The role of Astragalus membranaceus and its derivatives in digestive system diseases: reconstruction of immune tolerance

Abstract

The gastrointestinal tract, a vital immune organ in the human body, serves as the primary site of direct contact with external antigens. Maintaining immune tolerance is essential for preventing the onset and progression of digestive system diseases. Autoimmune diseases and tumors represent the overactivation and evasion of the immune system, respectively, and the imbalance of “immune tolerance” is the common core mechanism underlying both conditions. The function of traditional Chinese medicine in regulating the immune function of the digestive system has attracted wide attention, especially in the dual regulation of immune tolerance. Astragalus membranaceus and its derivatives exhibit remarkable efficacy in restoring immune tolerance. Mechanistically, these agents exert multi-target regulatory effects via modulating core signaling pathways, remodeling immune cell function and gut microbiota composition. Concurrently, they rebalance pivotal immune axes, such as Th1/Th2 and Treg/Th17, thereby systematically reinstating immune homeostasis rather than exerting isolated, unilateral modulations. This review systematically summarizes 112 studies published in PubMed, Web of Science and CNKI from December 2020 to December 2025, focusing on the immunomodulatory mechanisms and evidence of Astragalus membranaceus and its derivatives in the treatment of digestive diseases. It further examines the limitations of current studies and potential future research directions, thereby offering a theoretical basis for the development of novel drugs derived from Astragalus membranaceus and its active compounds.

1. Introduction

Immune tolerance refers to a state of antigen-specific immunological unresponsiveness, particularly toward self-antigens or harmless foreign antigens. It underpins the immune system’s capacity to discriminate between “self” and “non-self” (1), which allows the immune system to act precisely, killing pathogens or cancer cells while avoiding damage to normal tissues (2). If immune tolerance is lost, the immune system may attack the “self,” resulting in autoimmune diseases. Conversely, excessive or inappropriate immune tolerance may prevent the immune system from responding to harmful “non-self” substances, leading to chronic infections and tumors (3–5). Therefore, immune tolerance is the cornerstone for maintaining a stable internal environment and immune homeostasis.

The gastrointestinal tract is recognized as a part of the human body’s largest immune system, which is capable of not only defending against invasive pathogens but also maintaining immune tolerance toward non-pathogenic antigens such as those derived from food (6, 7). This dynamic balance between “acceptance” and “defense” is vital for preserving intestinal homeostasis (8, 9). Thus, the regulation of immune tolerance is recognized as a key and multifaceted player in digestive diseases. Concerning digestive diseases caused by immune tolerance disorders, such as inflammatory bowel disease (IBD), celiac disease, food allergies, and neoplasms, current treatments mainly aim to control inflammation and relieve corresponding symptoms, yet fail to solve the fundamental problems of the immune dysregulation (10). In contrast, traditional Chinese medicine (TCM) constitutes a different treatment framework.

Within this conceptual framework, the evolution from classical herbal compatibilities to modern bioactive extracts and innovative formulations has emerged as a pivotal trajectory in the modernization of TCM. Astragalus membranaceus (AM) has garnered significant attention owing to its profound theoretical foundations and well-defined translational potential in modern medicine. According to TCM theory, AM can stabilize the defense line by “Yi Qi Gu Biao” (a TCM strategy for reinforcing qi to stabilize the exterior), eliminate internal pathogenic factors and generate vital energy by “Qu Du Sheng Ji” (a TCM strategy for removing toxins to promote tissue regeneration), and ultimately achieve a state of “balancing Yin and Yang” (11). Furthermore, modern pharmacological investigations have not only validated the utility of AM and its derivatives in the prevention and adjuvant treatment of various related diseases, but also elucidated their characteristic multi-target, multi-pathway regulatory mechanisms at the molecular level (12–14). This mechanism is not simply to inhibit or enhance the immune function, but to restore the disordered immune state to the normal equilibrium point, which is the key to the reconstruction of immune tolerance. Hence, this review seeks to offer a novel perspective on the prevention and management of gastrointestinal disorders by integrating the mechanisms governing immune tolerance with the therapeutic properties of AM and its related compounds.

The literature search utilized keywords related to AM and its active ingredients, including Astragalus membranaceus (AM), Astragalus polysaccharide (APS), Astragaloside, Astragalus flavonoid (AF), as well as digestive diseases such as inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn’s disease, gastritis, colorectal cancer (CRC) and intestinal barrier injury.

Study selection strictly adhered to predefined inclusion and exclusion criteria based on the PICOS framework: (1) Participants: patients or experimental models with digestive diseases; (2) Intervention: AM or its derivatives; (3) Comparator: not restricted; (4) Outcomes: reports on immune tolerance-related indicators; (5) Study design: clinical trials and basic experimental studies. Only full-text articles in English or Chinese were considered. Exclusion criteria encompassed studies with irrelevant topics, data deficiency, and methodological flaws. Ultimately, 112 eligible publications were included for the systematic synthesis of the immunomodulatory mechanisms of AM in the treatment of digestive diseases.

2. AM and its derivatives

Astragalus is a large genus of leguminous plants with important medicinal value. As a key tonic herb for invigorating qi and strengthening the spleen, its use in China can be traced back thousands of years, and it is now widely used in many countries (15, 16). Recently, research on AM and its derivatives has extended far beyond its traditional applications, demonstrating significant pharmacological effects in immunomodulatory, anti-inflammation, antitumor and so on (17–19).

