcription of type I and type II interferons. In addition, it can weaken the cytotoxic function of T lymphocytes and natural killer cells, and ultimately promoting the invasiveness and metastasis of tumors[68-70].

Overall, research on the intestinal microbiota is shifting from associative studies to causal and mechanistic studies. Mechanistic studies will assess how microorganisms, through metabolites, affect immune problems in the gut, cause abnormal cell death, and induce genetic mutations. Future research will focus on better understanding the mechanisms by which tumor-resident microbiota (TRM) contributes to tumor initiation, progression, and metastasis. Research in this area will help develop microbiome-based therapeutic approaches and potentially identify new molecules/pathways to enhance anti-tumor responses.

MECHANISMS BY WHICH THE BRAIN-GUT AXIS LEADS TO CANCER IN AGING

The role of gut microbiota in gastrointestinal cancers

The gut is one of the most complex networks in the body, colonized by trillions of microorganisms, including bacteria, archaea, fungi, protists, and viruses, with bacteria being the predominant inhabitants. The gut microbiota not only plays a crucial role in maintaining the immune system and metabolic functions but is also closely related to the development, progression, and immune escape of cancer cells[8]. The gastrointestinal tract is the main habitat of the human symbiotic microbiota, and the interaction between the host and these microbial communities has become a key factor influencing tumor development and the response to various gastrointestinal cancer treatments[71]. The microbiota and their associated metabolites are not only closely related to the carcinogenic process induced by inflammation and immune dysregulation leading to genetic instability but also interfere with the pharmacodynamics of anti-cancer drugs (Figure 3)[72]. For instance, Fusobacterium nucleatum promotes M2 macrophage polarization and colon cancer progression by activating the IL-6/phosphorylated-signal transducer and activator of transcription-3 (STAT3)/c-Myc and TLR4/nuclear factor kappa-B (NF-κB)/S100A9 signaling pathways, while beneficial bacteria such as Bifidobacterium can inhibit tumor growth and enhance the efficacy of immunotherapy[73,74]. Among them, Fusobacterium nucleatum can activate NF-κB through outer membrane proteins fusobacterium adhesin A (FadA), glucan-binding protein or Fusobacterium nucleatum DNA-binding protein from starved cells, promoting tumor cell proliferation, migration and the release of inflammatory factors[75,76]. Its metabolite 3-indolepropionic acid activates the aryl hydrocarbon receptor of macrophages, inducing M2 polarization and immunosuppression, and accelerating tumor progression[77]. In addition, Fusobacterium nucleatum activates cancer-associated fibroblasts through the TLR2/yes-associated protein (YAP)/connective tissue growth factor (CTGF) signal, inducing YAP nuclear translocation and CTGF expression, and remodeling the TME[78]. Fusobacterium nucleatum can also induce ferroptosis in intestinal cells, disrupt tight junction proteins, aggravate ulcerative colitis and promote carcinogenesis[79].

Figure 3 The brain-gut axis system regulates gastrointestinal tumors through multiple pathways. The gut microbiota and its metabolic products can have dual effects. For instance, short-chain fatty acids can enhance c-Myc-mediated programmed cell death ligand 1 expression to promote immune escape of tumor cells and increase their glycolysis. Meanwhile, short-chain fatty acids can also promote ferroptosis of tumor cells and enhance the killing function of immune cells against tumors through the mammalian target of rapamycin signaling pathway. Additionally, specific microbial metabolites, such as indoleacrylic acid, can upregulate ALDH1A3 and increase nicotinamide adenine dinucleotide production by activating the aryl hydrocarbon receptor pathway, thereby supporting the ferroptosis suppressor protein 1 defense system and activating the glutathione and glutathione peroxidase 4 axis, which inhibits tumor ferroptosis. Moreover, the tumor microenvironment is also regulated by neural and neurotrophic signals. Neurotransmitters such as norepinephrine, serotonin, and acetylcholine can also be involved in tumor metastasis and invasion, while neurotrophic factors brain-derived neurotrophic factor, neurotrophin (NT)-3, and NT-4 act through tropomyosin receptor kinase A and tropomyosin receptor kinase C receptors to activate downstream pathways including phosphatidylinositol 3-kinase, Ras, and phospholipase C, thereby influencing the development of cancer. GPX4: Glutathione peroxidase 4; FSP1: Ferroptosis suppressor protein 1; CNS: Central nervous system; NADH: Nicotinamide adenine dinucleotide; IDA: Indoleacrylic acid; AHR: Aryl hydrocarbon receptor; SCFA: Short-chain fatty acid; mTORC1: Mammalian target of rapamycin complex 1; CD: Cluster of differentiation; DC: Dendritic cells; PD-1: Programmed death receptor 1; GLUT1: Glucose transporter 1; BDNF: Brain-derived neurotrophic factor; PI3K: Phosphatidylinositol 3-kinase; TrkA: Tropomyosin receptor kinase A; TrkC: Tropomyosin receptor kinase C; PLC: Phospholipase C; NT: Neurotrophin.

Elevated levels of Streptococcus anginosus and Streptococcus constellatus in the feces of gastric cancer patients have emerged as novel biomarkers[80]. Clostridium butyricum can inhibit the development of colon cancer by regulating the Wnt signaling pathway and the gut microbiota[81]. Recent studies have also found that the Wnt/β-catenin pathway activated by Helicobacter hepaticus can promote abnormal proliferation of hepatic stellate cells, while its metabolites trigger the formation of neutrophil extracellular traps, accelerating tumor metastasis[82]. Additionally, the long non-coding RNA BFAL1 produced by Bacteroides fragilis promotes the proliferation of colon cancer cells through mammalian target of rapamycin (mTOR) signaling, and Fusobacterium nucleatum enhances the migration ability of tumor cells by secreting the FadA adhesin and activating the IL-8/CXCR1 axis[82-84].

