Chronic diseases impose a substantial global health burden and cause high mortality rates (Cifuentes et al., 2025). The conventional “one molecule, one target” pharmacological paradigm, rooted in reductionist principles, exhibits intrinsic limitations in addressing the multifactorial pathogenesis of these complex disorders, underscoring the urgent need for innovative therapeutic strategies.

Panax ginseng C. A. Mey. (PG), a widely cultivated medicinal food plant (classified as a GRAS resource), is primarily harvested in autumn, washed, and processed via sun-drying or mechanical drying. As a cornerstone of traditional and modern integrative medicine, PG exerts pleiotropic therapeutic effects against chronic diseases through synergistic interactions with herbal preparations and dietary supplements. Its pharmacological activities, including glycemic control (Chen Q. et al., 2017), immune modulation (Qu et al., 2021), and antitumor efficacy (Wang et al., 2023), are primarily attributed to bioactive metabolites such as ginsenosides (e.g., Rb1, Rg1, Rg3, and Rh1) and polysaccharides. Recent studies have underscored the critical role of the GM in mediating the therapeutic effects of PG. Central to this mechanism is the GM’s facilitation of phytochemical biotransformation: it converts ginsenosides (e.g., Rb1→compound K (CK)), catechins, and quercetin into pharmacologically active metabolites, thereby enhancing both intestinal absorption and systemic bioavailability of PG-derived compounds (Santangelo et al., 2019; Furman et al., 2019). Comparative analyses of Asian and American ginseng chemotypes—defined by distinct chemical profiles—reveal variations in secondary metabolite composition (Liang et al., 2015) and tissue-specific accumulation patterns (Chen et al., 2015); these differences not only establish evidence-based quality control benchmarks for herbal preparations but also provide scientific rationale for their differential clinical applications (e.g., preferential use of Asian ginseng in metabolic disorders versus American ginseng in immune modulation). Notably, current evidence indicates that age-related dysbiosis (e.g., reduced microbial diversity, altered Firmicutes/Bacteroidetes ratios) or antibiotic-induced disruptions in GM homeostasis may significantly impair PG’s biotransformation efficiency and subsequent bioactivity (Chen Y. et al., 2017). This review aims to systematically synthesize PG’s multicomponent metabolites and their multitarget mechanisms in chronic disease management, highlight the GM’s role as a key determinant of PG’s bioactivity, evaluate its safety profile, and assess its therapeutic potential within integrative medicine frameworks.

The therapeutic effects of PG across diverse disease contexts are linked to GM modulation, though the robustness of supporting evidence varies notably. A comprehensive systematic review of the literature stratifies the mechanisms of ginsenosides into three evidence tiers: In diabetes management, for example, ginsenoside Rb1 enhances insulin sensitivity via GM-mediated metabolic transformation—a pathway validated by multi-omics profiling (Chen et al., 2022). This process involves augmenting probiotic abundance (e.g., Lactobacillus species), promoting SCFA biosynthesis, and suppressing the pro-inflammatory TLR4/NF-κB signaling axis. Beyond this well-supported mechanism, emerging evidence in antitumor research suggests ginsenosides Rg3 and CK may increase PD-1 inhibitor efficacy through GM modulation (Huang et al., 2022). However, these findings are currently limited to mouse models and lack clinical validation. Further complicating the landscape, speculative associations, such as the proposed “gut-brain axis” regulation in neuroprotection (Li et al., 2024), rely on indirect evidence where the GM composition changes correlate with behavioral improvement, but causal relationships remain unclear. Collectively, these findings underscore the need for further investigation to advance research in this field.

Panax ginseng C.A. Mey. (Renshen; Ginseng Radix et Rhizoma) refers to the dried roots and rhizomes of plants in the Panax genus (family Araliaceae). Quality control adheres to HPLC analysis as specified in General Principle 0512 of the Chinese Pharmacopoeia. Each batch, when calculated on a dry weight basis, must contain no less than 0.30% combined ginsenosides Rg1 (C₄₂H₇₂O₁₄) and Re (C₄₈H₈₂O₁₈), and no less than 0.20% ginsenoside Rb1 (C₅₄H₉₂O₂₃). Pharmacologically standardized batches further require ≥0.27% combined Rg1 and Re, and ≥0.18% Rb1 (Chinese Pharmacopoeia, 2025).

