Ginseng Compounds Targeting the Gut-Brain Link: Possible Treatments and How They Work in Complex Diseases

The gut-brain axis comprises the central nervous system (CNS), the enteric nervous system (ENS), and the autonomic nervous system (ANS). The CNS is responsible for regulating higher neural activities and integrating information. In contrast, the ENS is often referred to as the body’s “second brain” and contains tens of thousands of neurons that are extensively distributed within the intestinal wall. It has been demonstrated to independently regulate fundamental intestinal functions, including motility, secretion, and blood flow, without the need for intervention from the CNS [14]. The autonomic nervous system modulates intestinal activity through the sympathetic and parasympathetic nervous systems, thereby maintaining a state of functional equilibrium [15]. It has been established that neural pathways function as the primary conduit for information transmission within the gut-brain axis. It has been demonstrated that neurons within the gastrointestinal system and the vagus nerve, which modulates intestinal nerves, can directly interact with microbial products and microbiota-dependent immune mediators [16]. Local signals are transmitted via sensory circuits to brain regions that have been shown to be associated with cognition, emotion, and somatosensation. Conversely, the brain exerts a regulatory influence over gastrointestinal homeostasis through the release of efferent projections from the vagus nerve and the spinal cord that target the intestinal mucosa. These projections interact with the enteric nervous system, contributing to the maintenance of internal environment stability. Through top-down signaling and the modulation of gut neuronal activity by microbiota-associated molecules, which in turn affects gastrointestinal physiology, local immune function, and gut microbiota composition [17]. When the gastrointestinal system is exposed to noxious stimuli, enteric neurons initiate the transmission of signals to the brain via the vagus nerve. The brain receives these signals and generates corresponding feedback, thereby regulating intestinal motility to rapidly expel harmful substances [18].

Endocrine pathways have also been demonstrated to play a crucial role in gut-brain axis communication. The transmission of signals through enteroendocrine cells by microbial products and metabolites has been demonstrated to regulate neurotransmitter secretion [19]. Furthermore, certain subpopulations within the gut microbiota can directly synthesize and release neurotransmitters. These substances have the potential to be absorbed into the portal venous system, which may allow them to traverse the BBB and directly influence central neuronal activity [20]. The gut microbiota and hypothalamic-pituitary-adrenal cortex axis (HPA axis) have been demonstrated to influence neuroendocrine signaling pathways in a mutually reinforcing manner. Stress-induced activation of the HPA axis has been demonstrated to affect gastrointestinal function, altering the composition of the gut microbiota. Conversely, reduced microbiota abundance modifies HPA axis function. Research indicates that during periods of stress, the HPA axis is activated, leading to increased cortisol and other hormone secretion, affecting intestinal motility and digestive fluid secretion while altering gut microbiota structure. Conversely, dysbiosis has been demonstrated to influence the HPA axis, thereby modulating hormone secretion levels and consequently, systemic stress responses [21].

The immune pathway is pivotal for communication along the gut-brain axis, playing a crucial role in maintaining immune homeostasis and neural function. Microbial metabolites, including SCFAs, and membrane components can shape immune homeostasis and modulate pro-inflammatory or anti-inflammatory states in local immune responses [22,23]. Furthermore, the gut microbiota participates in regulating the development and function of microglia [24], the resident immune cells of the brain that maintain cerebral immune balance and neural function. During neuroinflammatory episodes, increased BBB permeability allows microbial products and peripheral immune cells to rapidly infiltrate the brain parenchyma, thereby initiating or exacerbating neuroinflammatory responses [25]. Conversely, brain inflammation disrupts gut microbiota homeostasis, further intensifying neuroimmune responses and worsening pathology [26], thereby creating a bidirectional inflammatory vicious cycle.