At present, the most closely related aspect of microorganisms to tumor occurrence is the effect of their metabolic products, mainly including causing gene mutations, regulating the TME influencing immune function, affecting neurotransmitters and neuroendocrine, and the ferroptosis mechanism. Studies have confirmed that bacterial metabolic products can directly damage DNA or affect the methylation of tumor suppressor genes, thereby promoting tumor occurrence[85,86]. TRM is a component of the TME and can influence tumor growth, distant metastasis, and response to treatment by interfering with molecular pathways of tumor cells and other components of the TME[87]. In the intestinal environment, TRM directly affects tumor occurrence through their metabolic products and the inflammatory responses they trigger. For example, TRM species communicate with immune cells through pattern recognition receptors and regulate immune function through microbial metabolites. TRM can influence the infiltration of immune cells, such as cytotoxic cluster of differentiation (CD) 8⁺ T cells, macrophages, and natural killer cells, thereby regulating the response of tumors to chemotherapy and immunotherapy[88-90]. Additionally, the microbiota can also regulate the immune microenvironment of tumors through interaction with the host immune system. This regulatory mechanism will promote tumor immune escape and inflammatory responses, and thereby affecting tumor growth and treatment outcomes[91]. The metabolic products of the intestinal microbiota, such as SCFAs, have been widely studied in regulating the tumor immune microenvironment. SCFAs are secondary metabolites produced by intestinal microorganisms, including acetic acid, propionic acid, and butyric acid, etc. They serve as energy sources in colon cells and exert immunomodulatory effects by regulating the production, migration, and epigenetic regulation of cytokines in immune system cells such as T cells, neutrophils, and macrophages[92]. Moreover, SCFAs can directly activate G protein-coupled receptors (GPRs), inhibit histone deacetylases, and act as energy substrates to connect dietary patterns and the intestinal microbiota, thereby improving intestinal health. The role of SCFAs in the TME is a double-edged sword. Under certain conditions, SCFAs can inhibit tumor growth. They can enhance the function of CD8⁺ T cells by promoting histone acetylation and mTOR signaling pathways, increasing the production of effector molecules and memory potential[93,94]. Additionally, studies have found that acetic acid produced by Lactobacillus reuteri can inhibit tumor growth and enhance the efficacy of anti-PD-1/PD-L1 therapy[95]. However, SCFAs can also promote tumor cell immune escape by enhancing c-Myc-mediated PD-L1 expression[96]. Additionally, SCFAs can precisely regulate the function of immune cells by activating GPR43 and GPR41[97,98]. GPR43 can inhibit the activity of NF-κB, reduce the production of pro-inflammatory factors, activate the nuclear factor erythroid 2-related factor 2 pathway to enhance antioxidant capacity, and inhibit inflammatory signals such as Janus kinase 2/STAT3[99]. Moreover, the SCFAs-GPR43/41 signal can enhance the integrity of the epithelial barrier, reduce the translocation of microbe-associated molecular patterns such as LPS, and block the intestinal inflammatory cascade[97]. Specifically, after binding to GPR43/41, SCFAs couple with inhibitory/other G-protein α subunit or G-protein αq subunit of the heterotrimeric G-protein proteins, reduce the level of cyclic adenosine monophosphate (cAMP), and activate pathways such as p38 mitogen-activated protein kinase (MAPK) and extracellular regulated protein kinases 1/2, thereby influencing the functions of immune cells. For instance, propionic acid reduces cAMP via GPR41 and activates p38 MAPK, thereby alleviating inflammatory responses[100]. Meanwhile, acetic acid regulates the gene expression of macrophages by activating the RhoA-YAP/transcriptional co-activator with PDZ-binding motif axis through GPR43[101]. In addition, SCFAs upregulate the expression of tight junction proteins through GPR43 and GPR41, repair the epithelial barrier, reduce pathogen invasion and bacterial translocation, and thereby achieve anti-inflammatory effects[97].

In addition, microbial metabolic products can affect intracellular signal transduction, leading to negative outcomes such as cancer cell proliferation and ferroptosis. Ferroptosis is an emerging form of cell death that differs from traditional apoptosis and necrosis, and it is caused by iron-dependent accumulation of peroxidized phospholipids[102]. Ferroptosis is strictly regulated by glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and the tetrahydrobiopterin system or the newly discovered dihydroorotate dehydrogenase, which function by converting lipid peroxides into non-toxic lipid alcohols[103]. In cancer, ferroptosis has a dual role: On one hand, it serves as a natural tumor suppressive mechanism, activating anti-tumor immunity through tumor suppressor genes such as p53 or immunogenic cell death; On the other hand, cancer cells often evade ferroptosis by upregulating defense systems such as GPX4 and FSP1 or through metabolic reprogramming, thereby promoting metastasis and chemotherapy resistance[104,105]. For instance, the tryptophan metabolite trans-3-indoleacrylic acid (IDA) produced by Peptostreptococcus anaerobius can promote the occurrence of colorectal cancer. Studies have shown that IDA treatment or Peptostreptococcus anaerobius implantation in xenograft models and Apcmin (min: Multiple intestinal neoplasia)/⁺ mice promotes the progression of colon cancer. As an endogenous ligand of the aryl hydrocarbon receptor, IDA upregulates the expression of ALDH1A3. ALDH1A3 uses retinaldehyde as a substrate to generate nicotinamide adenine dinucleotide, which is crucial for FSP1-mediated synthesis of reduced coenzyme Q10[106]. However, recent studies have shown that iron in the gut can modify the interaction between the host and microorganisms by altering the growth and virulence of the gut microbiota or influencing the host’s immune system[105]. For example, lactic acid bacteria such as Lactobacillus acidophilus, Lactobacillus rhamnosus, and Lactobacillus casei have been reported to increase trace iron, protect the host’s intestinal barrier, reduce intestinal inflammation, and regulate immune function, thereby inhibiting tumor occurrence[107]. Future research should focus on exploring how to enhance the induction of ferroptosis by regulating the microenvironment to improve the efficacy of tumor treatment.

Aging can lead to changes in the composition and function of the intestinal microbiota, presenting an ecological imbalance characterized by “enrichment of pro-inflammatory bacteria and reduction of beneficial bacteria”. Specifically, aging causes a significant decrease in the abundance of beneficial bacteria that produce SCFAs, weakening the anti-inflammatory, neuroprotective and intestinal barrier maintenance effects mediated by SCFAs[108]. Furthermore, the enrichment of Fusobacterium nucleatum in colon cancer tissues is associated with age-related alterations in the intestinal microenvironment[109]. Moreover, metagenomic studies have found that the abundance of Fusobacterium nucleatum is positively correlated with the age of patients, indicating that Fusobacterium nucleatum is more likely to exert carcinogenic effects in the intestine as age increases[110]. Moreover, the chronic systemic inflammation caused by microbiota dysbiosis is significantly amplified in aging. Aging is accompanied by a decrease in intestinal microbiota diversity, a reduction in beneficial bacteria and an expansion of pathogenic bacteria, leading to “leaky gut”. Neurotoxic metabolites such as LPS and trimethylamine-N-oxide translocate into the blood, triggering systemic inflammation[111].

With the in-depth development of single-cell sequencing, metabolomics, and research on the microbiota-host interaction network, the molecular pathways by which the gut microbiota regulates ferroptosis in cancer will gradually become clear. Intervention strategies targeting specific microbiota or metabolites are expected to become a new direction for reshaping the TME. At the same time, the combination of immunotherapy and microbiota regulation may break through the limitations of traditional treatments[112]. Additionally, dietary interventions (such as dietary fiber regulation of SCFAs production) or the development of new drugs (such as dihydroorotate dehydrogenase inhibitors) may become potential breakthroughs for regulating tumor progression mediated by ferroptosis[113,114]. However, the heterogeneity of the microbiota, the pleiotropy of metabolites, and the differences in individualized treatment responses remain urgent challenges that need to be addressed through multi-omics integration and clinical cohort validation, ultimately achieving the precise transformation of the gut microbiota from a “cancer-promoting agent” to an “anti-cancer ally”.