The pharmacological versatility of Astragalus is primarily ascribed to its abundant and varied chemical constituents, including polysaccharides, flavonoids, saponins, alkaloids and different mineral elements, which collectively endow it with multiple pharmacological properties (20, 21). Among these, polysaccharides, flavonoids, and saponins represent its most core active components and serve as the primary material basis mediating its pharmacological effects (22). As a major active component, APS is a water-soluble heteropolysaccharide predominantly composed of monosaccharides such as glucose, fructose, arabinose, and mannose (23). It can effectively activate an array of immune cells and promote the expression of cytokines and chemokines (24, 25). For instance, one study demonstrated that APS enhances CD8⁺ T cell function and inhibits colorectal cancer (CRC) development by regulating the STAT3/galectin-3 (Gal-3)/LAG3 pathway (26). Other studies have indicated that APS may repair intestinal barrier damage by upregulating tight junction protein levels and preventing ferroptosis of intestinal epithelial cells. Furthermore, APS modulates the balance of immune cells, suppresses the production of inflammatory mediators to maintain intestinal immune homeostasis, and regulates the gut microbiota and its metabolites to reshape the intestinal microecology, thereby exerting therapeutic effects in IBD (27). Notably, APS with different molecular weights or structures exhibits distinct mechanisms of action. Specifically, APS with a molecular weight below 10 kDa was shown to alleviate symptoms of UC more effectively than APS ranging from 10 to 50 kDa (28). In summary, APS primarily functions to modulate immune homeostasis and repair the intestinal barrier. Its mechanistic characteristics are highly consistent with and well interpret the traditional TCM theory of “reinforcing qi to stabilize the exterior”. Such consistency further highlights its role in enhancing the body’s immune defense capacity.

In addition to polysaccharides, flavonoids represent another major group of active components in AM. To date, more than 50 flavonoids have been identified in AM, which are powerful natural antioxidants with a variety of pharmacological effects (29–32). The flavonoid fraction of Astragalus is dominated by isoflavones and flavonols, exemplified by calycosin and formononetin (FMN). Structurally, these molecules feature a C6–C3–C6 backbone that is susceptible to hydroxylation, methylation, and glycosylation. These substitutions are pivotal in governing the physicochemical properties and pharmacokinetic profiles (e.g., bioavailability) of the compounds (33). Calycosin is one of the most representative isoflavones in Astragali Radix. Studies have shown that treatment with Astragali Radix total flavone or calycosin significantly increases serum IgA and IgG levels in weaned piglets, improved intestinal morphology and the abundance of goblet cells, and regulated intestinal microbial diversity and composition, thereby reducing the diarrhea rate (34). Similar to Calycosin, FMN is another key isoflavone in AM. On the one hand, it can alleviate the occurrence and development of IBD by activating the MAPK/PPAR-γ/ROS pathway and inhibiting the expression of NLRP3 inflammasome-related proteins (35). On the other hand, FMN inhibits the development of colitis-associated CRC by suppressing the proliferation of colon cancer cells, inducing autophagy and apoptosis pathways, and modulating lipid metabolism (36). These dual functions of FMN reflect its multi-target and multi-pathway properties, which coordinately modulate signaling pathways and cytokines to restore colonic tissue homeostasis. These findings demonstrate that the antioxidant and anti-apoptotic capacities of AFs provide a scientific rationale for the TCM principle of “removing toxins to promote tissue regeneration”.

The third key active ingredient of AM is Astragalus saponins (AS), a class of triterpenoid saponins typically comprising aglycones and sugar moieties linked by glycosidic bonds. The fundamental aglycone scaffold of these compounds is cycloastragenol. Based on variations in their sugar moieties, they can be classified into multiple types, among which the most extensively and deeply investigated one is Astragaloside IV(AS-IV) (37). Current research indicates that AS-IV induces an anti-inflammatory macrophage phenotype, a shift mediated by its regulatory action on the STAT pathway. Meanwhile, AS-IV suppresses the activation of the PI3K/AKT pathway, thereby reducing inflammation and enhancing intestinal epithelial barrier integrity (38, 39). Thus, AS-IV is capable of ameliorating experimental colitis symptoms both in vitro and in vivo, rendering it a promising candidate for IBD therapy. At the same time, AS-IV has been demonstrated to mitigate the progression of colonic adenomatous polyps (CAP) in mice subjected to a high-fat diet. This effect is mediated by the modulation of intestinal microbiota and metabolomic profiles, as well as by influencing the Wnt3a/β-catenin pathway (40). This indicates a prospective innovative approach to preventing CRC, highlighting the role of the contribution of AS-IV in antitumor effects. Taken together, the core pharmacological action of Astragalosides lies in their anti-inflammatory and antitumor effects, which also provides a direct modern biological interpretation for the traditional TCM efficacy of “removing toxins to promote tissue regeneration”. Mechanistically, these compounds facilitate wound healing and tissue regeneration by suppressing sustained inflammation and resolving microenvironmental barriers.