The gut microbiota plays a pivotal role in the gut-brain axis, typically comprising a vast and diverse array of microorganisms, including bacteria, fungi, and viruses. These microorganisms are involved in the process of food digestion and the absorption of nutrients [27]. Additionally, they are responsible for synthesizing beneficial substances, such as SCFAs [28]. Alterations in the composition and function of the gut microbiota are closely associated with the onset and progression of numerous major diseases, including irritable bowel syndrome [29], inflammatory bowel disease [30], and neurological disorders [31]. The discovery that the composition of the gut microbiota in PD differs significantly from that of healthy individuals suggests a potential influence of altered bacterial species on neuroinflammation and neurotransmitter metabolism via the gut-brain axis. This phenomenon may contribute to the pathogenesis of PD [32].

The vagus nerve serves as a pivotal structure in the gut-brain axis neural pathway, functioning as a conduit for bidirectional communication between the nervous and gastrointestinal systems. The vagus nerve is the longest and most widely distributed cranial nerve in the human body. The vast majority of its nerve fibers originate in the gut and project to the brain. Changes in gut microbiota can influence brain activity via the vagus nerve [33], while conversely, brain signals can regulate intestinal physiological functions through the vagus nerve [34].

Neurotransmitters are crucial chemical messengers in the gut-brain axis, with many, such as serotonin 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (GABA), and dopamine, synthesized in both the brain and gut [35]. Over 90% of serotonin is produced in the gut, regulating intestinal function and influencing mood and cognition via systemic circulation or the vagus nerve [36,37]. Gut microbiota also modulate GABA and dopamine metabolism to affect central nervous system activity [38,39].

Inflammatory cytokines (e.g., TNF-α) mediate bidirectional immune communication along the gut-brain axis [40]. Intestinal inflammation-induced cytokine release activates central microglia and disrupts neuronal function, while brain inflammation in turn alters gut microbiota homeostasis [41,42]. In patients with inflammatory bowel disease, persistent intestinal inflammation promotes massive release of inflammatory cytokines. Once these enter the bloodstream, they can impair brain neural function, leading to psychiatric symptoms like anxiety and depression [43]. Conversely, abnormal emotional states in the brain may also exacerbate intestinal inflammation through the gut-brain axis [44].

Consequently, as a multifaceted and exacting bidirectional communication system, the neural, endocrine, and immune pathways of the gut-brain axis are intricately interwoven. It has been established that a multitude of participants, including the intestinal microbiota, the vagus nerve, neurotransmitters, and inflammatory cytokines, collaborate to preserve the physiological and psychological equilibrium of the body. It has been demonstrated that the gut-brain axis is of great significance for revealing the pathogenesis of multifactorial diseases and in the development of novel treatment strategies (Figure 2).

Neurotransmitters function as crucial mediators in the communication between the gastrointestinal system and the brain. The extensive microbial communities residing within the gastrointestinal tract play a pivotal role in immune regulation and metabolism [104]. Moreover, these communities have been shown to exert bidirectional regulatory effects on intestinal health [105] and central nervous system homeostasis [106,107]. Current research confirms that gut microbiota can exert bidirectional regulation by modulating the synthesis and release of neurotransmitters such as dopamine [108], norepinephrine [109], 5-HT [110], or gamma-aminobutyric acid (GABA) [111], exerting profound effects on the organism.

Dopamine has been linked to a variety of functions, including reward, motivation, and motor control. Maintaining sustained normal levels of dopamine bioavailability has been shown to have a positive impact on brain physiology and can play a role in the prevention of neurosystem-related diseases [112]. Concurrently, the gut microbiota possesses intrinsic enzymatic activity highly involved in dopamine metabolism. This activity promotes both dopamine synthesis and degradation [113]. Wang et al. [114] demonstrated that ginsenoside Rb1 mediates effects through 5-HT, noradrenergic, and dopaminergic systems, exhibiting significant antidepressant activity in behavioral tests, chronic animal models, and drug interactions.