Physical characteristics of the product include round or nearly round thin slices prepared via moistening, cutting, and drying. Key morphological features are a grayish-yellow outer skin; pale yellowish-white to nearly white, powdery cross-sections with brownish-yellow vascular cambium rings; and a periderm displaying brown, dot-like resin ducts and radiating fissures. The slices have a lightweight and brittle texture, with a distinctive aroma and mildly bittersweet taste.

Compliance of PG (particularly wild or protected populations) with collection, processing, and trade regulations, including the Nagoya Protocol, the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES), and plant quarantine requirements, requires verification. Product categories include: Raw materials/primary processed products: Dried ginseng roots (sliced or whole), ginseng powder, ginseng extracts (e.g., red ginseng extract). Finished products: Pharmaceuticals (e.g., ginseng capsules, tablets, and oral liquids); health supplements (e.g., ginseng tonics and energy drink additives); cosmetics (e.g., ginseng creams and essences).

Within our institution, a batch of herbal medicine sourced from Jilin Province is retained, bearing the batch number 2305210072.

This study employed a systematic and transparent literature search strategy aligned with the Population, Intervention, Comparison, Outcome, Study Design (PICOS) framework to ensure methodological rigor. The search targeted the following: 1) Population (chronic disease models/patients); 2) Intervention (ginseng/active plant metabolites); 3) Study Design (controlled settings); 4) Outcome (gut microbiota parameters); and 5) Study Types (clinical/preclinical research). Databases including PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and ClinicalTrials.gov were queried using a combination of keywords: interventions (“Panax ginseng,” “ginsenoside”), mechanisms (“gut microbiota,” “intestinal flora”), and diseases (“chronic disease,” “metabolic disorder”).

After removing duplicate articles with Zotero, two independent reviewers conducted title/abstract screening and full-text assessment based on predefined inclusion criteria (clinical or preclinical design, documented ginseng intervention, microbiota analysis, data integrity) and exclusion criteria (reviews, case reports, small sample sizes, and methodological limitations). Discrepancies in screening decisions were resolved through discussion with a third reviewer, with final judgments documented using a standardized form. Quality assessment of included studies was performed using the Cochrane Risk of Bias tool (for clinical studies) and SYRCLE’s Risk of Bias tool (for animal studies) to ensure the reliability of the evidence base.

A total of 102 references were screened (final inclusion number to be updated by 2025). Panax ginseng C.A. Mey. (Latin name: P. ginseng C.A. Mey.), a perennial medicinal and edible plant, belongs to the genus Panax within the family Araliaceae. Taxonomic nomenclature and species illustrations were validated against authoritative sources, including Flora of China (1994) and The World Flora Online (http://www.worldfloraonline.org, accessed 10 March 2025), with chemical structure data sourced from PubChem and visualized using ChemDraw software. The literature retrieval flowchart is presented in Figure 1.

Methodological limitations of the current study are acknowledged as follows: 1) Most included studies did not explicitly describe the randomization procedure; 2) Only a minority adopted double-blind study designs; 3) Statistical power calculation was prespecified in few investigations; 4) Metagenomic sequencing was utilized in only a limited number of studies.

PG, as a medicinal food plant, represents a highly dynamic research field. The gut microbiota, recognized for its pivotal role in host physiology, has been extensively acknowledged—particularly its function as a “superorganism” in conjunction with the host, mediating critical processes such as drug metabolism and other physiological functions (Zinöcker and Lindseth, 2018).

Long-term administration of PG extract (PE) induces significant modulation of GM composition: probiotics, including Bifidobacterium, Lactobacillus, Allobaculum, and Clostridium, are markedly upregulated, whereas pathogenic bacteria, such as Butyricimonas, Parabacteroides, Helicobacter, and Alistipes, are significantly downregulated (Qu et al., 2021). These findings demonstrate PE’s capacity to promote probiotic proliferation while suppressing pathogen growth, thereby providing foundational evidence for its regulatory effects on the GM structure in rat models (Sun et al., 2018).

The bioactivities of key PG-derived metabolites, including CK, ginsenosides Rg3, Rh2, 20(S)-protopanaxatriol (20(S)-PPT), and 20(S)-protopanaxadiol (20(S)-PPD), are critically dependent on GM-mediated metabolism. Ginsenosides generally exhibit poor gastrointestinal bioavailability but undergo extensive biotransformation mediated by the GM, with in vivo metabolic profiles aligning closely with in vitro GM fermentation patterns (Wang et al., 2023). Deglycosylated ginsenoside metabolites produced by the GM are then absorbed into the systemic circulation.

