Panax ginseng as a microbial ecosystem modulator: implications for systemic health via the gut-organ axes

The gut-brain axis constitutes a bidirectional communication network linking the gut and the brain, integrating neural, endocrine, and immune pathways [ 13 , 14 ]. Disruption of this axis, often initiated by gut microbiota dysbiosis and impaired barrier function, is implicated in the pathogenesis of neuropsychiatric and neurodegenerative disorders [ [15] , [16] , [17] , [18] , [19] ]. Growing evidence indicates that ginseng and its bioactive components can counteract these pathological processes [ [20] , [21] , [22] ]. Critically, the strength of evidence supporting a microbiota-mediated mechanism varies, with the most compelling data arising from studies employing direct causal methodologies. Strong causal evidence, primarily from germ-free and fecal microbiota transplantation (FMT) studies, demonstrates that the neuroprotective efficacy of specific ginseng constituents is fundamentally dependent on an intact gut microbiota. For instance, FMT from ginseng-treated donor mice to aged recipients was sufficient to downregulated p53/p21/Rb signaling and upregulated the p16/p14, ATM, synapsin I/synaptophysin/PSD95, and CREB/ERK/AKT pathways, thereby attenuating aging-associated brain damage [ 23 ]. This directly implicates the microbiota in transferring ginseng's benefits. Similarly, germ-free models have been instrumental in validating gut microbiota as an essential mediator. The neuroprotective effect of ginsenoside CK against mild cognitive impairment was abolished in germ-free conditions, with mechanistic studies tracing its action to the enrichment of Akkermansia and propionate, leading to barrier repair and inhibition of the TLR4-p65 neuroinflammatory pathway [ 24 ]. Parallel findings confirm the microbiota-dependent nature of other saponins. FMT from NG-R1-treated donors conferred protection against ischemic stroke (IS) by inhibiting the TLR4/MyD88/NF-κB pathway in both the gut and brain [ 25 ]. Likewise, using a pseudo-germ-free model, the therapeutic effect of Panax notoginseng saponins (PNS) against IS was shown to require the gut microbiota, specifically through lactobacillus reuteri -mediated histamine synthesis that elevates cerebral histamine levels [ 26 ]. Furthermore, the pseudo germ-free model confirmed that ginsenoside Rb1 protects against cerebral ischemia/reperfusion injury by regulating gut microbiota components such as Lactobacillus helveticus and downstream GABA receptors [ 27 ]. Collectively, these interventional studies provide direct proof that the gut microbiota is not merely associated with, but is necessary for, the neuroprotective effects of these ginseng components. In addition to these causal demonstrations, a substantial body of associative evidence further supports the role of ginseng and its constituents in modulating the gut-brain axis. These studies, which typically report parallel changes in gut microbiota composition, circulating or brain metabolites, and neurological outcomes, provide compelling correlative links. Their findings collectively implicate ginseng components in the regulation of gut barrier integrity, systemic and neuroinflammation, oxidative stress, and, most distinctively for the gut-brain axis, neuroendocrine and neurotransmitter pathways ( Fig. 1 and Supplementary Table 1 ). For example, Korean red ginseng (KRG) has been associated with an increased abundance of Lactobacillus , improved BBB integrity, and reduced amyloid-β accumulation in models of Alzheimer's models [ 28 ]. In models of Parkinson's disease, KRG supplementation correlated with a modulated microbiota and reduced α-synuclein pathology [ 29 , 30 ]. Furthermore, several ginseng components, including red ginseng extract, ginsenoside CK, and Rk3, have been observed to alleviate oxidative stress alongside the modulation of taxa such as Akkermansia , Prevotella , and Lactobacillus [ 23 , [31] , [32] , [33] , [34] ]. These microbial shifts were linked to enhanced antioxidant capacity, suggesting a potential microbiota-mediated pathway for mitigating