Regulation of tumors by the brain-ENS

There is a close connection between the digestive system and the nervous system. The activities of the gastrointestinal tract are regulated externally by the sympathetic and parasympathetic nerves and internally by the ENS. In the intestinal neural network, the metabolic activities of bacteria can produce various substances that affect the function of the nervous system, many of which are the same as the neurotransmitters[115]. Traditionally, neurotransmitters such as Ach and norepinephrine were long believed to be mainly or exclusively derived from neurons. However, there is now increasing attention on the interaction between cancer cells in the TME and the nervous system, as well as the impact of non-neuronal neurotransmitters produced by bacteria in the intestinal microbiota on tumors[116,117]. Previous studies have shown that tumor growth can attract the growth of nerve fibers, a process known as tumor innervation. Factors released by tumor cells can promote the growth of nerve fibers and the formation of nerve endings, which release neurotransmitters such as norepinephrine, dopamine, and substance P (SP), enhancing the metastatic and invasive capabilities of tumors[118]. Additionally, a reduction in Ach weakens the cholinergic anti-inflammatory pathway, leading to the polarization of tumor-associated macrophages towards the M2 tumor-promoting phenotype[119,120].

Among them, the neurotransmitters produced by the intestinal microbiota can directly act on gastrointestinal tumor cells. Intestinal bacteria not only secrete neurotransmitters but also respond to them, including excitatory and inhibitory neurotransmitters such as dopamine, serotonin, and GABA, as well as norepinephrine similar to that in the brainstem, which jointly activate the sympathoadrenal medullary system[116]. Moreover, intermediate compounds produced by microorganisms, such as SCFAs, tryptophan, and secondary bile acids, are also involved in communication with the CNS[115]. These neurotransmitters secreted by the intestinal microbiota promote the occurrence and development of digestive tract tumors. For instance, studies have shown that norepinephrine promotes epithelial-mesenchymal transition, enhances invasiveness, and increases the migratory ability of gastric cancer cells, inducing malignant transformation. These research results suggest that gastric cancer expressing high levels of NGF may promote sympathetic innervation within the tumor tissue, thereby promoting malignant transformation through norepinephrine signaling[55]. In addition, 5-HT derived from enterochromaffin neurons acts on the HTR1B, HTR1D, and HTR1F receptors highly expressed in colorectal cancer stem cells (CSC), directly initiating the Wnt/β-catenin signaling pathway and driving CSC self-renewal and tumorigenesis[121]. Meanwhile, the intestinal microbiota metabolite isovaleric acid promotes TPH2 expression and 5-HT synthesis by inhibiting the binding of the nucleosome remodeling complex to the TPH2 promoter, thereby participating in tumorigenesis[121]. In addition, in the chronic sleep deprivation model, the level of GABA in the peripheral blood of mice increased, specifically promoting the expression of miR-223-3p in colon cancer cells and enhancing the proliferation and migration abilities of colon cancer cells[122]. In addition, SP promotes cell proliferation, migration, invasion and angiogenesis in colorectal cancer by activating the neurokinin-1 receptor, and interacts with immune and endothelial cells in the TME, exacerbating inflammatory responses and tumor progression[123].

The ANS plays a significant role in the occurrence and progression of digestive system tumors. Research has revealed that the regulatory effect of the vagus nerve-M3 muscarinic Ach receptor, through Wnt signaling in stem cells, promotes the development of gastric cancer. In colon cancer, activated M3 muscarinic Ach receptors upregulate metalloproteinases (MMPs), enhancing the invasiveness and metastatic ability of cancer cells[56,124]. Additionally, neuropeptides and neurotransmitters can influence the genomic stability, epigenetics, and metabolic state of tumor cells, while shaping the TME such as immune infiltration and extracellular matrix, thereby affecting the occurrence of gastrointestinal cancers. Conversely, tumor cells can also hijack the signals released by nerve cells in the gastrointestinal tract to their advantage for survival[125]. The ENS mainly affects the occurrence of gastrointestinal tumors through neurotrophic factor and neurotransmitter pathways. Neurotrophic factors, also known as NGFs, include highly homologous precursor proteins that are cleaved into active peptides such as BDNF, glial cell line-derived neurotrophic factor, neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). These proteins stimulate neural development and survival through multiple signaling mechanisms[126]. Neurotrophic factors are released in the early stages of cancer, stimulating local nerve growth and increasing nerve density, which is associated with more aggressive cancers. Meanwhile, the neurotrophic factors released by cancer cells facilitate neurogenesis, axonogenesis, and neural migration, while the neurotransmitters released by neurons and glial cells stimulate tumor growth and invasion[127]. Additionally, in the interaction between neurotrophic factors and tumor cells, NGF binds to specific receptors such as tropomyosin receptor kinase A and tropomyosin receptor kinase C (TrkC), promoting receptor homodimerization, autophosphorylation of the tyrosine kinase domain, and activation of downstream effectors such as phosphatidylinositol 3-kinase, Ras, and phospholipase C[128,129]. For instance, NT-3, activated through the TrkC receptor, may have an inhibitory effect on pancreatic ductal adenocarcinoma[6,129]. NT-4, by down-regulating autophagy-related gene 5/NT-4, promotes autophagy and inhibits colon cancer[130]. Studies have confirmed that patients with high sympathetic nerve density (SND) in gastric cancer tissues have significantly shorter survival periods, and high expression of NGF in tumor tissues is significantly associated with increased SND and poor prognosis[127].

During the aging process, the ENS undergoes morphological changes and degeneration, characterized by a reduction in cholinergic neurons, alterations in interstitial cells of Cajal subtypes, and changes in enteric glial cells, all of which jointly affect neurotransmitter homeostasis[41]. This phenomenon has been observed in both animal models and humans, and it may influence CNS diseases through the brain-gut axis, while simultaneously weakening its regulatory capacity over intestinal immunity, barrier function, and microbiota homeostasis. Future research needs to further dissect the bidirectional signaling network between neurons and cancer cells and explore methods to block tumor further invasion through axon guidance molecules. Moreover, modulating specific microbiota to alter their metabolites’ impact on the nervous system may also become a new strategy for treating tumors (Table 1).

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.

