Introduction

Edible fungi represent a valuable source of both food and functional ingredients, holding significant importance in daily diets and garnering increasing attention in global nutrition and health research. This category encompasses commonly consumed culinary mushrooms (e.g., Lentinula edodes, Hericium erinaceus) as well as fungi like Ganoderma lucidum, which are integral to traditional practices in East and Southeast Asia and are increasingly used as functional foods. To comprehensively explore their potential in modulating the gut microbiota, this review primarily adopts a mechanism-based approach, focusing on the shared bioactive components (e.g., polysaccharides, terpenoids) among these fungi. It is important to note that this inclusive approach, while providing a holistic perspective, may overlook differences in efficacy and application between culinary and medicinal mushrooms, a limitation that will be discussed in later sections.

It is important to note, however, that consumption patterns vary significantly: culinary mushrooms are integrated into regular diets, whereas medicinal fungi such as Ganoderma lucidum are primarily consumed as functional foods or supplements within specific cultural contexts, notably in East Asia, where they are esteemed for their health benefits. These fundamental differences in usage, along with critical considerations regarding dosage and regulatory status, will be discussed in detail in Section 4.5, focusing on their distinct applications in food and clinical nutrition They are rich in various bioactive components, including high-quality protein, dietary fiber, vitamins (such as B vitamins and vitamin D), minerals (such as selenium and zinc), as well as unique polysaccharides (e.g., β-glucans), terpenoids (e.g., ganoderic acids), and polyphenols1,2,3,4,5. These constituents confer multiple physiological functions upon edible fungi, such as enhancing immunity6, exerting antioxidant7 and antitumor effects8, and regulating blood lipids and glucose levels9. In recent years, a growing body of research has demonstrated that edible fungi can also exert broad health benefits through the regulation of gut microbiota. Particularly notable are their roles in improving intestinal barrier function, promoting the production of short-chain fatty acids (SCFAs), and inhibiting the colonization and growth of pathogenic bacteria10,11, highlighting their considerable potential in functional foods and precision nutritional interventions.

The gut microbiota constitutes the most complex microbial ecosystem in the human body, and its balance is closely associated with host health. A normal gut microbial composition not only participates in food digestion and nutrient absorption but also influences systemic metabolism and immune homeostasis through gut microbial metabolites (such as SCFAs) and immunoregulatory mechanisms12,13,14. However, modern lifestyles—characterized by high-fat and high-sugar diets15, antibiotic overuse16, and environmental stressors17,18 —readily lead to gut dysbiosis. This imbalance can subsequently trigger various diseases, including inflammatory bowel disease, obesity, diabetes, and colorectal cancer19. Consequently, restoring microbial balance through dietary interventions has emerged as a novel strategy for disease prevention and treatment.

Owing to their multi-component and multi-target characteristics, edible fungi exhibit edible fungi are thought to exhibit potential advantages in regulating gut microbiota20,21,22. The polysaccharides and dietary fibers they contain act as prebiotics, selectively promoting the proliferation of beneficial bacteria such as Bifidobacterium and Lactobacillus23,24,25. Meanwhile, terpenoids and polyphenols possess anti-inflammatory and antimicrobial activities, helping to suppress the growth of opportunistic pathogens26. Furthermore, components of edible fungi can influence immune responses and metabolic pathways through microbiota-host interactions, forming a tripartite health-promoting model of “component–microbiota–host”10. Therefore, a systematic exploration of the mechanisms by which edible fungi modulate the gut microbiota will not only deepen the understanding of their functional properties but also provide a critical scientific foundation for developing fungal-based microecological modulators and personalized nutritional strategies. A schematic diagram of the core mechanisms discussed in this review is presented in Fig. 1.