Table 1 summarizes the evidence that AM and its derivatives have pharmacological effects on digestive diseases. These components often work in synergy through multiple targets and pathways in the body, jointly forming the modern pharmacological basis for the traditional effects of AM.

Table 1.

Mechanisms of action of AM and its derivatives on the Digestive system diseases.

Model	AM and its derivatives	Disease	Role of AM and its derivatives	Reference
Mice	APS	CRC	Modulating the STAT3/Gal-3/LAG3 pathway to specifically enhance CD8+ T cell function.	(26)
Mice	APS	UC	Regulating Tfh/Treg cell balance and related cytokine expression.	(27)
Mice	APS-G2 (homogeneous α-1,4-glucan backbone)	IBD	Regulation of the SIRT1/PGC-1 α/NF-κB pathway and FXR-mediated signaling via anti-inflammatory and anti-apoptotic actions.	(28)
Mice and cells	APS	UC	Inhibition of the Nrf2/HO-1 pathway prevents ferroptosis in DSS-induced mice and RSL3-stimulated Caco-2 Cells.	(112)
Piglets	Total flavone or Calycosin	Diarrhea	Elevation of serum IgA and IgG levels and improvement of intestinal health via morphology, goblet cells, and microbiota modulation in weaned piglets.	(34)
Mice and cells	FMN	IBD	Inhibition of mitochondrial dysfunction and suppression of NLRP3 inflammasome via MAPK/PPAR-γ/ROS pathway activation and NF-κB nuclear translocation reduction.	(35)
Mice and cells	FMN	Colitis-associated colon cancer	Inhibition of colon cancer cell growth through activation of autophagy/apoptosis and regulation of lipid metabolism.	(36)
Mice	AS-IV	IBD	Regulation of macrophage phenotype via modulation of the STAT signaling pathway.	(38)
Human and Mice	AS-IV	UC	Suppression of inflammation and improvement of intestinal barrier integrity via PI3K/AKT pathway inhibition and microbiota modulation.	(39)
Mice	AS-IV	CAP	Increase the proportion of beneficial intestinal bacteria, suppress the expression of pro-inflammatory cytokines, tumor-associated markers, and Wnt/β-catenin pathway proteins in the colon, and effectively inhibit the proliferation of human colon cancer cell lines (HT29, HCT116, and SW620).	(40)

3. Mechanism exploration: how do AM and its derivatives achieve “bidirectional regulation” of immune tolerance in the digestive system?

Although numerous studies have reported the potential of AM and its derivatives for treating various disorders and possible molecular mechanisms, it is still unclear how AM and its derivatives exert dual immune tolerance. This uncertainty poses certain challenges to their clinical translation. Therefore, gastrointestinal immune regulation constitutes a key intersection between traditional TCM practice and modern pharmacological research. An in-depth understanding of this mechanism not only reveals the pathogenesis of tumors, autoimmune diseases, chronic intestinal inflammation and other diseases, but also holds the potential to yield new therapeutic targets and approaches. Here, we organize and analyze the relevant data to clarify how AM and its derivatives exert the “bidirectional regulation” of immune tolerance in the digestive system.

3.1. Immunological basis of the digestive system

The digestive system is equipped with a sophisticated and unique immune defense and regulatory network. Astragalus exerts a beneficial influence on the immune function of the digestive system, with the intestinal tissue—serving as the largest and most pivotal immune organ within this system—representing a primary target of Astragalus. Its core mission is to continuously cope with exposure to massive foreign antigens, accurately distinguish between self and non-self and harmless/harmful agents, establish symbiotic tolerance to food antigens, and effectively defend against pathogens (41). This relies on the robust physical and chemical barriers of the digestive tract, its distinctive tissue structure, key immune cells and the gut microbiota (Figure 1).

Figure 1.

Mucosal immunity of the digestive system. The physical barrier formed by intestinal epithelial cells, goblet cells, tight junction proteins, and the mucus layer secreted by them, together with the chemical barrier formed by gastric acid, bile acid, and antimicrobial peptides, prevents the invasion of foreign pathogens. Gut-associated lymphoid tissues (GALT) primarily comprise Peyer’s patches (PP), isolated lymphoid follicles (ILF), appendix and Waldeyer’s ring, which fulfill a crucial function in antigen recognition and uptake. The mesenteric lymph node (MLN) is the main site of immune induction. Following antigen uptake and processing, antigen-presenting cells actively migrate to MLN through lymphatic vessels and present antigen information to T cells and B cells. Intraepithelial lymphocytes (IEL) exert direct cytotoxic effects through CD8⁺T cells to rapidly and precisely eliminate local threats. Immunoglobulin A (IgA) secreted by lamina propria lymphocytes (LPL), mainly mature plasma cells, can enter the mucosal surface, neutralize antigens and protect the body. CD4⁺ helper T cells, subsets of CD8⁺T cells, regulatory T cells, innate lymphoid cell 3 (ILC3) cells and other cells secrete various cytokines and contribute to immune modulation.