neural oxidative damage. Fig. 1 Ginseng modulation of the gut-brain axis. Pathways and components directly validated by causal microbiota studies are enclosed in solid-line boxes (left); whereas proposed or correlative connections are indicated with dashed-line boxes (right). Ginseng modulation of the gut-brain axis. Pathways and components directly validated by causal microbiota studies are enclosed in solid-line boxes (left); whereas proposed or correlative connections are indicated with dashed-line boxes (right). A particularly distinctive mechanism of the gut-brain axis, compared to other gut-organ axes, is the direct and indirect regulation of neurotransmitter systems. Associative studies highlight this link. Ginsenoside Rk3 alleviated depression-like behaviors, an effect correlated with the correction of gut tryptophan metabolic and the subsequent restoration of brain serotonin homeostasis [ 33 ]. Similarly, ginsenoside Rg1 administration was reported to enrich Lactobacillus murinus , increase levels of the microbial metabolite indole-3-acetic acid and oxytocin signaling in the brain, and improve markers of neurogenesis, collectively implicating it in the modulation of the gut microbiota and GABAergic system [ 35 , 36 ]. This modulation of key neurotransmitter and neuroendocrine pathways, often mediated by microbial metabolites, represents a unique communication within the gut-brain axis that is less prominently featured in other axes. The gut-liver axis is crucial for metabolic and immune homeostasis, and its dysregulation contributes to diseases such as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) [ [37] , [38] , [39] ]. In contrast to the gut-brain axis, evidence for ginseng's hepatoprotection via this axis is primarily associative. Studies correlate ginseng intervention with improvements in liver pathology, metabolic parameters, and beneficial modulation in gut microbiota composition, collectively suggesting modulation of the gut-liver axis as a plausible mechanism ( Fig. S1 and Supplementary Table 2 ). Ginseng intake is associatively linked to attenuated hepatic inflammation and a reinforced intestinal barrier [ [40] , [41] , [42] ]. This is supported by observations that ginseng components correlate with beneficial microbial shifts and reduced inflammatory markers. For example, ginsenoside Rk3 correlated with increased Bacteroidetes and Akkermansia in HCC models [ 38 ], while ginseng extracts were associated with a reduced Firmicutes/Bacteroidetes (F/B) ratio and alleviated inflammation in NAFLD [ 40 ]. In ALD models, ginsenoside Rg1 was linked to increased Bacteroidetes and Verrucomicrobia , upregulation of tight junction proteins, and reduced LPS translocation [ 41 ]. This strategy of enriching barrier-strengthening bacteria like Akkermansia represents a convergent mechanism shared with the gut-brain axis [ 23 , 24 , 41 , 43 ]. These interventions are further correlated with the modulation of key microbial metabolites, such as short-chain fatty acids (SCFAs) and bile acids (BAs) [ 44 ]. Ginseng extracts and saponins are associated with changes in SCFA-producing bacteria like Muribaculaceae and mitigation of HFD-induced reductions in SCFAs [ 40 , 45 , 46 ]. Notably, ginseng polysaccharides serve as fermentable prebiotic fibers, leading to SCFA production and enriching beneficial genera [ 47 , 48 ]. Ginsenoside interventions are also associated with enhanced BA metabolism, potentially through bacteria involved in BA transformation [ 43 ]. Improved lipid metabolism is another key functional outcome linked to ginseng. Ginseng extracts, Rb1, and CK are associated with reduced hepatic triglycerides and total cholesterol alongside the enrichment of beneficial bacteria such as Parabacteroides and Muribaculaceae [ 40 , 49 , 50 ]. Ginsenoside supplementation also correlates with increased Blautia , a bacterium linked to lipid homeostasis [ 43 , 48 , 50 ]. The modulation of the F/B ratio appears to be a common feature, as observed with ginsenoside Rb1 pretreatment in alcohol-treated models [ 41 ]. Critically, ginseng polysaccharides have been specifically