5-HT exhibits multifaceted activity in major diseases associated with both gastrointestinal function [115] and neuroinflammation [116]. Chen et al. [117] established a neuropsychiatric model of morphine dependence, which is also intrinsically linked to gut microbiota dysbiosis. Results indicate that ginsenoside Rg1 significantly ameliorates morphine-induced gut microbiota dysbiosis. This effect is achieved by inhibiting tryptophan metabolism derived from the gut microbiota and reducing serotonin receptor levels in the serum, including 5-HT1B and 5-HT2A receptors. Xu et al. [118] demonstrated that ginsenoside Rg3 prevents decreases in progesterone, estradiol, and 5-HT levels in the prefrontal cortex and hippocampus, thereby improving anxiety- and depression-like behaviors in CUMS model mice.

GABA, an inhibitory neurotransmitter that plays a crucial regulatory role in the central nervous system, is involved in reducing neuronal excitability [119]. Consequently, GABA imbalance has been identified as a contributing factor to the onset and progression of neurological disorders. Recent findings support the hypothesis of a dynamic relationship between GABA levels, cerebral changes, and alterations in gut microbiota composition [120]. Shao et al. [121] discovered that ginsenosides Rg5 and Rk1 exert sedative and hypnotic effects by influencing the GABAergic system and 5-HT pathways. They increase the GABA/Glu ratio while upregulating 5-HT1A expression, with similar results observed for GABA and 5-HT in mouse cecal tissue.

The HPA axis is a critical element of the body’s stress response system. HPA dysfunction is associated with various mental and physical disorders, including depression [122], anxiety [123], and metabolic syndrome [124]. As a core component of the neuroendocrine system, the HPA axis directly mediates psychological and physical stress responses [125] and regulates numerous normal physiological processes. Simultaneously, the HPA axis facilitates direct communication with the gut microbiota. HPA axis activity has been demonstrated to alter gut microbiota composition and regulate intestinal permeability, thereby inducing chronic tissue inflammation [126]. Therefore, regulating the HPA axis holds significant promise for treating multiple diseases.

Ginseng has been demonstrated to modulate the HPA axis and exhibits significant biological activities, including anti-stress, neuroprotective, and immunomodulatory effects. Its precise regulation of HPA axis function is considered a key mechanism underpinning its role in modulating the gut-brain axis and treating diseases. Yang et al. [93] summarized the mechanisms by which ginsenoside Rg1 improves depressive-like behavior, including suppression of HPA axis hyperactivity, modulation of synaptic plasticity, and regulation of gut microbiota, highlighting Rg1′s potential in treating neuropsychiatric disorders. Findings by Shao et al. [127] demonstrated that ginsenoside Rh4 significantly mitigates neuronal and synaptic damage, alleviates depressive-like behaviors in mouse models of depression, and resolves HPA axis dysregulation. Concurrently, it improves gut microbiota composition, increases short-chain fatty acid levels, and inhibits the LPS/NLRP3/caspase-1/IL-1β signaling pathway, thereby exerting key therapeutic effects. Zhang et al. [128] demonstrated that red ginseng total saponins (RGTSF) significantly modulate HPA axis-related indicators while regulating gut-brain axis-related markers and improving spleen deficiency syndrome, highlighting ginseng’s potential in regulating the HPA axis and treating gut-related disorders. These effects are more pronounced in acute stress models, while greater interindividual variability is observed in chronic stress models.

The vagus nerve, a critical component of the parasympathetic nervous system, plays a pivotal role in facilitating communication between the gut and the brain [129]. Existing research has confirmed the antidepressant activity of ginsenosides. Rk3 has been shown to modulate tryptophan metabolism in the brain-gut axis by targeting tryptophan hydroxylase, thereby reshaping gut microbiota composition, mitigating intestinal barrier damage, and subsequently improving hypothalamic-pituitary-adrenal axis dysfunction in mice. This intervention has been shown to mitigate neuronal damage in the hippocampal and prefrontal cortical regions of mice, thereby ameliorating depressive-like behaviors [9]. Similarly, studies have confirmed Rg1′s anti-inflammatory, antioxidant, and neuroprotective activities. It exerts therapeutic effects in early-stage and mid-to-late-stage Alzheimer’s disease by repairing dendrites and axons and resolving inflammation associated with microglia and astrocytes. This primarily relies on its activation of the vagus nerve, thereby mediating gut-brain axis signaling pathways [93] (Figure 4).