The mechanical barrier includes intestinal epithelial cells, goblet cells, tight junction proteins, and the mucus layer they produce, which prevent the invasion of foreign pathogens, along with the chemical barrier formed by gastric acid, bile acid, antimicrobial peptides, and other components (42–44). Meanwhile, gut-associated lymphoid tissue (GALT), a major and multifaceted component of the mucosa-associated lymphoid tissue (MALT), mainly includes Peyer’s patches (PP), isolated lymphoid follicles (ILF), appendix and Waldeyer’s ring (45). PP fulfills a crucial function in antigen capture and local immunity based on its M cells that take up a variety of antigens in the intestinal lumen (46). ILF is the main component of GALT, in which over 90% of cells are lymphocytes, with a slightly higher proportion of T cells than B cells (47).

The mesenteric lymph nodes (MLNs) serve as the main immune decision-making site. After capturing antigens, intestinal antigen-presenting cells migrate to MLNs via lymphatic vessels and present antigen information to T and B cells, making the final immune decision to attack or tolerate (48–51). Therefore, PP, ILF and MLN are recognized as the “induction sites” of immune responses. Subsequently, the immune command is carried out by the intestinal mucosa epithelium and lamina propria. Intraepithelial lymphocytes (IEL), the largest lymphocyte population in the body, primarily utilize CD8⁺T cells to precisely and rapidly eliminate local threats through direct cytotoxic effects (52).

Mature plasma cells account for the majority of lamina propria lymphocytes (LPLs). These plasma cells secrete abundant IgA, which is then transported to the mucosal surface, neutralizes antigens, and protects the body (53). Secondly, the number of T lymphocytes is also quite large, mainly CD4⁺ helper T cells, a small number of CD8⁺T cells, regulatory T (Treg) cells and innate lymphoid cells. These cells secrete distinct cytokines and play an immunomodulatory role together (54). Mucosal antigen-specific T and B cells can migrate from the initiation site of the immune response to the mucosal effector sites, such as the intestine, differentiate into antigen-specific effector cells, and mediate systemic mucosal immune responses.

Ultimately, the immune function of the digestive system is fundamentally characterized by a complex and dynamic regulatory network arising from the interplay among the epithelial barrier, immune cells, and symbiotic flora. AM and its derivatives achieve their bidirectional immunomodulatory effects precisely by orchestrating this intricate system.

3.2. Regulation of immune cells and their functions by AM and its derivatives

AM and its derivatives have become one of the current research hotspots in the field of disease therapy due to their significant immunomodulatory effects on various immune cells. As shown in Figure 2, immune cells regulated by AM mainly include macrophages, dendritic cells (DCs), natural killer cells (NK cells), and T cells. APS can activate macrophages and DCs, which can significantly induce the surface expression of costimulatory molecules on antigen-presenting cells, thereby promoting the activation and functional maturation of immune cells (55, 56). Such maturation is essential for efficient antigen presentation and the initiation of adaptive immune responses. In contrast, AM has been shown to suppress the secretion of pro-inflammatory cytokines from overactivated macrophages, thereby attenuating inflammatory responses in UC and other inflammatory disease models (57, 58). This bidirectional regulatory ability of AM may be achieved by modulating associated signal transduction, such as inflammation and cell growth. On the one hand, AM promotes M1 macrophage polarization, enhancing phagocytosis, antigen presentation, and pathogen clearance by inducing the moderate release of proinflammatory mediators (59, 60). On the other hand, it can also induce M2 polarization, stimulate the secretion of anti-inflammatory factors such as IL-10, inhibit excessive inflammation, and participate in tissue repair (24, 42). This modulation of the M1/M2 phenotypic balance is a central manifestation of its bidirectionality.

Figure 2.

AM and its derivatives regulate immune cells and their functions. The immune cells regulated by Astragalus membranaceus (AM) and its derivatives encompass DCs, macrophages, NK cells and T cells. AM and its derivatives can activate DCs and enhance the surface expression of costimulatory molecules on antigen-presenting cells, thereby driving the activation and functional maturation of immune cells. They can also suppress the secretion of pro-inflammatory cytokines triggered by excessive activation of macrophages, thereby alleviating inflammation. AM and its derivatives can promote the M1 polarization, thereby enhancing their phagocytosis ability, antigen presentation ability and pathogen killing function. Alternatively, they can induce the M2 polarization of macrophages, thereby eliciting the production of anti-inflammatory mediators such as IL-10. AM and its derivatives can significantly enhance the activity of NK cells and the phagocytosis of macrophages, potentially through the activation of the NF-κB signaling pathway and increased production of reactive oxygen species (ROS). AM and its derivatives can induce the proliferation and activation of T lymphocytes, such as enhancing the activity of CD8⁺ cytotoxic T lymphocytes (CTL) by down-regulating inhibitory checkpoint molecules such as Tim-3, thereby improving anti-tumor immune function. These compounds help regulate the balance among Th1, Th2, Th17, and Treg cells, contributing to the suppression of inflammatory responses.

In addition, as an important component of innate immunity, NK cells also exhibit bidirectionality after treatment with AM and its derivatives. For example, the combination of ginseng, AM and Burar root significantly increased NK cell activity and macrophage phagocytosis, which may be achieved by activating reactive oxygen species and NF-κB signaling pathways (61). However, AS-IV prevents the recruitment of NK cells to the brain after ischemia by inhibiting the chemotaxis mediated by glial cell-derived CCL2. Furthermore, AS-IV can also inhibit the STAT3 signaling pathway and diminish the chemotactic infiltration of NK cells into the brain tissue after ischemia to exert neuroprotective effects in acute ischemic brain injury, offering a potential strategy for immunotherapy of ischemic stroke (62).