observed to modulate fecal microbiota composition and hepatic lysine degradation, changes that coincide with attenuated obesity and liver lipid accumulation [ 51 ]. This highlights the direct impact of polysaccharide-induced microbial metabolic shifts on host energy and lipid homeostasis. The gut microbiota influences cardiovascular homeostasis through multiple pathways, including the production of metabolites such as trimethylamine N-oxide, SCFAs, and BAs, as well as the maintenance of intestinal barrier function [ 52 , 53 ]. Similar to the gut-liver axis, current evidence for ginseng's cardioprotective via this axis remains primarily associative, linking its intervention to improved microbial and metabolic profiles alongside cardiac benefits ( Fig. S2 and Supplementary Table 3 ) Atherosclerosis is strongly correlated with gut dysbiosis [ 54 ]. Panax ginseng and its ginsenosides have been associated with counteracting this dysbiosis. Ginsenoside Rb1, for instance, correlated with increased Lactobacillus abundance, enhanced bile salt hydrolase (BSH) activity, and suppression of the enterohepatic FXR-FGF15 axis, promoting cholesterol elimination [ 55 ]. In a HFD-induced model, Rb1 was further linked to a decreased F/B ratio, enriching of SCFAs-producing Oscillospira, depletion of Desulfovibrio , and elevated anti-inflammatory SCFAs, alongside normalized arachidonic acid and BA metabolism [ 56 ]. In the context of heart failure, black ginseng (BG) administration has been linked to restored Lactobacillus abundance, increased SCFAs production, and suppression of pro-inflammatory cytokines [ 57 ]. Associative studies also report that BG may normalize the estradiol/testosterone ratio to activate eNOS-NO signaling and enhance acetylcholinesterase activity [ 57 ]. However, direct causal evidence linking these systemic effects to gut microbiota mediation is still needed. Chronic lung disorders are frequently associated with intestinal symptoms, underscoring the functional connectivity of the gut-lung axis [ 58 ]. Clinical and experimental observations, such as the correlation between reduced infant gut microbiota diversity and asthma risk, establish the gut microbiota as a crucial modulator of pulmonary immunity [ 59 , 60 ]. Bioactive ginseng components that modulate both gut microbial ecology and pulmonary inflammation have thus emerged as promising candidates for targeting this axis ( Fig. 2 and Supplementary Table 4 ). The evidence supporting this mechanism varies in strength, encompassing both causal demonstration and associative findings. Fig. 2 Ginseng modulation of the gut-lung axis. Pathways and components directly validated by causal microbiota studies are enclosed in solid-line boxes (left); whereas proposed or correlative connections are indicated with dashed-line boxes (right). Ginseng modulation of the gut-lung axis. Pathways and components directly validated by causal microbiota studies are enclosed in solid-line boxes (left); whereas proposed or correlative connections are indicated with dashed-line boxes (right). A clear causal role for the gut microbiota has been established for the anti-fibrotic effect of ginsenoside PPD in pulmonary fibrosis (PF).Administration of PPD restored gut microbiota diversity and suppressed the pro-fibrotic SPHK1/S1P signaling pathway in a PF model [ 61 ]. Critically, FMT from PPD-treated mice attenuated lung fibrosis in recipient animals, while antibiotic-induced microbiota ablation abolished PPD's therapeutic efficacy. These interventional experiments directly demonstrate that the gut microbiota is necessary for PPD's anti-fibrotic action, positioning it among the best-characterized ginseng components with a microbiota-mediated remote organ effect [ 61 ]. In contrast, evidence for ginseng's role in asthma models remains associative. In a cold-stimulated asthma model, mountain-cultivated ginseng (MCG) enhanced the efficacy of dexamethasone [ 62 ]. This combined effect was associated with a restoration of gut microbial balance—including normalization of the F/B ratio, enrichment of SCFA-producing taxa, and increased levels