Neuroendocrine and gastrointestinal cancer

The neuroendocrine-hormone network is a cross-system regulatory system composed of neuroendocrine cells, hormone signaling molecules, and their target organ receptors, which maintains homeostasis and responds to internal and external environmental changes by integrating neural, endocrine, and immune signals[131]. Its core feature lies in the spatiotemporal coupling of neural signals and hormone secretion, as well as the multi-level feedback regulation ability. The ANS, ENS and CNS form the core communication framework of the brain-gut axis through a complex neuroendocrine network[7,132]. The ANS serves as a bridge connecting the CNS and the gastrointestinal tract. Its sympathetic nerve branches transmit inhibitory signals (such as norepinephrine) through the spinal cord to regulate gastrointestinal blood flow and barrier function, while the parasympathetic nerve, especially the vagus nerve, releases neurotransmitters such as Ach to directly activate ENS neurons and regulate intestinal motility, secretion, and immune responses[23,133]. The ENS, as the “second brain”, independently regulates local functions of the digestive tract, such as intestinal mucosal permeability and smooth muscle contraction, and forms a bidirectional loop with the CNS through the vagus nerve and spinal cord afferent/efferent fibers, allowing the emotional state of the CNS to affect gastrointestinal activity in real time and vice versa[134]. The CNS integrates internal and external signals through the HPA axis and limbic system to regulate ANS activity and thereby shape the local microenvironment driven by the ENS[134,135]. The three systems work together through neurotransmitters, metabolic products, and epigenetic modifications mediated by the microbiota-gut-brain axis to maintain gastrointestinal homeostasis. Their dysregulation in diseases such as inflammatory bowel disease and colorectal cancer highlights the potential target value of their interaction mechanisms in TME remodeling and treatment response[16].

The HPA axis and EECs can also achieve bidirectional regulation. Metabolites of the gut microbiota can directly act on EECs, promoting the secretion of glucagon-like peptide-1, peptide YY and serotonin, which affect the metabolic regulation and emotional response of the brain through the blood circulation[30]. At the same time, the activation of the HPA axis leading to the release of cortisol can change the composition of the gut microbiota, and the disorder of the microbiota can in turn inhibit the function of the HPA axis, forming a vicious cycle[136]. In addition, the brain regulates intestinal function by secreting hormones such as CRH, and the indole derivative metabolites of the gut microbiota can regulate the expression of CRH receptors, further affecting endocrine homeostasis[33,136]. This interactive network plays a key role in metabolic diseases and neuroendocrine diseases. In addition, oxytocinergic neurons in the paraventricular nucleus of the thalamus are involved in regulating the progression of colorectal cancer in mice[137]. Stimulating oxytocin neurons with celastrol has been proposed as a potential strategy for the treatment of colorectal cancer[137]. There is a close connection between hormonal imbalance and the occurrence of digestive tract tumors. The brain-gut axis regulates the secretion of key gastrointestinal hormones such as gastrin (GAS), motilin, and somatostatin through the neuroendocrine network. Its imbalance may lead to damage to the mucosal barrier function and the induction of chronic inflammation. For example, the continuous increase in GAS levels in patients with chronic atrophic gastritis inhibits the secretion of gastric growth hormone, which may lead to mucosal atrophy and intestinal metaplasia. It will become a key mechanism for precancerous lesions of gastric cancer[138]. At the same time, abnormal secretion of cholecystokinin and vasoactive intestinal peptide can reduce the pressure of the lower esophageal sphincter, promoting gastroesophageal reflux. Long-term acid exposure may cause Barrett’s esophagus and increase the risk of cancer[139,140]. Imbalance of the gut microbiota may over activate the 5-HT signaling pathway, leading to visceral hypersensitivity and abnormal esophageal motility, exacerbating mucosal damage. In addition, abnormal vagus nerve activity may stimulate the expression of neurotrophic factors in the TME, promoting cancer cell invasion and perineural invasion[140,141]. Therefore, compared with the traditional perspective that only focuses on the endocrine of the intestine itself, the brain-gut axis provides a new perspective on the mechanism of digestive tract tumors. Future research needs to adopt an overall concept to analyze the balance of digestive tract endocrine homeostasis and provide new ideas for the treatment of digestive tract tumors.

REGULATION OF GASTROINTESTINAL CANCERS BY INFLAMMATORY BODIES IN BRAIN-GUT AXIS

Inflammation is a fundamental innate immune response when tissue homeostasis is disrupted, and it can promote tumorigenesis through genomic instability, abnormal proliferation, remodeling of the stromal environment, and abnormal differentiation between epithelial and mesenchymal states[142]. Imbalance of the intestinal microbiota in aging can disrupt the intestinal barrier function, allowing harmful bacteria and their metabolites to enter the bloodstream and trigger chronic inflammatory responses. A persistent low-grade inflammatory environment can promote DNA damage and abnormal proliferation in cells[4]. Secondly, aging-induced inflammaging in the gastrointestinal tract weakens the body’s ability to clear cancerous cells, while pro-inflammatory factors secreted by senescent cells further exacerbate the inflammatory state of the tissue microenvironment, forming a “inflammation-senescence” vicious cycle[2,4,14]. Studies have shown that chronic inflammation caused by aging can produce oxygen free radicals that damage DNA, promote pro-inflammatory mediators that favor cell survival, increase cell proliferation and angiogenesis, and induce remodeling of gastrointestinal tissues, thereby creating a microenvironment that promotes tumor growth[143]. In addition, repeated cycles of inflammatory damage and repair can lead to abnormal cell proliferation, which may develop into dysplasia during intestinal mucosal repair and eventually evolve into colorectal cancer (Figure 4)[144]. This aging-induced intestinal inflammatory state affects the TME through the bidirectional pathway of the brain-gut axis. On one hand, pro-inflammatory cytokines IL-1β, tumor necrosis factor (TNF)-α, IL-6 and the Wnt/β-catenin signaling pathway are activated, creating a pro-TME[54]. On the other hand, the neural signaling pathway directly participates in the progression of gastrointestinal tumors through the crosstalk mediated by neurotrophic factors and neurotransmitters[54]. Meanwhile, the abnormal expression of intestinal microbiota metabolites and neural signaling molecules can further disrupt intestinal homeostasis, intensify inflammatory responses, and promote tumor development[145].

Figure 4 Relationship between aging-related inflammation and gastrointestinal tumors. The occurrence of gastrointestinal tumors is closely related to gastrointestinal inflammation caused by aging. Inflammation impairs the integrity of the intestinal barrier, allowing microorganisms and metabolites to enter the bloodstream, along with oxygen free radicals that induce cellular DNA damage and mutations. Age-related decline in immune function is characterized by weakened immune function and decreased pathogen clearance. Senescent cells secrete pro-inflammatory factors, which aggravate the inflammation of the tissue microenvironment and synergize with angiogenesis to form a cancer-promoting microenvironment. The above pathological processes stimulate abnormal mucosal hyperplasia of the digestive tract and eventually lead to gastrointestinal cancer.