The bidirectional immunomodulatory effect of AM on T lymphocytes is one of its most essential and intricate mechanisms. AM has been demonstrated to stimulate the proliferation and activation of T lymphocytes, especially enhancing the activity of CD8⁺ cytotoxic T lymphocytes (CTL) by downregulating inhibitory checkpoint molecules like Tim-3, thereby potentiating antitumor immunity (63, 64). Studies have indicated that administration of Astragalus preparations can restore immune balance by modulating the Treg/Th17 cell ratio, thereby alleviating the autoimmune pathology observed in Sjogren’s syndrome and morphine-induced immunosuppression (65, 66). In the experimental autoimmune encephalomyelitis model, Huangqi-Guizhi-Wuwu Decoction inhibited inflammatory infiltration in the central nervous system. It upregulated IL-10 and Foxp3 production by increasing the proportion of Treg cells and downregulated the expression of IFN-γ and IL-17 by reducing the proportion of Th1 and Th17 cells, thereby effectively inhibiting the activation of CD4⁺ T cells (67).

Taken together, these findings confirm that AM and its derivatives can modulate the activities of innate and adaptive immune cells via multiple targets, thereby maintaining the immune homeostasis and strengthening the host defense against various diseases. This characteristic of “guided by the situation and bidirectional regulation” makes AM and its derivatives different from the simple immune “stimulants” or “inhibitors”, which are more in line with the concept of “strengthening healthy and eliminating pathogenic factors” and “regulating the balance of Yin and Yang” in TCM. This also underlies its wide clinical application and relatively low incidence of side effects.

3.3. The regulation of intestinal microecology by AM and its derivatives

AM and its derivatives are regarded as promising prebiotics for maintaining intestinal health. They can exert direct or indirect impacts on immune tolerance through the modulation of gut microbiota composition, immune responses and barrier protection, as summarized in Table 2.

Table 2.

Effects of AM and its derivatives on gut microbiota.

Models	AM and its derivatives	Disease	Alterations in the Intestinal microecology	Reference
Broiler chicken	APS	Intestinal barrier dysfunction	Parabacteroides distasonis and Bacteroides uniformis	(68)
Mice	AM extract	UC	Lactobacillus and Akkermansia	(69)
Human	FAPS	–	Lactobacillus, E. faecalis, Brautobacterium, Shigella, Romboutsia, and Clostridium_sensu_stricto_1	(70)
Mice	APS	UC	Muribaculaceae, Prevotellaceae_UCG- 001, Alistipes, Rikenellaceae_RC9_gut_group and Muribaculum	(71)
Mice	APS-E1F1	Immuno suppressed	Butyrate-producing bacteria	(72)
Mice	APS	Immune injury	Linoleic acid and α-linolenic acid in polyunsaturated fatty acid	(73)
Broiler chickens	APS	Necrotic enteritis	Romboutsia, Halomonas, propionic acid, butyric acid, formononetin, taurine, cholic acid and equol	(74)
Mice	APS	Constipation	Blautia;acetate,butyrate,and propionate	(75)
Mice	AM and Curcuma aromatica Salisb.	Colon cancer	Adlercreutzia, Lachnospiraceae_UCG-001,and Parvibacter, Citrobacter and Candidatus_Arthromitus; deoxycholic acid, lithocholic acid and ursodeoxycholic acid	(76)
Mice	APS	Dampness stagnancy due to spleen deficiency	Pseudoflavonifractor and Paraprevotella, Parasutterella, Parabacteroides, Clostridium XIVb, Oscillibacter, Butyricicoccus, and Dorea	(77)

AM and its derivatives restructure the gut microbiota toward a beneficial state, enhancing commensals and suppressing pathogens. This modulation effectively promotes the restoration and maintenance of immune homeostasis in a variety of disease models (68–70). Research indicates that APS can restore dietary polysaccharide-induced intestinal barrier dysfunction by selectively enriching Parabacteroides distasonis and Bacteroides uniformis, thereby activating signaling pathways associated with intestinal barrier function (68). In another study, Lactobacillus rhamnosus was applied for APS fermentation, and fecal samples from healthy volunteers were incubated with fermented Astragalus polysaccharides (FAPS). The findings indicated that FAPS exerted a marked effect on the gut microbiota by remodeling its community structure and enriching beneficial bacterial populations, including Lactobacillus, Enterococcus faecalis, and Brautobacterium, while suppressing pathogenic genera such as Shigella, Romboutsia, and Clostridium_sensu_stricto_1 (70).