of propionate and butyrate. These microbial and metabolic shifts correlated with attenuated pulmonary inflammation [ 62 ]. The strategy of increasing anti-inflammatory SCFAs represents a convergent mechanism shared with ginseng's action on other gut-organ axes [ 24 , 46 ], suggesting a plausible pathway for MCG's activity, albeit one requiring direct causal validation. The gut-kidney axis plays a pivotal role in renal pathophysiology, where dysbiosis and intestinal barrier disruption facilitate the systemic translocation of endotoxins and gut-derived metabolites, driving renal inflammation and functional decline [ 63 , 64 ]. Emerging, albeit limited, associative evidence suggests that ginseng bioactives may confer renoprotection by modulating this axis ( Fig. S3 and Supplementary Table 5 ). In diabetic kidney disease, ginsenoside CK treatment was associated with a counteraction of characteristic dysbiosis—specifically, a reduction in Bacteroides and Paraprevotella alongside an increase in Lactobacillus and Akkermansia [ 65 ]. This microbial shift correlated with reduced levels of the metabolite imidazole propionate, reinforced gut barrier function, and attenuated TLR4-driven renal inflammation and fibrosis [ 65 ]. The enrichment of beneficial genera like Akkermansia to strengthen the intestinal barrier presents a potential conserved mechanism, aligning with observations in other gut-organ axes [ 24 ]. In chronic kidney disease (CKD) models, PNS have been linked to the upregulation of tight junction proteins and enhanced secretory IgA production, contributing to the restoration of intestinal barrier integrity and corresponding with normalized serum markers of gut damage [ 63 ]. Similarly, a mixture of rare ginsenosides containing Rg3, Rk1, Rg6, and Rg5 have been reported to modulate gut microbiota by enhancing diversity, restoring the F/B ratio, and increasing beneficial genera, changes which correlated with reduced renal inflammation and oxidative stress in a hyperuricemia model [ 66 ].

Panax ginseng is generally well-tolerated at recommended doses, with the most frequently reported adverse effects being mild, dose-dependent, and reversible [ 71 ]. These commonly include central nervous system effects such as headache, insomnia, and nervousness, as well as gastrointestinal disturbances. Contraindications and precautions are advised for specific populations due to its biological activities. Caution is warranted in individuals with hormone-sensitive conditions (e.g., breast cancer, endometriosis) or autoimmune diseases, attributed to its immunomodulatory properties and mild estrogenic activity of certain ginsenosides [ 72 , 73 ]. Furthermore, the potential of ginseng to inhibit platelet aggregation supports the standard recommendation to discontinue its use at least 7–14 days prior to elective surgery to mitigate bleeding risk [ 74 ]. A critical component of its safety profile involves potential drug interactions. Concomitant use with anticoagulants like warfarin may reduce the International Normalized Ratio (INR), while interactions with stimulants (e.g., caffeine) or hypoglycemic agents could potentiate their effects; case reports also suggest interactions with phenelzine and alcohol [ 71 ]. An emerging consideration that aligns with the central theme of this review is the role of the gut microbiota in individualized safety and response. The biotransformation of ginsenosides into active or inactive metabolites is highly dependent on the host's microbial composition [ 9 ]. This variability may lead to significant inter-individual differences not only in efficacy but also in the susceptibility to adverse effects, underscoring the complexity of predicting uniform safety outcomes. In summary, although short-term use of Panax ginseng is considered safe for most individuals, healthcare providers should be aware of its contraindications and potential interactions. Future clinical trials targeting the gut-microbiota axis should prospectively integrate detailed safety monitoring and microbiome analysis to better define its risk-benefit ratio across diverse populations.