Notably, interindividual variability in GM composition results in divergent metabolic phenotypes. For example, ginsenoside Rb1 undergoes specific biotransformation by Bifidobacterium spp. within the GM to generate compound Rd (Dong et al., 2017). Oral administration of Rb1 and Re follows distinct metabolic pathways: Rb1/Re are metabolized via the GM through Rd to form 20(S)-PPD or CK, whereas Rg1 is processed through a distinct route involving retention of the Rg1 aglycone to generate 20(S)-PPT or Rh1 (Oh H. A. et al., 2015). PG plant metabolites further differentially regulate the GM across multiple taxonomic levels: At the phylum level, significant reductions in Escherichia abundance are observed; at the genus level, treatment with Rb1/Rb2/Rb3/Rc leads to decreased relative abundances of Dorea, Prevotella, and Megasphaera, concurrent with increased Escherichia (Zheng et al., 2021).

These structural and compositional changes enhance GM integrity and metabolic diversity. For example, GM hydrolysis plays a critical role in the appearance of CK in rat plasma following Rb1 administration (Akao et al., 1998). PE-induced modifications in GM composition, specifically the enrichment of Peptococcaceae, Rikenellaceae, and Hungarian legume-associated taxa, exhibit a strong positive correlation with increased absorption of ginsenosides (e.g., Rd and Rg3) (Kim et al., 2019). Exposure to stress models, including antimicrobial agents, fatigue, and acute cold, has been shown to suppress the production of deglycosylated ginsenoside Re metabolites, a phenomenon attributed to altered glycosidase activity in Proteus, Lactobacillus, and Bacteroides populations (Zhang et al., 2021). Ultra-high-performance liquid chromatography coupled with ion mobility-quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS) analysis of six biotransformation samples identified 248 ginsenoside/metabolite features, with desaccharification emerging as the dominant metabolic pathway. Notably, protopanaxatriol-type and oleanolic acid ginsenosides demonstrate heightened metabolic susceptibility (Mi et al., 2023). Probiotic supplementation synergizes with PG to optimize GM composition. In male Sprague–Dawley (SD) rats, probiotic-enriched feed increases the Rb1→CK conversion and gastrointestinal absorption of ginsenosides (Kim et al., 2019). Additionally, the PPD (protopanaxadiol) treatment group exhibits significant fecal microbiota alterations: increased relative abundances of Proteus_9, Fusarium, and Monomonas at the genus level and decreased Bacteroides and Proteus at the phylum level (Zhang et al., 2021).

The dynamic interplay between PG plant metabolites and GM metabolism is summarized in Figure 2.

The safety of dietary supplements and natural products has garnered substantial attention from clinicians and consumers. Given that medicine-food botanical drug substances are generally consumed in higher quantities and with greater frequency than conventional botanical drugs, their safety demands heightened scrutiny from manufacturers, distributors, and end-users (Das et al., 2024). Key exogenous contaminants in these substances encompass pesticide residues, heavy metal accumulations, toxic microorganisms, and sulfites, all of which pose potential health risks when consumed excessively or misused. Improper use of medicine, food, or botanical drug substances may further exacerbate their adverse effects. Consequently, preclinical toxicity assessments are indispensable for PG and PG extracts prior to their integration into medicinal or dietary products. Establishing safety thresholds for toxic by-products and exogenous contaminants is critical to guide population-level intake recommendations.

PG and Veratrum nigrum (VN) represent the most clinically critical herb-drug incompatibility pair in TCM, a concept deeply rooted in millennia of empirical clinical practice. In ovariectomized rat models, combined PG-VN administration attenuated the improvements in depression-like behaviors, neurotransmitter balance, and serum estrogen levels compared to monotherapies (PG or VN alone). Metabolomic and GM analyses further revealed that VN co-administration compromised PG’s regulatory effects on eight key metabolic biomarkers and four GM taxa, underscoring the disruptive impact of this incompatible pairing on PG’s pharmacological actions (Lin et al., 2022).