AM and its derivatives have been reported to enhance the synthesis of short-chain fatty acids (SCFAs) and show the potential to maintain immune homeostasis in disease models by improving the integrity of the intestinal barrier and modulating immune responses (71). Butyrate, an important SCFA produced by gut microbial metabolism, is most closely related to immunomodulatory activity. Research indicated that oral administration of APS markedly increased butyrate production in the intestine of mice, effectively restored the structural integrity and diversity of gut flora induced by cyclophosphamide (72). APS can also ameliorate the disrupted ratio of linoleic acid to α-linolenic acid in polyunsaturated fatty acid metabolism and effectively alleviate the immune injury and intestinal mucosal damage induced by chemotherapy (73). Additionally, APS enhances key microbial metabolites (e.g., propionate, butyrate, equol) and host compounds (e.g., formononetin, taurine), but lowers levels of uric acid, L-arginine, and serotonin. This phenomenon may be associated with inflammatory responses and the equilibrium between Th17 and Treg (74). However, some studies revealed that in aged rats with constipation, APS enhanced the abundance of Blautia while diminished the concentrations of acetate, butyrate, and propionate, and accordingly regulated glycolysis/glucose de novo metabolism and pyruvate metabolism (75). Another interesting study found that Astragalus mongholicus Bunge and Curcuma aromatica Salisb effectively inhibited CRC growth and reduced histological damage by regulating the flora structure to enhance the levels of beneficial bacteria like Adlercreutzia and reduce pathogens like Citrobacter, while also changing the bile acid composition (76). It may be related to the enrichment of specific bacteria and the up-regulation of FabG and baiA genes to promote the metabolic transformation of lithocholic acid. In summary, APS may trigger beneficial metabolic reprogramming of intestinal epithelial cells through the “microbiota-metabolite” axis. AM and its derivatives can reshape the structure of gut microbial and promote the conversion of ingested substances into specific metabolites (such as SCFAs, secondary bile acids, indole derivatives, etc.). These metabolites act as signaling molecules and energy substances, combining with local cells or remote tissues to regulate immune responses, thereby restoring the immune disorders caused by diseases (77, 78).

Current studies mainly concentrate on the direct effects of AM and its derivatives on the composition and metabolites of gut microbiota. Its potential antimicrobial activity and specific modulation of pathogenic microbes play a pivotal role in reshaping a healthy gut microecology and maintaining flora homeostasis. These microbiota-level alterations inevitably influence the host’s ultimate physiological or pathological phenotypes. Collectively, the mechanisms underlying the effects of AM and its derivatives on the digestive system can be consolidated into three synergistic dimensions. First, AM establishes a localized structural basis for immunomodulation by fortifying epithelial barrier function and regulating GALT responses within the intestine’s mucosal immune microenvironment. Second, AM and its derivatives achieve a precise equilibrium between suppressing hyperinflammation and maintaining immune tolerance by directly modulating immune cells. Third, indirect modulation of host immune homeostasis is exerted via the ‘microbiome-immunity axis’ through remodeling of gut microbiota composition and metabolism. In conclusion, AM acts as a “bridge” between the gut microbiota and the host system, providing a coherent mechanistic explanation for the “biphasic regulation” characteristics observed in digestive diseases.

4. Application of AM and its derivatives in digestive diseases

The digestive system possesses a unique mucosal immune structure that fulfills a critical function in preserving immune homeostasis and fostering immune tolerance. As a TCM with a long history, AM exhibits clear strengths in managing digestive ailments owing to its multi-component and multi-target features. Notably, AM and its extracts can produce therapeutic effects through different aspects in the treatment of IBD, CRC and gastric carcinoma, among others.

IBD is a chronic recurrent autoimmune disorder with unknown etiology. It represents one of the most challenging disorders of the gastrointestinal, mainly including UC and Crohn’s disease (79, 80). These disorders often arise when the immune system erroneously targets autologous tissues, resulting in inflammation and tissue injury. This process often involves dysregulated responses from various immune cells and cytokines (81–83). The main pathological mechanisms of the disease include the destruction of immune tolerance, the production of specific autoantigens, the activation of immune cells, and the dysregulated expression of cytokines (84–86). At present, most drugs used in the clinic have immunosuppressive effects, which could heighten the susceptibility to infection and cancer while ameliorating IBD. AM has been widely studied as a natural medicine, which plays an immunomodulatory role by enhancing the function of macrophages and T cells and controlling cytokine production to modulate immune responses, thereby alleviating symptoms associated with autoimmune diseases (87–89).

Gastrointestinal cancer is a diverse group of malignant tumors, mainly including esophageal cancer, gastric carcinoma, liver cancer, pancreatic cancer, and CRC (90). The development of these tumors involves intricate mechanisms, usually related to genetic factors, external influences, dietary habits, infection and other factors. For instance, Helicobacter pylori is a critical driver of gastric carcinogenesis, whereas CRC is closely linked to age, family history, dietary habits and certain genetic syndromes (91–93). In addition, the tumor microenvironment (TME) is instrumental in their development. Tumor cells coordinately regulate proliferation, invasion and distant metastasis via the interaction with surrounding stromal cells and immune cells (94, 95). AM and its derivatives can play an anti-cancer role by inducing apoptosis, modulating autophagy, inhibiting epithelial-mesenchymal metastasis, regulating immune response, and remodeling TME (96). Meanwhile, AM and its derivatives possess the potential to enhance the therapeutic efficacy of chemotherapeutic agents while alleviating their side effects, such as gastrointestinal discomforts including nausea and vomiting (97).