A systematic of the evidence across the gut-brain, -liver, -heart, -lung, and -kidney axes reveals that the systemic benefits of Panax ginseng are orchestrated through core mechanisms and organ-specific adaptive pathways. This framework posits that ginseng first establishes a foundation of systemic homeostasis via conserved, microbiota-influenced actions, which then enables and amplifies highly specific pathways to resolve distinct organ pathologies. The convergent core mechanism is the consistent enhancement of intestinal barrier integrity and the subsequent suppression of systemic inflammation. This action is consistently accompanied by, and mechanistically linked to, the enrichment of beneficial bacteria such as Akkermansia and Lactobacillus . These microbial changes are associated with strengthened tight junctions, increased production of anti-inflammatory metabolites including SCFAs, and dampened pro-inflammatory signaling, notably via the TLR4/MyD88/NF-κB pathway. The association of this barrier-enhancing, anti-inflammatory strategy with therapeutic outcomes is observed across all axes: it coincides with mitigated neuroinflammation in the gut-brain axis [ 24 , 29 ], improved hepatic steatosis in the gut-liver axis [ 41 , 46 ], attenuated atherosclerosis in the gut-heart axis [ 55 , 56 ], alleviated pulmonary fibrosis in the gut-lung axis [ 61 ], and reduced renal inflammation in the gut-kidney axis [ 63 ]. These convergent effects position the attenuation of “leaky gut” and metabolic endotoxemia as a foundational, system-wide event in ginseng's pharmacology, in which gut microbiota modulation is strongly implicated, albeit with varying levels of causal evidence across different organ axes. In contrast, the divergent, adaptive pathways determine the specific therapeutic outcomes by interfacing with the unique pathophysiology of each target organ. The modulation of neurotransmitters and neurotrophic factors distinctly characterizes the gut-brain axis [ 36 ]. The gut-liver axis features specialized regulation of lipid metabolism [ 43 , 50 ], while the gut-heart axis involves the regulating of FXR-FGF15 signaling axis [ 55 ]. The gut-lung axis is defined by the suppression of organ-specific pro-fibrotic signaling such as the SPHK1/S1P pathway [ 61 ], and the gut-kidney axis is closely tied to the management of uremic toxins and associated microbes [ 65 ].

While preclinical models provide compelling mechanistic insights, clinical evidence directly linking ginseng's health benefits to gut microbiota modulation in humans is still emerging. Existing studies are often limited by small sample sizes, short duration, and the inherent difficulty of establishing causality, further complicated by known differences between rodent and human microbiota. The following sections summarize key findings within this preliminary yet hypothesis-generating context, while explicitly acknowledging these translational constraints. Several clinical trials report promising associations between ginseng intake and metabolic health. In a randomized controlled trial of NAFLD patients, KRG significantly reduced serum liver enzymes, an improvement correlated with an enrichment of Lactobacillus , Paraprevotella , and Lachnospira compared to placebo [ 67 ]. Another 8-week trial in individuals with metabolic syndrome found that KRG reduced systolic blood pressure and modulated gut microbiota, with efficacy dependent on baseline enterotype; insulin sensitivity improved only in Bacteroides -dominant individuals [ 68 ]. Similarly, ginseng supplementation in obese women was associated with weight loss, which correlated with baseline enrichment of Bacteroidetes and Tenericutesin responders [ 69 ]. These studies collectively suggest that an individual's baseline microbiota may influence ginseng's metabolic efficacy, a hypothesis requiring validation in larger cohorts. Evidence for cognitive benefits, while encouraging, remains associative. A double-blind study of 61 healthy adults reported that American ginseng (Cereboost®) improved working memory and attention [ 70 ]. An accompanying in vitro SHIME® model study proposed a mechanistic link, showing ginsenoside metabolism increased SCFAs production and promoted beneficial bacteria like Akkermansia muciniphila and Lactobacillus [ 70 ]. However, direct evidence in humans linking these specific microbial changes to cognitive outcomes is currently lacking. Translating preclinical findings faces significant hurdles due to interspecies differences in gut microbiota and host physiology. Clinical studies to date have primarily established correlations. Therefore, claims about clinical relevance must be tempered until supported by larger, well-designed trials that incorporate longitudinal microbiome and metabolomic profiling, and ideally, causal tools like FMT. The current evidence is best viewed as a foundation for generating personalized, microbiota-based intervention hypotheses.