Fig. 1: Schematic diagram of the core mechanisms of edible fungi regulating gut microbiota and disease intervention.
Fig. 1: Schematic diagram of the core mechanisms of edible fungi regulating gut microbiota and disease intervention.The alternative text for this image may have been generated using AI.
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Illustrates the core mechanisms by which bioactive components of edible fungi (e.g., β-glucans, triterpenoids) modulate gut microbiota and intervene in diseases: These components restructure the gut microbiota composition (e.g., promoting the proliferation of beneficial bacteria such as Bifidobacterium and Lactobacillus, while suppressing pathogens like Enterobacteriaceae), thereby increasing the production of beneficial metabolites, particularly short-chain fatty acids (SCFAs, notably butyrate). On one hand, SCFAs enhance intestinal barrier function, mitigate inflammation, and promote regulatory T cell (Treg) differentiation by activating G protein-coupled receptors (GPR41/43, GPR109A) and inhibiting histone deacetylases (HDACs). On the other hand, they regulate host metabolism and epigenetic processes. Additionally, fungal constituents directly suppress inflammatory pathways such as TLR4/NF-κB. These synergistic mechanisms effectively counteract diseases associated with microbial dysbiosis, including inflammatory bowel disease (IBD), metabolic syndrome (obesity/diabetes), and colorectal cancer.

Gut Microbiota Features and Pathological Regulatory Mechanisms

Gut microbiota structure and microenvironmental characteristics

The human gut microbiota forms a vast and complex dynamic ecosystem encompassing bacteria, archaea, fungi, viruses, and parasites27 With a total microbial biomass of 1013–1014 cells28 comparable to human somatic cells, the gut harbors approximately 1000 microbial species29. Dominant phyla include Bacteroidota, Bacillota, Actinomycetota, and Pseudomonadota, with Bacteroidota and Bacillota combined constituting over 90% of the core microbiota30. The functional classifications and disease associations of key gut microbial phyla and genera are summarized in Table 1.

Table 1 Classification of Gut Microbiota and Their Functional Roles in Disease
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The composition of the gut microbiota, which is influenced by various factors such as genetics, diet, age, and medication use, exhibits significant individual variability and regional specificity31. For instance, a high-fat diet can lead to an increased proportion of Bacillota, while dietary fiber intake promotes the proliferation of Bacteroidota32. This diet-microbiota interaction mechanism provides a direct basis for the regulation of gut microbiota by edible fungi through their dietary fiber components.

The stability of the intestinal microenvironment relies on the synergistic effects of the physical barrier, chemical barrier, and immune regulation. Tight junctions between intestinal epithelial cells form the mechanical barrier, and their impairment can lead to microbial and antigen translocation, triggering immune imbalance33. Simultaneously, Paneth cells (PCs) maintain a sterile local microenvironment by secreting antimicrobial peptides (AMPs) such as α-defensins and peptide YY (PYY 1-36)34,35. Short-chain fatty acids (SCFAs), key microbial metabolites, play a central role in maintaining intestinal homeostasis. For instance, butyrate enhances barrier function, suppresses inflammation, and promotes regulatory T cell differentiation by inhibiting histone deacetylases (HDACs) and activating G protein-coupled receptors (e.g., GPR41/43)36,37. SCFAs can also regulate gene expression via epigenetic pathways, influencing host metabolism and immune responses, thereby serving as key signaling molecules linking the microbiota and host health.

In the intestinal microenvironment, specific bacterial species such as Fusobacteriota corrig38 and Escherichia coli39,40 can promote inflammation and tumorigenesis by activating the TLR4-MYD88-NF-κB pathway. For example, F. nucleatum drives colorectal carcinogenesis via TLR4-Keap1-NRF2-mediated cytochrome P450-epoxy octadecenoic acid axis activation41,42. In contrast, probiotics such as Lactobacillus enhance tight junction protein expression and elevate concentrations of beneficial microbial metabolites (lactate and SCFAs)43,44,45,46, thereby preserving intestinal barrier integrity47. Gut dysbiosis is closely associated with various disease states, including the proliferation of pathogenic bacteria in colorectal cancer48,49,50 and reduced butyrate synthesis leading to insulin resistance in metabolic diseases51,52,53,54. Notably, emerging research suggests that active components in edible fungi may exert probiotic-like functions, potentially suppressing pathogenic bacteria growth and improving the intestinal microenvironment through multiple mechanisms. These mechanisms include supporting SCFA production and influencing immune signaling pathways (e.g., TLR4/NF-κB). Based on preclinical evidence, these activities suggest potential for future intervention in microbiota-related diseases.