To date, the therapeutic potential of AM and its derivatives is strongly supported in IBD, CRC, and gastric cancer by extensive preclinical evidence; while the lack of robust clinical evidence in humans greatly constrains clinical translation. Currently, some studies suggest that the Huangqi Sijunzi Decoction can improve chemosensitivity in advanced gastric cancer by modulating IL-8 levels, whereas Astragalus injection combined with parenteral nutrition can facilitate postoperative recovery (98, 99). However, existing clinical studies on gastric cancer are largely limited by small sample sizes and inadequate design of blinding and control settings; Meanwhile, high-quality and large-scale randomized controlled trial (RCT) evidence for its application in IBD and CRC is still lacking. Although direct clinical evidence in gastroenterological diseases remains scarce, the well-documented clinical efficacy of AM in other conditions supports its broad therapeutic application prospect. For example, APS combined with adjuvant chemotherapy can alleviate chemotherapy-associated adverse effects and improve the health status of premenopausal breast cancer patients (100). Moreover, the results of a multicenter, evaluation-blinded, RCT in chronic kidney disease showed that the addition of AM therapy to standard therapy further stabilized renal function (101). AM and its derivatives have also shown promising preliminary clinical effects in the treatment of urinary tract infections and the prevention of chemotherapy-induced cardiotoxicity (102, 103). Collectively, existing clinical data highlight the promising future application prospects of AM and its derivatives.

5. Safety assessment and potential risks of AM and its derivatives

As a natural botanical, AM has demonstrated favorable safety and tolerability in both long-term traditional use and modern clinical investigations. Existing clinical evidence mainly focuses on compound formulations; for instance, the Huangqi Jianzhong Decoction exhibits therapeutic effects in Western medicine for chronic superficial gastritis without obvious adverse events (104). Furthermore, Cheng et al. reported that AM-containing formulas combined with platinum-based chemotherapy reduced treatment-related toxicity in patients with advanced gastric cancer (105).

While AM demonstrates favorable safety in polyherbal formulations, substantial heterogeneity exists among the toxicological profiles of its principal constituents: APS is characterized by a well-defined safety margin (106), AS-IV poses distinct developmental toxicity risks (107), yet safety data for flavonoids remain critically scarce. This underscores the necessity of transitioning the safety assessment of AM from the ‘whole herb’ level to the ‘component-specific’ level. Consequently, future safety evaluations and clinical guidance must account for this compositional heterogeneity to promote rational pharmacotherapy based on precise toxicological evidence.

AM demonstrates significant potential in specific combinational therapies; for instance, its co-administration with Metformin exerts synergistic efficacy and attenuates toxicity in diabetes management, while combination with chemotherapeutic regimens for colon cancer reduces the incidence of gastrointestinal adverse events (108, 109). Nevertheless, the extensive pharmacological activities of AM also raise potential risks in combinational therapy, mainly due to its inhibitory effects on major drug-metabolizing enzymes (CYP3A4 and CYP1A2) and the efflux transporter P-glycoprotein (110, 111). Such inhibition can alter the pharmacokinetic disposition of co-administered drugs metabolized via these pathways, potentially resulting in supratherapeutic plasma concentrations and subsequent toxicities. Therefore, clinicians should exercise caution, screen for overlapping metabolic pathways, and adopt therapeutic drug monitoring to ensure safe combinational therapy.

6. Conclusion and perspectives

AM is an important medicinal material in TCM. Its major active ingredients, including APS, AS and AF, have been widely investigated, especially for autoimmune disorders and tumors associated with the digestive system. A comprehensive review of current evidence indicates that AM and its derivatives can pull the disordered immune state back to a normal balance state by regulating the immune variety of cells as well as the intestinal microecology. This dual regulatory mechanism of AM and its derivatives forms a critical basis for developing therapies against conditions associated with immune dysregulation, such as cancer, autoimmune diseases, infection, and metabolic disorders.

Although AM has shown great potential in clinical application and mechanism research, it still faces multiple challenges to fully leverage its bidirectional immunomodulatory effect. To address these challenges and accelerate the translation of therapeutic potential into clinical benefits, this review systematically summarizes the available literature. First, we summarize the pharmacological effects of distinct AM components in Table 1, aiming to provide useful information for further studies. Current research on AM and its derivativesmainly focus on digestive system disorders, particularly CRC, IBD, and diarrhea. Current evidence indicates that specific bioactive fractions exhibit unique therapeutic priorities: polysaccharides are effective in modulating immune homeostasis, flavonoids are prominent for mitigating oxidative stress, and saponins demonstrate superior efficacy in anti-inflammatory responses. We note that current studies mainly focus on the functional mechanisms of AM components, while research on their structural characteristics remains limited, which may be the key to restricting their further validation. Furthermore, there is no clear standard for the extraction method, dose, and cycle of AM, which makes it difficult to ensure its repeatability. Secondly, this study systematically delineates the immunomodulatory mechanisms of AM using schematic diagrams: Figure 1 illustrates the structural and functional basis of mucosal immunity in the digestive system, Figure 2 elucidates the direct modulation of immune cells and their functions by AM and its derivatives, while Table 2 summarizes the key regulatory effects on the gut microbiota. Numerous studies have validated the interactions between AM and its derivatives, intestinal microbiota and immune regulation, whereas the causal relationship between specific strains or their metabolites and immune regulation is still unknown. Third, an analysis of AM’s therapeutic applications indicates that the existing body of work is heavily skewed towards preclinical research. Robust evidence from large RCTs is still lacking to validate its safety and efficacy in diverse disease contexts. This represents the most critical challenge in transitioning from traditional empirical use and preclinical research to recognition by evidence-based medicine. Without overcoming this challenge, the efficacy, safety, optimal indications, and dosage of AM and its derivatives will continue to lack the high-grade evidence support that is widely accepted by the international medical community.