This review synthesizes evidence, encompassing both preclinical and clinical studies, to assess the systemic health benefits of Panax ginseng and its bioactive constituents by modulating the gut microbiota and gut-organ axes. A critical evaluation reveals a hierarchy across the different axes: direct causal proof from germ-free or FMT studies robustly supports microbiota-dependent mechanisms for neuroprotection (gut-brain axis) and anti-fibrosis (gut-lung axis). For the gut-liver, -heart, and -kidney axes, the compelling preclinical evidence remains primarily associative, linking ginseng intervention to beneficial microbial modulation, improved barrier function, and ameliorated organ pathology. Emerging clinical studies corroborate that ginseng supplementation modulates the human gut microbiota and is associated with improved metabolic and inflammatory parameters. Safety assessments confirm ginseng is generally well-tolerated, while noting important contraindications and drug interactions crucial for clinical translation. However, translating these promising findings into validated applications is contingent upon overcoming several interconnected challenges. First, a primary hurdle is the marked imbalance in evidence strength across axes. While direct causal evidence from germ-free and FMT studies robustly supports microbiota-dependent mechanisms for the gut-brain and gut-liver axes, evidence for the gut-heart, -lung, and -kidney axes remain predominantly correlative. A key priority is therefore to establish causality in these less substantiated axes using such gold-standard methods integrated with multi-omics analyses. Beyond causality, a deeper mechanistic elucidation is essential. This requires employing interventional models, such as receptor knockouts, to clarify the detailed signaling pathways of key microbial metabolites and to distinguish the prebiotic contributions of ginseng components—which involve direct modulation of microbial ecology—from their postbiotic effects mediated by metabolites like SCFAs. Compounding this evidence gap is the substantial heterogeneity in ginseng preparations and dosing regimens, which presents another major translational barrier. The interchangeable use of various processed forms (e.g., white, red, black, fermented) and isolated compounds, which possess distinct chemical profiles, coupled with an extremely wide range of administered doses, complicates cross-study comparisons and obscures the precise attribution of observed effects. Implementing standardized chemical characterization (e.g., via chromatographic fingerprints) and conducting well-designed dose-response studies are therefore paramount to identify effective, physiologically relevant regimens and to establish clear cause-effect relationships between specific components and microbiota-mediated functions. This methodological and biological heterogeneity likely underlies the considerable inconsistency in reported effects of ginseng on specific microbial taxa (e.g., Akkermansia , Lactobacillus , F/B ratio), where studies often show opposite directional changes. Key confounding variables include: the chemical profile of the ginseng preparation used (e.g., whole extract vs. isolated ginsenoside), the administered dose, the host's genetic background and baseline diet, the specific pathophysiology of the disease model, and the duration of treatment. For instance, a taxon may decrease in a high-dose intervention in one disease model but increase with a low dose in a different model. Therefore, future studies must move beyond reporting isolated taxonomic shifts. A priority is to systematically investigate how these variables influence microbial outcomes, and to focus on functional convergence (e.g., consistent increases in SCFA production despite taxonomic variation) rather than purely compositional changes. This mechanistic, cause-and-effect approach is vital for reconciling disparate findings and building a predictive understanding of ginseng's microbiota-modulating effects. Furthermore, to construct a complete mechanistic picture, future research requires integrating the role of non-saponin components, particularly polysaccharides. These compounds act as fermentable prebiotic substrates, enhancing SCFAs production and barrier integrity [ [75] , [76] , [77] ], yet direct evidence that these local effects translate to benefits for distal organs via the gut microbiota remains limited compared to ginsenosides. Therefore, a key future direction involves delineating the individual and synergistic contributions of saponin versus non-saponin components. Critical steps will include determining whether their mechanisms of action are complementary or independent, employing causal models such as germ-free animals or FMT to directly validate the systemic therapeutic benefits of polysaccharides mediated by the gut microbiota, and elucidating their distinct signaling pathways. A holistic understanding of this multi-component synergy is crucial for fully appreciating ginseng's systemic effects and developing precise therapies based on whole extracts or tailored component combinations. Finally, to bring these mechanistic insights to the clinic, advancing translation necessitates well-designed, large-scale human trials. These must not only validate efficacy but also integrate comprehensive safety assessments and employ deep phenotyping to identify predictive patient enterotypes, enabling personalized, microbiota-targeted therapies. By systematically addressing these priorities, the field can evolve from descriptive observations to a predictive, mechanistic understanding, ultimately accelerating the development of ginseng as a validated microbiome-targeted therapy.