Additionally, aging can also cause the dysregulation of cancer immune editing in the gastrointestinal tract. Cancer immune editing refers to the dual role played by the immune system in tumor development: Protecting the host while potentially promoting tumor growth, a complex process that includes three key stages: Elimination, equilibrium, and escape[146]. Specifically, under immune selection pressure, tumor cells may lose the expression of major histocompatibility complex or acquire the expression of immunosuppressive genes, which help tumor cells evade immune recognition and attack, thereby promoting tumor progression. Recent studies have shown that the gut microbiota has become a potential factor in the ability of cancer to evade immune responses[66]. In aging, the composition of the microbiota undergoes significant changes, leading to inflammaging. Inflammaging is characterized by elevated levels of pro-inflammatory cytokines in the circulation and the disruption of the integrity of the intestinal and blood-brain barriers, resulting in antigen transfer to the host and the initiation of systemic inflammation[147,148]. The pro-inflammatory cytokines of the IL-17 family play a crucial role in maintaining intestinal homeostasis by regulating mucosal immunity and intestinal barrier integrity. The IL-17-IL-17 receptor A (RA) signaling pathway is associated with the occurrence and development of various autoimmune diseases and gastrointestinal cancers, including pancreatic cancer, gastric cancer, and colon cancer[149-151]. Specifically, IL-17RA signaling activates a protective pathway to prevent excessive inflammatory responses, which otherwise could lead to increased oxidative stress and DNA damage and has been shown to promote the development of gastric cancer after Helicobacter pylori infection[150]. An increase in the number of specific microorganisms such as Prevotella and Bacteroides can lead to the loss of the IL-17-IL-17RA signaling pathway, thereby increasing the incidence of gastrointestinal cancers[150]. The intestinal microenvironment constructed by the gut microbiota and its metabolites significantly affects the immune function in this region. Correspondingly, specific disease states also regulate and influence the composition of the intestinal microbiota. There is a continuous and complex interaction between the gut microbiota and the immune system[152]. For example, the gut microbiota secretes various metabolites and bacteriocins. In addition, the gut microbiome activates the immune system by expressing specific antigens, attaching to epithelial cells, and interacting with pattern recognition receptors. These metabolites include SCFAs, which can be absorbed by intestinal epithelial cells as an energy source or act as signals to activate the immune system through recognition by GPRs, inducing the production of cytokines and chemokines and activating the regional immune system[18,153]. A reduction in SCFAs weakens the energy supply and anti-inflammatory capacity of the intestinal epithelium. Meanwhile, the release of toxins such as LPS by pathogenic bacteria activates the immune system and triggers Inflammaging[154]. Additionally, with age, the structure of the intestinal epithelial barrier is damaged, directly increasing the frequency of contact between microorganisms and the epithelium, which is closely related to the development of chronic inflammation[155]. At the same time, the secretion pattern of antimicrobial proteins changes, with abnormal elevations of proteins such as regenerating lslet-derived protein III gamma in elderly mice, which may further exacerbate barrier dysfunction by disrupting the balance of the microbiota[156,157]. Finally, these changes form a vicious cycle with immunosenescence the dysfunction of intestinal epithelial cells weakens the immune system’s ability to regulate microorganisms, while the decline in immune cell function fails to effectively repair the damaged barrier, jointly promoting the progression of inflammatory diseases.

The imbalance of neural pathways and neurotransmitters related to aging promotes the occurrence of intestinal cancer through multiple pathways, including direct regulation of tumor stem cells, activation of oncogenic signaling pathways, and mediation of the interaction between the microbiota and the nervous system. Studies have shown that the imbalance of neurotransmitters in the gastrointestinal tract can cause intestinal mucosal damage, immune dysregulation, and chronic inflammatory responses by activating HTR1B/HTR1D/HTR1F and Wnt/β-catenin pathways[121]. Moreover, the imbalance of neurotransmitters also disrupts the intestinal barrier function and promotes the proliferation of tumor stem cells, thereby increasing the risk of exposure to carcinogens and the incidence of gastrointestinal tumors[121]. The vagus nerve exerts anti-inflammatory effects by releasing Ach, a process known as the cholinergic anti-inflammatory pathway, which reduces inflammation through the HPA axis and the cholinergic anti-inflammatory pathway. Stimulation of the vagus nerve can reduce the release of pro-inflammatory cytokines such as TNF, IL-6, and IL-1β, without affecting the level of anti-inflammatory cytokine IL-10[29]. The anti-inflammatory effect of the vagus nerve has been confirmed in animal models. For example, in a dinitrobenzenesulfonic acid-induced colitis model, vagotomy led to aggravated intestinal inflammation, indicating that the vagus nerve has an anti-inflammatory effect in acute colitis[158].

In summary, the intricate relationship between age-related gastrointestinal inflammation and tumor development unveils a dynamic network that encompasses the interaction of numerous systems and factors. At its core is the formation and perpetuation of the “aging-inflammation-carcinogenesis” dynamic process. Future research must delve deeper into the mechanisms behind the coordinated imbalance of the intestinal microbiota, immune homeostasis, neural regulation, and epithelial barrier function as they relate to aging. It should also explore critical intervention points. By establishing an “anti-inflammatory-anti-aging-anti-cancer” integrated intervention system, future research may uncover a potential breakthrough strategy for slowing down age-related gastrointestinal diseases and lowering cancer incidence.

Inflammasomes in gastrointestinal tumors

Inflammasomes are a class of signaling platforms composed of multiple proteins, responsible for regulating inflammatory responses and coordinating the host’s antibacterial defense mechanisms. As an important component of innate immunity, inflammasomes play a key role in intestinal homeostasis and the development of colorectal cancer. Inflammasomes are mainly divided into two categories: Canonical inflammasomes and non-canonical inflammasomes[159]. Canonical inflammasomes are composed of sensor proteins, such as NLRP3, NLRC4, AIM2, the adaptor protein apoptosis-associated speck-like protein containing a CARD, and the effector protein caspase-1, which can recognize pathogen or damage signals and activate inflammatory responses. Non-canonical inflammasomes are triggered by the direct binding of caspase-4/5/11 to LPS and other substances, inducing pyroptosis and amplifying inflammatory signals. Pattern recognition receptors are key components of inflammasomes[159,160]. When these receptors detect pathogenic microorganisms or danger signals in the host cytoplasm, they trigger a cascade of inflammatory responses involving cysteine proteases, promoting the maturation and release of pro-inflammatory cytokines such as IL-1β and IL-18, ultimately leading to pyroptosis of inflammatory cells[159,160]. It should be emphasized that inflammasomes are crucial for the early defense of pathogens and abnormal cells by the immune system[161]. Their activation induces the release of pro-inflammatory cytokines such as IL-1β and IL-18, which enhance the immune response and can promote the clearance of damaged or transformed cells[159]. This inflammation is a protective mechanism that prevents tumor initiation by eliminating abnormal cells before they can proliferate. However, when the activation of inflammasomes persists beyond the acute phase, this protective mechanism becomes a double-edged sword. Chronic inflammasome activation can lead to persistent inflammation, which is a known carcinogenic factor. Persistent inflammation in the TME can promote cell survival, increase angiogenesis, and stimulate tumor-promoting signaling pathways[159]. This transformation from protective to pathological inflammation has been associated with the development of gastrointestinal cancers[8].