Etiology and mechanisms of gut dysbiosis

Exogenous and endogenous factors

The triggers of gut microbiota imbalance can be categorized into exogenous and endogenous factors. Among exogenous factors, antibiotic overuse, such as vancomycin and metronidazole, notably reduces the abundance of Bacillota and Verrucomicrobiota, increases the proportion of Pseudomonadota, disrupts gut microbiota structure, and impairs bile acid metabolism, thereby mediating inflammatory responses via the TGR5 (Takeda G protein-coupled Receptor 5) receptor55. In contrast, studies have found that Ganoderma lucidum polysaccharides can alleviate antibiotic-induced gut microecological collapse and promote the recovery of beneficial bacteria such as Bifidobacterium and Lactobacillus56,57. Poor dietary habits, such as high-fat diets have also been confirmed to induce microbiota dysbiosis; for example, they reduce Bacillota abundance and promote LPS translocation and low-grade inflammation. Meanwhile, animal studies suggest that Phellinus linteus polysaccharides may improve high-fat diet-induced metabolic disorders and dysbiosis by enriching butyrate-producing bacteria and elevating levels of short-chain fatty acids (SCFAs)58. Separately, polysaccharides from Trametes versicolor (PSK/PSP) have been observed in animal models to modulate gut microbiota structure under high-fat dietary conditions, such as by increasing the abundance of beneficial bacteria like Faecalibacterium prausnitzii59. Additionally, immune-mediated disorders like Type 1 Diabetes mellitus (T1D) exhibit bidirectional interactions with gut dysbiosis. In late-stage T1D, pancreatic β-cell dysfunction results in metabolic waste accumulation within the intestinal lumen, altering the microenvironment and aggravating microbiota imbalance60. This “host metabolism-microbiota interaction” forms a self-reinforcing feedback loop that perpetuates a vicious cycle of dysbiosis61. Extracts of Hericium erinaceus and its active components, such as its polysaccharides, may modulate tryptophan metabolism and enhance intestinal barrier function, suggesting a potential to ameliorate this vicious cycle62. Collectively, these findings suggest that bioactive constituents from edible fungi may function through microbiota-host interactions, allowing them to interface with multiple etiological factors. The main causative factors and specific mechanisms leading to gut dysbiosis are comprehensively outlined in Table 2.

Table 2 Main causative factors and mechanisms of intestinal flora imbalance
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Imbalanced gut microbiota

The stability of gut microbiota homeostasis relies on intricate interactions among the host, microorganisms, and environmental factors. Dysregulation mechanisms encompass genetic susceptibility, intestinal barrier dysfunction, pathogen invasion, dietary interventions, antibiotic exposure, and neuroendocrine regulation. Among these, genetic background exerts profound effects on microbiota composition by modulating host immune responses. Genome-wide association studies (GWAS) have identified critical roles of innate immune genes such as NOD2 and ATG16L1 in maintaining microbial equilibrium63. Notably, Paneth cells—immune effector cells highly expressing NOD2 in the ileum—sustain microbiota homeostasis under physiological conditions by secreting antimicrobial peptides (e.g., lysozyme, sPLA2, defensins) in response to bacterial ligands like Muramyl dipeptide (MDP), the NOD2-specific agonist64. Consequently, NOD2 mutations disrupt host-microbe interactions, increasing susceptibility to the development of ileal inflammation.