The strongest causal evidence across all GBA regulatory mechanisms comes from rodent faecal microbiota transplantation and vagotomy studies, which have confirmed the central roles of gut microbiota remodelling and vagal nerve signalling in mediating ginseng’s effects. In vitro studies have also validated the molecular mechanisms of intestinal barrier protection and anti-inflammation. However, there have been no human studies that have directly measured the effects of ginseng on intestinal permeability or vagal nerve activity, and it is unclear how these preclinical mechanisms can be translated to humans. Additionally, the necessity of the vagus nerve pathway has only been verified in a limited number of disease models.

Alzheimer’s disease is the most prevalent cause of dementia worldwide and is classified as a neurodegenerative disorder. This condition is characterized by the progressive degeneration of neurons, which is associated with the formation of β-amyloid plaques and neurofibrillary tangles [130]. The gut microbiota comprises complex microbial communities residing within the intestinal ecosystem. These microorganisms can participate in gut-brain axis activity, thereby influencing cognitive function and associated behaviors [131]. Growing evidence indicates that dysbiosis of the gut microbiota may compromise immune responses and promote inflammation, which could potentially impact the digestive or nervous systems [132]. This dysbiosis has been posited as a potential initiating factor in the onset and progression of AD. Ginsenosides, the active constituents of natural medicines, possess potent antioxidant properties. The mechanisms by which they exert their neuroprotective effects include the restoration of the gut-brain axis through modulation of the gut microbiota and brain neurotransmitters [133]. According to the findings of previous studies, the administration of Rg1 has been shown to alter the abundance of gut microbiota in mice, thereby improving AD, with Proteobacteria and Verrucomicrobia being key bacterial groups [134]. Lee et al. [91] found that oral red ginseng improved cognitive behavior in mice, reduced Aβ deposition and microglial hyperactivation, decreased blood-brain barrier permeability, and altered gut microbiota diversity by increasing Lactobacillus species. This demonstrates red ginseng’s ability to mitigate Alzheimer’s pathology via the gut-brain axis. Shin et al. [135] used a 5 × FAD transgenic mouse model of AD and found that the non-saponin fraction with rich polysaccharide (NFP) of red ginseng significantly reduced Aβ deposition in the hippocampi of model mice, alleviated neuroinflammation, neuronal loss, and mitochondrial dysfunction. It also improved mitochondrial defects in Aβ-treated HT22 cells and promoted cognitive recovery in AD mice, confirming that red ginseng polysaccharides exert therapeutic effects against AD by modulating the gut-brain axis.

PD is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain and the subsequent abnormal aggregation of α-synuclein (α-syn) [136]. Recent studies have identified a potential role for the gut microbiota in the pathogenesis of PD through the gut-brain axis [137]. This suggests that α-syn accumulation in the gut may be transmitted to the brain through the vagus nerve, contributing to the development of PD. The inflammatory response and metabolite changes caused by the disorder of the gut microbiota are manifested as a sharp reduction in the content of short-chain fatty acids, which eventually aggravates nerve damage. Therefore, targeting the gut-brain axis holds significant promise for alleviating neuroinflammation and inhibiting α-syn pathological propagation. Currently, ginseng’s active components have been demonstrated to alleviate PD motor dysfunction by reshaping gut microbiota structure, enhancing intestinal barrier function, and suppressing inflammatory pathways [138]. Ginseng shows promising preclinical potential in treating neurodegenerative disorders. Research has confirmed that red ginseng modulates intestinal tight junctions and inflammation in the colon of a Parkinson’s disease mouse model, improves motor dysfunction, inhibits the disruption of tight junction proteins in the colon, reduces inflammatory factor levels, and prevents the accumulation of α-syn in the colon and substantia nigra. This indicates that red ginseng may influence the progression of Parkinson’s disease by regulating gut-related indicators, involving mechanisms related to the gut-brain axis [139].