With aging, gastrointestinal homeostasis undergoes significant shifts that in turn create an inflammatory environment that promotes tumor development. In the brain-gut axis, the aging phenomenon leads to a reduction in the diversity of gut microbes, an over-proliferation of harmful flora, and the release of bacterial toxins such as LPS. These components activate the NF-κB signaling pathway through pattern recognition receptors, thereby promoting the expression of the proinflammatory factors IL-1β, IL-18, and triggering the assembly of the NLRP3 inflammasome[162,163]. In addition, aging can lead to impaired mitochondrial function in intestinal epithelial cells and immune cells, resulting in excessive production of reactive oxygen species (ROS). ROS can directly activate the NLRP3 inflammasome and promote the maturation and release of IL-1β. At the same time, ROS damage mitochondrial DNA (mtDNA) through oxidative stress, and mtDNA released into the cytoplasm acts as a danger signal to further activate the inflammasome[13]. Mucin secreted by intestinal epithelial cells is reduced, and the expression of tight junction proteins, such as occludin and zonula occludens-1, is down-regulated, leading to increased intestinal permeability. This allows bacterial endotoxins and microbial metabolites to easily enter the circulation and activate the inflammasome in macrophages and dendritic cells[155]. At the same time, intestinal epithelial cells and immune cells in the aging state secrete a large number of proinflammatory factors such as IL-6, IL-1β and matrix MMPs through the SASP, leading to a chronic low-grade inflammatory environment in the gastrointestinal tract[164]. These factors activate NLRP3 inflammasome in surrounding cells in an autocrine or paracrine manner, creating a vicious cycle.

Studies have shown a higher incidence of intestinal inflammation and tumors in colitis-related cancer models in NLRP3-deficient mice. NLRP3 reduces inflammation-driven tumorigenosis by promoting mature secretion of IL-1β and IL-18, maintaining intestinal epithelial barrier function and inhibiting overactivation of NF-κB. In addition, exogenous IL-18 was able to restore protection against colitis in CASP1-deficient mice. However, overactive inflammasome forms the molecular and pathophysiological basis of gastrointestinal cancer[165]. During aging, intestinal stem cells continue to up-regulate major histocompatibility complex-II and TNF-α signaling pathways through epigenetic changes, forming “inflammatory memory”[166]. The NLRP3 inflammasome is activated during this process, leading to over-secretion of pro-inflammatory cytokines such as IL-1β and IL-18, promoting chronic low-grade inflammation of the intestine. These factors promote the occurrence of colorectal cancer by activating pathways such as NF-κB, disrupting intestinal homeostasis and intensifying the inflammatory microenvironment[166]. Helicobacter pylori infection activates NLRP3 inflammasome through Cag pathogenic island and urease, triggering excessive secretion of IL-1β, which is closely related to gastric mucosal injury and carcinogenesis[166,167]. These results indicate that aging induces intestinal inflammasome disorders through multiple mechanisms such as microbiome imbalance, barrier destruction, mitochondrial damage, SASP and immune aging, forming pro-inflammatory microenvironment, and then inducing gastrointestinal tumors.

THE BRAIN-GUT AXIS REGULATES THE CIRCADIAN RHYTHM TO INDUCE TUMORS

The circadian rhythm system, as the core regulatory network of the physiological rhythm of organisms, modern lifestyle factors such as shift work and sleep deprivation not only directly disrupt the host’s metabolism and energy balance, but also aggravate the above pathological processes by reshaping the composition and function of the gut microbiota[168,169]. During the aging process, the expression rhythms of core clock genes (such as Clock, Bmal1, Per2) change. For example, the rhythmic expression of lipid metabolism-related genes in the liver of aged rats is significantly weakened. Transcription factors such as early growth response 1 disrupt lipid metabolism homeostasis by regulating target genes such as Cidea, leading to triglyceride accumulation and accelerated cellular aging[170]. This rhythm disorder also weakens the intestinal barrier function by inhibiting the synthesis of SCFAs, increasing the risk of bacterial endotoxins entering the blood[171] (Figure 5).

Figure 5 Disruption of circadian rhythms and gastrointestinal tumors. The aging process induces the aberrant expression of core biological clock genes (Per/Clock/Bmal1), resulting in disrupted circadian rhythm regulation and consequent abnormalities in lipid metabolism in the liver, diminished intestinal barrier function, and immunosuppression within the tumor microenvironment. At the molecular level, this is evidenced by abnormal H3K4me1 histone modifications, activation of oncogenes, and suppression of DNA repair mechanisms. MDSCs: Myeloid-derived suppressor cells; Treg: Regulatory T cell.

Studies have shown that the circadian rhythm maintains the integrity of the intestinal barrier by regulating the expression of tight junction proteins, occludin and claudin, in intestinal epithelial cells[172]. Disruption of the rhythm can lead to dysregulation of tight junction genes (occludin), damage to the intestinal barrier integrity, and subsequently promote the entry of bacteria and their metabolites into the bloodstream, triggering systemic inflammation and metabolic disorders[9]. The latest research indicates that the gut microbiota can influence the circadian rhythm through the brain-gut axis system, and circadian rhythm abnormalities caused by aging or other diseases can also affect the composition of the gut microbiota[168,173,174]. Such changes will directly lead to alterations in microbial metabolites, thereby promoting tumor formation[169,173,175]. Specifically, after the disruption of the circadian rhythms, the abundance of Ruminococcus torques increases, while that of Lactobacillus johnsonii decreases. Ruminococcus torques is a known bacterium that reduces intestinal barrier integrity, while Lactobacillus johnsonii helps maintain the intestinal epithelial cell layer[176]. Additionally, disruption of the circadian rhythm leads to the down-regulation of genes related to pathways promoting beneficial immune responses in the host, as well as the up-regulation of genes related to the synthesis and transport of LPS[177].

Altered circadian rhythms contribute to the onset and progression of gastrointestinal tumors through various mechanisms. Metabolically, they influence the expression of key clock genes like Clock and Per2, leading to imbalances in fatty acid oxidation and glucose metabolism. For example, in colorectal cancer cells lacking Per2, cyclin D1 expression markedly increases, thereby accelerating cell proliferation[178]. Regarding the immune microenvironment, disruptions in circadian rhythms promote the accumulation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells within the TME, which dampen anti-tumor immune responses. In colorectal cancer patients, such disruptions are associated with increased MDSC aggregation and elevated PD-L1 expression, facilitating lung metastasis[179]. At the epigenetic level, bile acids produced by gut microbiota metabolic activities enhance H3K4me1 histone modifications, activating oncogene expression while inhibiting DNA repair pathways. Disruptions in circadian rhythms can exacerbate these effects, fostering tumor development[179,180]. Furthermore, circadian rhythm disturbances also modulate cancer stem cells and their surrounding microenvironment, promoting tumor formation and metastasis[175]. In mouse models, deleting Bmal1 significantly alters gut microbiota composition, increasing pro-inflammatory bacteria such as Bacteroides while reducing tumor-suppressive bacteria like Lactobacillus, thus accelerating colorectal cancer progression[175].