The human gut microbiota, a complex and dynamic ecosystem composed of trillions of microorganisms, is now recognized as a pivotal “virtual endocrine organ” that is integral to host physiology and homeostasis [ 1 ]. Its essential functions include nutrient metabolism, synthesis of bioactive compounds, immune regulation, and maintenance of intestinal barrier integrity [ [1] , [2] , [3] ]. The conceptual framework of gut-organ axes has emerged to describe the bidirectional communication pathways between the gastrointestinal tract and distant organs, such as the brain, liver, heart, lungs, and kidneys [ 4 ]. This framework is critical for understanding how gut-derived signals regulate systemic health. Consequently, gut dysbiosis—a state of microbial imbalance—is both a hallmark and a pathogenic driver of numerous chronic diseases spanning metabolic, neurological, hepatic, and cardiovascular systems. Panax ginseng C.A. Meyer, a cornerstone of traditional Eastern medicine, has been used for centuries to enhance vitality, cognitive function, and overall resilience [ 5 , 6 ]. Modern pharmacology attributes its broad therapeutic potential primarily to ginsenosides, a diverse class of triterpenoid saponins with documented anti-inflammatory, antioxidant, and neuroprotective properties [ 6 ]. A significant pharmacokinetic hurdle for many major ginsenosides (e.g., Rb1, Rg1, Re) is their poor oral bioavailability, owing to their large molecular size and low membrane permeability, which limits absorption in the upper gastrointestinal tract [ 7 ]. As a result, a substantial portion of orally ingested ginsenosides reaches the colon, where the gut microbiota performs essential biotransformation [ 8 ]. Specific bacterial enzymes hydrolyze sugar moieties from protopanaxadiol (PPD)-type and protopanaxatriol (PPT)-type ginsenosides, generating smaller, more lipophilic, and often more bioactive metabolites such as compound K (CK), ginsenoside Rh1, PPD, and PPT [ 9 ]. The enhanced pharmacological activity of these microbiota-derived metabolites underscores the crucial role of gut ecology in mediating the efficacy of oral ginseng. Therefore, the systemic health benefits of ginseng arise from a dynamic, bidirectional interaction with the gut microbiota, forming a self-amplifying cycle central to its mode of action [ 10 ]. This interplay features two complementary mechanisms: the microbiota acts as a bio-transformer, converting ginsenosides into more active metabolites, while ginseng and its metabolites function as microbial modulators, reshaping the community structure and function towards a more beneficial state [ 11 , 12 ]. Thus, ginseng's systemic effects are best understood as the net result of a personalized, bidirectional dialogue between ginseng components and the gut ecosystem—a prebiotic-like feedback loop mediated via specific gut-organ axes. Despite accumulating evidence, a comprehensive synthesis integrating the effects of ginseng across all major gut–organ axes are currently lacking. A holistic and multi-axis perspective is crucial to fully decipher the systemic and interconnected nature of ginseng's mechanisms, which often confer simultaneous benefit across multiple organ system. This review aims to synthesize and critically evaluate the current evidence on how ginseng influences host health, with a focus on its interactions with the gut microbiota ranging from established mediators to associative links long the gut–brain, –liver, –heart, –lung, and –kidney axes. To conduct this comprehensive review, literature research was performed across electronic databases including PubMed, Google Scholar, Scopus, Web of Science, and ScienceDirect, using a range of search terms related to “ginseng”, “gut microbiota”, “intestinal function”, and various concepts such as “gut–brain axis”, “gut–liver axis”, “gut–heart axis”, “gut–lung axis”, and “gut–kidney axis”. Duplicates records were removed using EndNote, and relevant studies were identified through screening of title, abstract, and full text based on eligibility criteria, resulting in a refined dataset for in-depth analysis.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.