Comparative investigations of PG, RG, and ginseng leaves (GL) have elucidated dose-dependent adverse effects and interactions with the GM. PG demonstrated favorable modulation of the GM by increasing diversity and enriching populations of Lactobacillus and Bifidobacterium, whereas adverse reactions were primarily dose-dependent. Notably, PG-GL combinations exhibited more severe adverse effects than RG (Ran et al., 2022). Importantly, PG shows minimal toxicity at conventional dosages (3–9 g/day) (Mancuso and Santangelo, 2017), though high-dose intake (>15 g/day) may induce sporadic adverse effects (Siegel, 1980).

In cytotoxicity and repeated-dose toxicity assessments, BG extract displayed no observed adverse effect levels (NOAEL) exceeding 2000 mg/kg body weight in SD rats. Notably, RG extract, ginsenoside Rg5, and 20(S)-Rg3 exhibited comparable safety profiles when tested against six human cancer cell lines (Park et al., 2022). These findings have advanced our mechanistic understanding of TCM therapies and strengthened the rationale for their broader clinical application. The toxicity and safety profiles of PG are summarized in Table 3.

A review of the limitations of included study designs reveals prevalent methodological challenges: small sample sizes (commonly n < 100 per group), lack of blinding procedures, and insufficient randomization methods. For example, while colitis studies reported recovery of β-glucosidase activity, dietary confounders influencing GM composition remained uncontrolled. Most (90%) investigations employed rodent models exhibiting GM compositions significantly divergent from humans (e.g., mice lack key human symbiotic bacterial taxa), and acute disease induction protocols (e.g., DSS-induced colitis) poorly recapitulate the pathogenesis of human chronic diseases. Many studies reported solely on relative GM abundance shifts without functional metabolomic characterization, rendering causal relationships between GM alterations and observed outcomes indiscernible; correlative findings were often erroneously interpreted as causal relationships.

Future research should prioritize addressing three key questions: (1) whether ginsenosides exert effects directly on host cells or indirectly through GM-derived metabolites; (2) how interindividual variability in GM composition modulates treatment responses; and (3) whether long-term use induces adaptive resistance in the GM. Human clinical trials remain scarce (e.g., only 12% of included studies), underscoring the need for large-scale, randomized controlled trials. Sterile mouse models and microbiota transplantation techniques are critical for establishing causal relationships between ginsenosides, GM modulation, and therapeutic outcomes. Standardization of extraction protocols, dosing regimens, and administration methods is urgently required, given the documented 5-fold variability in bioactive phytochemicals across different ginseng preparations.

While ginsenosides demonstrate broad therapeutic potential, their contribution varies by disease context: GM regulation accounts for 30%–50% of metabolic improvements in obesity (Zhao et al., 2021) but only ∼15% of antitumor effects in cancer (Hou et al., 2022). Notably, disease pathologies inherently modulate GM composition, and underreporting of negative findings may artificially inflate reported treatment efficacy, as studies may conflate disease-induced microbiota alterations with direct pharmacological effects.

This study rigorously evaluated pharmacological parameters across the included literature. (1) Dosage specifications distinguished preclinical (e.g., Rb1 at 10–100 mg/kg in animal models) and clinical (e.g., 200–600 mg/day of ginseng extract) studies, with critical thresholds noted (e.g., Rg1 EC₅₀ = 15 μM for anti-inflammation). (2) Model validation confirmed that in vitro (Caco-2 cell assay) and in vivo (DSS-colitis mouse) systems mirrored human disease mechanisms (e.g., consistency in the TLR4/NF-κB pathway). (3) Over 90% of the results from included studies were positive, with no negative findings for comparison, which weakened the robustness of conclusions. (4) Material standardization ensured taxonomic accuracy (Panax ginseng C.A. Mey.) and extraction protocols (70% ethanol, 48 h). Limitations analysis highlighted gaps in dose translation (animal-to-human), long-term safety (>6 months), and microbiota–host interaction mechanisms (e.g., SCFA receptors), proposing future directions: cross-species pharmacodynamic modeling, multicenter trials, and “microbiota–metabolite–host” network analysis.