In summary, the circadian system integrates gut microbiota, metabolic processes, and immune networks, serving as a critical nexus that links lifestyle factors, inflammatory microenvironments, and gastrointestinal tumors. Dysregulation of this system presents novel therapeutic targets for intervention.

POTENTIAL TREATMENT OPTIONS AND LIMITATIONS

Throughout the long battle between humanity and diseases, gastrointestinal tumors have always been the “silent killers” threatening global health. Esophageal cancer, gastric cancer, colorn cancer and other digestive tract tumors, due to their high drug resistance and complex microenvironment, often leave traditional treatment methods at an impasse. However, with the in-depth research on the brain-gut axis in the scientific community, this bidirectional communication network connecting the CNS and the gastrointestinal tract is bringing disruptive breakthroughs to tumor treatment. It not only reveals how tumor cells hijack neurotransmitters, metabolites and immune signals to achieve malignant proliferation, but also guides us to reshape the TME by intervening in this pathway, opening up new paths for precise treatment.

Fecal microbiota transplantation (FMT) is a therapeutic approach that involves transplanting intestinal microbiota obtained from the feces of a healthy donor into a patient’s gastrointestinal tract to improve the microenvironment within the patient’s gut. In most cases, this therapy is used to treat gastrointestinal diseases caused by the activity of pathogenic or opportunistic microorganisms, such as inflammatory bowel disease and colon cancer[181]. In recent years, an increasing number of studies have focused on the synergistic effect of FMT and tumor treatment in the brain-gut axis and have played an important role in the treatment of refractory tumors. Combined immunotherapy is currently a cutting-edge research direction for FMT. Studies have shown that for proficient mismatch repair/microsatellite stable-type colorectal cancer that is unresponsive to traditional immunotherapy, FMT combined with anti-tislelizumab and bevacizumab can reduce the tumor to a resectable size, and some patients achieve a pathological complete response[182]. During the combined immunotherapy process, FMT can increase the abundance of immune-regulating bacteria such as Akkermansia muciniphila, activate CD8⁺ T cell responses, and enhance the efficacy of immunotherapy[182,183]. In addition, FMT has been proven to help improve the tolerance of tumor patients to radiotherapy and chemotherapy. FMT can restore the intestinal flora disorder caused by chemotherapy, reduce side effects such as diarrhea and bone marrow suppression, and enhance the anti-tumor effect of drugs such as 5-fluorouracil[184]. However, FMT still has some limitations at present, such as donor screening and prevention of potential infection risks, individual differences and uncertainties in efficacy, and poor patient acceptance. In the future, with the development of microbiota isolation technology, individualized donor matching, and capsule formulations, FMT is expected to overcome current limitations and become an important tool for precision medicine in the treatment of gastrointestinal tumors.

In recent years, therapeutic strategies targeting neurotransmitters and modulating neural transmission pathways have emerged as highly promising approaches in the treatment of gastrointestinal tumors. Studies have shown that the use of CGRP receptor antagonists can block the binding of neurotransmitters to cancer cells, significantly inhibit tumor growth and metastasis, and prolong the survival of mice[185,186]. Additionally, blocking the chemotaxis of neurons to tumors through entrectinib or genetic knockout of NGF can reduce neural density and thereby suppress tumor growth. This strategy has been validated in N-methyl-nitrosourea-induced gastric cancer models[185]. Meanwhile, the use of neuroablation and optogenetic techniques can disrupt neural pathways that favor tumor progression, achieving therapeutic goals. Research has demonstrated that pharmacological or genetic ablation of sensory neurons can reduce neural innervation in the TME and inhibit tumor progression. This approach has shown survival benefits in gastric cancer xenograft models and colorectal cancer models[185,187]. Selective regulation of neuronal activity using light-activation technology can intervene in tumor-neural circuits in real time, providing a new tool for precision treatment. However, current research is mainly based on mouse models, and the safety and efficacy of CGRP inhibitors and NGF-targeted drugs in humans need further validation. In the future, combining neuro-targeted therapy with immune checkpoint inhibitors or chemotherapy is expected to achieve multi-pathway synergy to enhance anti-tumor effects.

In addition, treating tumors by adjusting the disrupted circadian rhythm in the gastrointestinal tract has become a cutting-edge direction in current research. Gene editing techniques to alter the expression of clock genes and optimized therapies targeting cellular circadian clocks play a crucial role in tumor treatment. Studies have revealed that the Bma1 and Clock influence the maintenance of cancer stem cells by regulating the Wnt/β-catenin and Hippo signaling pathways. Inhibiting the Bmal1 gene can reduce the YAP1-mediated tumor incidence in colon cancer[173]. Moreover, the clustered regularly interspaced short palindromic repeats associated protein 9 technology has been used to repair Clock mutations, successfully restoring the circadian rhythm oscillation of intestinal epithelial cells in a familial adenomatous polyposis model, resulting in a 73% reduction in polyp numbers and a decreased risk of precancerous lesions developing into colon cancer[188]. In combination with existing treatment options, it is expected that prognostic models based on circadian gene expression, targeted drugs, as well as radiotherapy will be developed in the future to achieve synergy. In addition, personalized treatment strategies combining FMT with circadian regulation will be further explored (Table 2).

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.

It is noteworthy that traditional Chinese medicine plays an irreplaceable role in regulating gut microbiota via the brain-gut axis, modulating neurotransmitters and inhibiting gastrointestinal tumors. Berberine significantly reduces the number of colonic polyps, improves intestinal barrier function, and suppresses inflammation and oncogenic pathways such as the Hedgehog pathway in colitis-associated colorectal cancer models[189,190]. It exerts these effects by enriching probiotics such as Bifidobacterium, depleting pathogenic bacteria, and regulating the balance between SCFAs and LPS[191]. Furthermore, berberine increases the levels of BDNF and serotonin via the brain-gut axis, reduces the levels of IL-1β, TNF-α and corticosterone, and restores the SCFAs disorder induced by stress[192]. Similarly, curcumin can also improve intestinal flora imbalance, enhance the integrity of the intestinal barrier, increase the level of SCFAs, and alleviate systemic inflammation[193]. Various carriers, such as κ-carrageenan/Lobia protein gel and chitosan-benincasa gel system, can target curcumin to the colon for controlled release in the intestinal tract. Such designs help curcumin exert its regulatory effects on the flora and improve the barrier function locally in the intestine[194,195]. However, at present, traditional Chinese medicine still faces core challenges in the depth of brain-gut axis mechanism analysis, clinical transformation efficiency, and individualized application strategies. The complex composition of traditional Chinese medicine formulas makes it difficult to distinguish the contribution of individual components from the overall effect, which increases the difficulty of exploring specific molecular targets[196]. In addition, for some traditional Chinese medicines, such as berberine, the oral bioavailability is relatively low, which is beneficial for exerting local effects in the intestine but requires further clarification of the mechanism of systemic effects[190]. How to develop corresponding intestinal drug delivery systems in the future also needs in-depth research.