Obesity and its associated type 2 diabetes mellitus (T2DM) are two inextricably linked metabolic disorders. According to statistical data, approximately 463 million individuals worldwide are affected. The underlying causes of these conditions are primarily attributed to the expansion of adipose tissue and systemic inflammatory responses triggered by genetic susceptibility or prolonged nutritional excess. This leads to a surge in pro-inflammatory cytokine levels, disrupting insulin signaling pathways [143]. Notably, T2DM is frequently accompanied by altered gut pathophysiology, manifesting as dysbiosis [144]. Concurrently, obesity disrupts the balance between beneficial probiotics and harmful pathogens within the body [145]. Thus, modulating this microbial imbalance presents a novel therapeutic avenue.

A growing body of research corroborates the notion that ginseng’s primary active components exert bidirectional regulation on the structure of gut microbiota, thereby promoting the proliferation of beneficial bacteria while impeding the growth of pathogenic microorganisms [146]. Wei et al. [147] investigated the effects of ginsenoside Rg5 on the gut microbiome of diabetic db/db mice. Data indicated that Rg5 treatment improved hyperglycemia, restored intestinal barrier function, alleviated inflammation associated with metabolic endotoxemia, and reversed dysbiosis in the colonic microbiota. Reversing gut dysbiosis and diabetes-associated metabolic disorders in a type 2 diabetes context, reducing intestinal permeability and subsequent systemic endotoxemia, contributes to maintaining normal gut-brain axis function. Administration of ginsenoside Rg1 significantly reduced blood glucose levels in high-fat diet and streptozotocin (STZ)-induced T2D rats, mitigating insulin resistance, oxidative stress, and inflammatory responses. It modulates gut microbiota composition by increasing the proportion of Lachnospiraceae_NK4A136_group and Lachnoclostridium while decreasing Lactobacillus content, thereby improving gut microbial composition and exerting anti-diabetic activity [148]. Hyperlipidemia is also one of the hallmarks of type 2 diabetes. Gamma-aminobutyric acid-fructose-glucose (GABAFG), a Maillard reaction product of ginseng, increased Akkermansia and decreased Romboutsia abundance in a high-fat diet/streptozotocin (HFD/STZ)-induced T2DM mouse model of hyperglycemia and hyperlipidemia. This reshaped the gut microbiota and reduced serum glycerophospholipid metabolism, thereby alleviating T2DM-induced dyslipidemia [149]. Han et al. [150] found that ginseng peptides (GP) significantly reduced fasting blood glucose levels, improved insulin resistance (IR), and corrected lipid metabolism disorders in T2DM mice. while also regulating gut microbiota dysbiosis and short-chain fatty acid metabolism. GP activates the IRS-1/PI3K/Akt and AMPK signaling pathways to modulate glycogen synthesis, gluconeogenesis, and glucose transport, and improves IR by inhibiting mitochondrial apoptosis signaling pathways. Polysaccharides, as one of the primary active components in ginseng, have been found to possess hypoglycemic and hypolipidemic activities. Investigations into the effects of rhamnogalacturonan-I-enriched pectin (GPS-1), abundant in ginseng, on lipid metabolism in T2DM rats revealed that GPS-1 modulates gut microbiota composition, increases short-chain fatty acid levels, and improves lipid metabolism by activating the AMP protein kinase pathway [151].

The pathological hallmark of NAFLD is excessive accumulation of lipids in the liver without significant alcohol consumption. Its progression can range from simple steatosis to non-alcoholic Steatohepatitis (NASH), fibrosis, and ultimately cirrhosis [152]. The pathogenesis of NAFLD is primarily driven by insulin resistance, dyslipidemia, and chronic inflammation. Studies indicate that high-fat diets induce gut microbiota dysbiosis, characterized by reduced abundance of beneficial bacterial genera [153,154]. This dysbiosis compromises the intestinal barrier, allowing microbial byproducts and endotoxins to translocate to the liver via the portal vein. Within the liver, these substances trigger mitochondrial dysfunction, oxidative stress, and lipogenesis [155,156].