Conventional safety assessments of AM have predominantly focused on organ-level parameters, such as acute toxicity, hepatorenal function, and reproductive development. However, as a classic immunomodulator, the safety profile of AM is not merely reflected in the lack of direct cytotoxicity, but also lies in its ability to precisely regulate immune homeostasis, particularly the maintenance and enhancement of immune tolerance. AS-IV induces neurodevelopmental delays in offspring at doses devoid of overt maternal toxicity, suggesting a toxicity mechanism distinct from classical organ damage—likely involving disruption of the early neuro-endocrine-immune network. Although AS-IV exerts anti-inflammatory effects, its targeted immune pathways may overlap extensively with those critical for sustaining pregnancy tolerance; consequently, excessive or inappropriate immunosuppression may disrupt the delicate immunological equilibrium required for gestation. In contrast, APS facilitates immune tolerance via modulating immune homeostasis, which may account for its satisfactory clinical safety performance. Therefore, whether the developmental toxicity of AS-IV stems from its dysregulation of the immune-tolerant microenvironment during pregnancy represents a pivotal scientific question for future toxicological elucidation.

Future research in this field should prioritize clinical translation and practical application; however, translating AM into routine practice remains challenging. To address this issue, we propose the following strategies oriented toward clinical translation. First, to address the inherent variability in raw materials, processing, and formulation of AM, future research should systematically characterize the structural features of key components and elucidate the interaction mechanisms among multi-components and with other drugs. Advanced experimental models, including organoids, organ-on-a-chip, and immune-organoid co-culture systems, should be employed to investigate the effects of AM on intestinal immunity, barrier function, and microbiota metabolism. With high physiological relevance and throughput potential, these platforms can not only facilitate the intuitive validation of therapeutic efficacy by circumventing the limitations of traditional cell and animal models, but also support the development of personalized medicine via patient-specific modeling. Future studies should also focus on the integration of information technologies (e.g., network pharmacology, AI-assisted computational simulation, and high-throughput screening) with novel delivery systems such as nanoformulations and inclusion complexes, so as to enhance bioavailability and targeting efficiency. This integrated research strategy will facilitate the establishment of scientifically standardized quality control and pharmacokinetic evaluation systems, thereby promoting clinical translation and large-scale application of AM. Meanwhile, the interactions between AM and its derivatives and gut microbiota require further investigation to clarify dynamic changes in microbial composition and metabolites and their long-term effects on host immunity. Future studies should integrate multi-omics technologies, such as non-targeted metagenomics and serum/feces metabolomics, to systematically elucidate the intrinsic associations between functional modules involved in the intestinal barrier, immune responses, and systemic metabolism under AM modulation. To further establish the causal mechanisms of AM within the “microbiota-host” axis, future research should combine in vivo validation approaches, such as fecal microbiota transplantation and germ-free animal models, with the identification of key effector molecules. Clarifying the structure-function relationships of these components will facilitate significant breakthroughs in the mechanistic depth of related research. In addition, rigorous clinical trials are pivotal for verifying the results of preclinical studies and formulating standardized guidelines for the clinical application of AM and its derivatives for immunomodulation. Future clinical investigations should adopt mature research paradigms from other therapeutic areas to accelerate the clinical evaluation of AM and its derivatives in IBD, CRC, and other gastrointestinal diseases. Furthermore, future research should prioritize enhancing the clinical applicability and therapeutic development value of AM. For gastrointestinal diseases, RCTs should be designed to evaluate the combined regimen of “Western Medicine + AM,” assessing its synergistic effects on core clinical indicators, including symptom remission rate, recurrence rate, and quality of life. Furthermore, the clinical application value of AM in alleviating chemotherapy-induced vomiting and immunosuppressant-related hepatotoxicity remains to be further explored. It is anticipated that evidence-based AM regimens will be integrated into clinical pathways for digestive diseases, thereby standardizing their therapeutic application. The current deep integration of immunology, microbiology and pharmacology in this field provides broad prospects for translating these research results into personalized and effective therapies for immune-mediated diseases. Therefore, continuous interdisciplinary research and clinical verification are essential to fully unlock the therapeutic potential of AM and its derivatives in precise immune regulation.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This research project was funded by the Natural Science Foundation Project of Shaanxi Province (2025JC-YBMS-966), Shanxi Province Basic research projects (Grant No.202303021211112), Science Research Start-up Fund for Doctor of Shanxi Medical University (Grant No.XD1811), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (Grant No.2020L0184).

Author contributions

XC: Writing – original draft, Writing – review & editing, Visualization. XZ: Writing – original draft. HG: Writing – review & editing. XY: Writing – original draft. JZ: Writing – original draft. KZ: Writing – review & editing, Resources. LL: Writing – review & editing, Resources.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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