FUTURE PROSPECTS

The introduction of the brain-gut axis concept has systematically revealed the multi-dimensional cascading regulatory mechanisms, including intestinal flora imbalance, abnormal neurotransmitters, immune imbalance, and circadian rhythm disorders, that affect gastrointestinal tumors. It has clarified the key role of the “microbiota-gut-brain” bidirectional communication network in shaping the TME, providing a new perspective for exploring the mechanisms of tumor occurrence and treatment. However, current research on the brain-gut axis still has limitations. Firstly, there is a severe lack of high-quality clinical evidence: Existing studies mostly focus on animal models or in vitro mechanism exploration, lacking high-quality prospective cohort studies and randomized controlled intervention trials on the relationship between the brain-gut axis and gastrointestinal tumors, making it difficult to establish causal relationships and clinical translational value[197]. Animal models have species differences and individual variations, poor experimental reproducibility, and are difficult to truly reflect the dynamic interaction process of the human brain-gut axis. Although in vitro platforms such as organ chips offer new ideas, their maturity and generalizability in simulating the TME and neuro-immune interactions still face challenges[198]. Therefore, conducting population-based prospective cohort studies, combined with FMT, probiotic intervention, and other means, to verify the preventive and adjuvant therapeutic effects of brain-gut axis regulation on gastrointestinal tumors is crucial for research in this field. At the same time, exploring the application of brain-gut axis-related biomarkers in the early screening and prognosis assessment of tumors will help further promote the clinical translation of this field[199].

In addition, the current research hotspots on the brain-gut axis mainly focus on metabolic diseases, neuropsychiatric disorders, and irritable bowel syndrome, etc.[200]. There is a significant lack of targeted discussions on gastrointestinal tumors, especially those other than colorectal cancer. Although most studies have mentioned the association between intestinal microbiota and tumors, they have not systematically analyzed the “brain-gut” bidirectional communication axis as the core framework. Therefore, it is crucial to deepen the exploration of tumor occurrence mechanisms and the mining of therapeutic targets. The roles of vagal nerve signals, the HPA axis, and the interaction between microbial metabolites and neurotransmitters in the occurrence, progression, and treatment response of gastrointestinal tumors should be analyzed in detail. Among them, targeting neurotransmitter signaling pathways or specific microbial metabolites may become new anti-tumor strategies. Based on the bidirectional regulatory characteristics of the brain-gut axis, the synergistic effects of non-invasive intervention methods combined with traditional therapies are also worth further exploration.

Innovative technology platforms based on the brain-gut axis mechanism show significant potential in revealing new pathways of tumor occurrence and developing multimodal intervention strategies. On one hand, it is necessary to strengthen cross-disciplinary collaboration and standardization, promoting teamwork among neuroscientists, oncologists, microbiologists, and clinical medical experts, and establishing unified research designs, data collection, and validation standards. On the other hand, it is essential to optimize human-like intestinal models, brain-gut organ chips, and multi-omics integration analysis techniques to enhance the simulation ability of in vitro models for human brain-gut axis-tumor interactions. Combined with imaging-assisted analysis, it can help improve the repeatability of research and the predictive efficacy in clinical settings. Among them, imaging genetics can bridge the gap between macroscopic phenotypes and microscopic molecules in traditional mechanism research[201,202]. It provides visual and quantifiable intermediate phenotype evidence for brain-gut axis disorders, which is conducive to the development of precise treatment plans targeting the brain-gut axis. Studies have shown that the intestinal microbiome can significantly affect brain structure and functional connectivity, and brain imaging-derived phenotypes provide quantitative indicators for analyzing the microbiome-brain association[203]. For instance, through multimodal magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, and other techniques, the corresponding relationship between intestinal microbiota dysbiosis and brain structure/function abnormalities can be directly observed. Regarding Alzheimer’s disease (AD), some studies have used integrated longitudinal neuroimaging data and genetic data to explore the pathogenesis of AD[204]. In the field of neuro-oncology, differences in intestinal microbiota composition have been found to be associated with metabolic function changes in tumor patients[205]. Meanwhile, the “neuro-gut microbiota-immune” axis has been proposed to be involved in the regulation of tumor occurrence and development[205]. Combining brain imaging with microbial analysis can help identify the dynamic changes of brain-gut axis disorders in the tumor process. Despite the promising prospects, current challenges include the complexity of causal inference, individual baseline microbiota differences, and interference from host genetic backgrounds[206-208]. Additionally, this technology is currently mainly focused on CNS diseases, and how to use this technology to assess the development process of digestive tract tumors still needs further exploration. In the future, it is necessary to develop individualized models combining host genomes, baseline microbiota, and dynamic imaging monitoring to enhance the precision of brain-gut axis-targeted interventions. At the same time, explore multimodal designs such as “gene sequencing + brain imaging + microbiota analysis” to reveal the hierarchical regulatory relationship of the “gene-brain-microbiota” axis during tumor occurrence.

CONCLUSION

This review provides new insights into the role of the brain-gut axis in the proliferation, invasion and metastasis of gastrointestinal tumor cells during aging. Mechanistically, the bidirectional signaling of the brain-gut axis is complex, involving the transport of metabolites and toxins from the gut microbiota, the regulation of neurotransmitters and hormones, the immune and TME, cell signaling transduction, and circadian rhythm regulation. Therefore, it is meaningful to elucidate the occurrence of gastrointestinal tumors from the perspective of the brain-gut axis, and it opens up new prospects for the diagnosis and treatment of cancer. In this review, we discuss current findings and summarize the effects of the gut microbiota, neural pathways, and the neuroendocrine immune system on the growth of gastrointestinal cancers, and conduct in-depth discussions using specific microbiota, neurotransmitters, and neuroendocrine axes as examples. Aging-induced microbiota imbalance can lead to abnormal microbiota metabolites, triggering inflammation, abnormal secretion of intestinal neurotransmitters, ferroptosis and other abnormal cell behaviors, as well as the simulation and inactivation of the CNS and the sympathetic and parasympathetic nervous systems, or changes in the innervation of the gastrointestinal tract, which may alter the immune regulatory effects of the vagus nerve, promoting the inflammatory process and leading to a high incidence of gastrointestinal cancers. In addition, the role of inflammasomes and circadian rhythms in the brain-gut axis in gastrointestinal tumors is further explored. Therefore, a better understanding of the remodeling of the brain-gut axis during aging and the roles represented by each component of the brain-gut axis in tumorigenesis may provide a promising strategy for future cancer treatment.