Ginsenosides exhibit structural similarity to steroid hormones [157]. Research indicates that ginsenoside extract (GE) exerts a significant therapeutic effect on symptoms of NAFLD induced by a high-fat diet (HFD), exhibiting a dose-dependent response. In addition to its efficacy in alleviating NAFLD symptoms, GE has been observed to promote gut microbiota balance, reduce intestinal permeability, and mitigate metabolic endotoxemia [158]. Shi et al. [92] similarly identified ginsenoside Rg5-mediated gut-microbiome axis activity in an HFD-induced NAFLD model to exert therapeutic effects against NAFLD. Rg5 intervention altered gut microbiota composition, promoting increases in beneficial bacteria such as Bacteroides and Akkermansia while reducing the relative abundance of harmful bacteria. Similar outcomes were observed in fecal microbiota transplantation (FMT) experiments, further confirming Rg5′s ability to mitigate NAFLD activity in mice by actively participating in gut microbiota restoration via FMT.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions primarily comprising Crohn’s disease (CD) and ulcerative colitis (UC). The etiology of the condition under investigation may be attributed to a combination of genetic predisposition, immune dysregulation, environmental factors, and gut microbiota dysbiosis [159]. Typically, patients suffering from IBD exhibit a significant imbalance in the composition of their gut microbiota. Concurrently, the disruption of microbial metabolic functions leads to reduced SCFA synthesis, impaired tryptophan metabolism, and abnormal bile acid conversion. These alterations further compromise intestinal barrier integrity and exacerbate inflammation [160]. Consequently, modulating gut microbiota has emerged as a novel therapeutic strategy for IBD. Ginseng active components, such as ginsenosides, have demonstrated preclinical therapeutic effects through multi-targeted interventions in microbiota-host interactions [161]. Research indicates that the primary metabolites of American ginseng following intestinal microbial conversion are CK and ginsenoside Rg3. These metabolites significantly alleviate chemically induced colitis and abdominal pain by suppressing pro-inflammatory cytokine expression, demonstrating that ginseng’s gut microbial metabolites possess promising preclinical therapeutic activity against inflammatory bowel disease [162].

UC is a chronic, non-specific inflammatory bowel disease. Its pathogenesis has been linked to genetic factors [163], immune dysregulation [164], gut microbiota imbalance [165], and environmental influences [166]. At present, the modulation of the gut microbiota has emerged as a highly promising therapeutic strategy for ulcerative colitis. Ginseng, a time-honored herbal remedy, is characterized by its active constituents, which exhibit a wide array of biological functions. Liu et al. [167] established a UC model using dextran sulfate sodium (DSS) and found that ginsenoside Rg3 administration suppressed NLRP3 inflammasome activation, pyroptosis, and apoptosis while partially restoring gut microbiota abundance at phylum and genus levels in UC mice. Meanwhile, Shin et al. [45] established a UC-associated anxiety and depression model by exposing mice to restraint stress or transplanting fecal matter from UC and depression patients, and found that ginsenoside Rd and CK suppressed anxiety-depression-like behaviors while partially restoring gut microbiota fluctuations induced by fecal transplants from UC and depression patients. This suggests they may alleviate colitis by modulating the microbiota-gut-brain axis (Figure 5).

In terms of therapeutic applications, there is the most extensive preclinical evidence for neurodegenerative diseases and mood disorders, with consistent findings across multiple independent rodent models. Metabolic and gastrointestinal diseases also show promising preclinical results. However, almost all studies are currently limited to animal models, with only a few indications having been investigated in small-scale observational studies and pilot trials. To date, no large-scale randomised controlled trials have evaluated the efficacy of ginseng components targeting the GBA in any human disease. Additionally, critical clinical translation gaps remain, including insufficient long-term safety data, a lack of standardized dosing regimens across different ginseng preparations, and significant interindividual variability in response driven by gut microbiota composition differences.