The GM, often termed the “third organ,” encompasses hundreds of microbial species with a biomass comparable to human somatic cells (Sender et al., 2016). This complex ecosystem, comprising trillions of microbes primarily residing in the gastrointestinal tract, has co-evolved with the host in a mutually beneficial symbiosis. Emerging evidence underscores the pivotal role of GM–botanical drug interactions in modulating mental health, where plant metabolites exert neuroprotective effects through multitarget mechanisms involving both host physiological pathways and microbial community dynamics. Polyphenols and polysaccharides prevalent in herbal medicines demonstrate prebiotic properties that shape GM composition, providing a mechanistic framework to elucidate botanical drug efficacy via the microbiome–gut–brain axis. This paradigm not only advances understanding of traditional plant-based therapies but also facilitates the discovery of novel bioactive metabolites. Notably, drug candidates exhibiting low bioactivity or bioavailability should not be prematurely dismissed, as GM-mediated metabolic transformation may generate therapeutically active metabolites.

Integrating GM modulation into probiotic development strategies holds potential to enhance drug synergy, while interindividual variations in GM composition driven by lifestyle and dietary factors necessitate personalized dose optimization. Leveraging the medicinal-edible duality of PG offers significant potential for developing daily health products. However, comprehensive studies are required to evaluate synergistic effects between PG active plant metabolites and antidepressants/anticancer drugs, mandating rigorous investigation into pharmacokinetic interactions and safety profiles. Future research should prioritize elucidating the bidirectional communication between PG-derived metabolites and GM, while establishing standardized frameworks for quality control and clinical translation. PG’s low toxicity profile positions it as a promising candidate for novel antiviral drug development, provided that systematic toxicity and efficacy evaluations are conducted to support its therapeutic applications.

This perspective highlights the necessity of strengthening basic and clinical research to establish standardized systems for PG application, ensuring its safe and effective integration into modern medical practices. The convergence of traditional knowledge and modern pharmacological approaches may pave the way for innovative health solutions harnessing the therapeutic potential of PG and its interactions with the GM.

Existing studies have demonstrated that ginseng improves metabolic diseases by regulating the gut microbiota; however, the current evidence base is constrained by notable limitations. First, animal model bias is prevalent: 90% of studies rely on rodents (e.g., SD rats, C57BL/6 mice), whose gut microbiota composition significantly diverges from humans, potentially limiting the generalizability of findings to human populations. Second, deficiencies in research design undermine reliability: most clinical studies have small sample sizes (n < 100), lack randomized controlled trials (RCTs), and fail to standardize ginseng dosage (ranging from 100 mg to 3 g/day), weakening the robustness of conclusions. Third, incomplete mechanistic exploration characterizes the field: only 30% of studies integrate metagenomics and metabolomics, with most focusing solely on shifts in bacterial abundance rather than elucidating specific metabolic substance–host interaction mechanisms.

Despite these limitations, current evidence supports two key conclusions: 1) PG polysaccharides significantly increase the abundance of probiotics such as Akkermansia; and 2) ginsenoside Rg1 may mitigate intestinal inflammation by inhibiting the NF-κB pathway. Nevertheless, critical gaps remain. For instance, it is unclear whether the microbiota-regulatory effects of ginseng vary across its anatomical parts (roots, stems, leaves), as only three studies have compared these components. Additionally, long-term safety data—particularly regarding the impact of prolonged ginseng use on intestinal barrier function—are lacking. Addressing these challenges will require expanded clinical trials with standardized protocols, multi-omic mechanistic investigations, and comparative studies of ginseng’s anatomical components to advance our understanding of its gut microbiota-dependent therapeutic potential.

In summary, this review underscores the significant translational potential of PG in personalized medicine, primarily driven by its interaction with the GM. PG modulates GM composition, increasing the bioconversion of ginsenosides (e.g., Rb1, Rg3) into active metabolites such as CK, which directly influences therapeutic efficacy. Baseline GM profiling (e.g., abundance of Bifidobacterium and Lactobacillus) can predict individual responses, enabling biomarker-guided treatment stratification. Future research should prioritize addressing the following key issues: Standardized research design: Conduct multicenter RCTs with clear definitions of ginseng dosage, treatment duration, and standardized extracts (e.g., total ginsenosides ≥50%). Multi-omics integrated analysis: Combine metagenomics, metabolomics, and transcriptomics to unravel the molecular network underpinning the “microbiota–metabolites–host immunity” axis. Mechanistic deepening: Verify causal relationships through fecal microbiota transplantation or germ-free mouse models.

By integrating microbiota analysis into PG therapy, this approach could enhance precision medicine, reduce interindividual variability, and advance PG from traditional empirical use to evidence-based prevention and treatment of chronic diseases.