Barrier integrity is a physical prerequisite for microbiota stability. Studies using Slc26a3 (DRA-KO) mice by Kumar et al. showed that chloride exchanger dysfunction downregulates tight junction proteins (ZO-1, occludin) and adherens junction proteins (E-cadherin) in colonoids, concomitant with reduced microbial diversity and pathobiont proliferation65. Al-Ghadban’s inflammatory epithelial cell model further validated these findings: pro-inflammatory stimuli induced abnormal distribution of connexins (Cx26/Cx43) and reduced expression of junctional complexes (E-cadherin, ZO-1), forming a characteristic “pore-leakage” phenotype66. Critically, environmental factors like chronic titanium dioxide nanoparticle exposure exacerbate barrier dysfunction synergistically with dietary stressors, highlighting intestinal barrier disruption as a convergence point for multifactorial insults67. Against this backdrop, several studies have linked edible fungi to the repair of the intestinal barrier. For example, in experimental models, Ganoderma lucidum polysaccharides have been associated with enhanced expression of tight junction proteins and alleviation of intestinal epithelial barrier injury, potentially through activation of the TLR4/Dectin-1 signaling pathway68,69. Similarly, polysaccharides from Grifola frondosa may contribute to barrier function by increasing mucin secretion and promoting the colonization of probiotics70,71.

At the microbial level, pathogen invasion remodels microbiota structure through ecological niche competition. A zebrafish model study by Yang et al. demonstrated that γ-Pseudomonadota invasion not only notably alters microbial composition but also triggers innate immune responses by inducing excessive ROS production and upregulating antimicrobial peptide genes (quantified by RT-qPCR)72. Clinically, Klebsiella pneumoniae employs a toxin-mediated attack mechanism via its type VI secretion system (T6SS), with its abundance showing a strong positive correlation with IBD endoscopic scores, highlighting the pathogenic driver role of conditional pathobionts in dysbiosis73. This suggests a “bidirectional vicious cycle” in pathogen-driven dysbiosis: altered microbiota structure weakens host defenses, thereby creating a favorable microenvironment for pathogen expansion. In contrast, cordycepin has been reported to exhibit direct inhibitory activity against various intestinal pathogens (e.g., Helicobacter pylori, Escherichia coli) in experimental studies. Additionally, its ability to modulate intestinal pH may contribute to the suppression of pathogen colonization74,75.

Diet-microbiota interactions exhibit dynamic bidirectional regulation, where microbial metabolites (e.g., SCFAs) reciprocally modulate host appetite centers and dietary preferences, forming an ecological-behavioral feedback loop. Systematic experiments reveal that plant-based protein diets promote the proliferation of Bifidobacteriaceae and Lachnospiraceae while notably boosting SCFAs production. In contrast, animal protein intake increases the relative abundance of Enterococcus and reduces SCFAs synthesis76. Notably, studies on dietary fiber metabolism suggest that specific microbes (e.g., Akkermansia) can activate the AhR/PXR signaling pathways via the tryptophan-indole metabolic axis. These pathways are involved in important intestinal functions, including supporting barrier integrity, reducing permeability, and modulating pro-inflammatory cytokine expression77,78. Notably, many edible fungi are considered high-quality sources of dietary fiber. For example, polysaccharides from Lentinula edodes may function as prebiotics, with studies reporting their association with the promoted growth of Bifidobacterium and Lactobacillus and increased production of SCFAs79. Similarly, extracts from Inonotus obliquus have been linked to a reduced Bacillota/Bacteroidota ratio and appear to alleviate microbiota disturbances caused by high-animal-protein diets80. Antibiotic-induced ecological collapse exerts long-lasting effects. In a chronic stress-induced depression model by Deng et al., 8-week antibiotic intervention notably reduced α-diversity indices (e.g., Shannon index decline) while activating lipoic acid metabolism pathways and upregulating lipid A synthesis genes81. Shao’s diarrhea model further confirmed that gentamicin/cephradine treatment increased Enterococcus abundance by 5.97% compared to controls, with functional profiling showing marked downregulation of carbohydrate metabolism pathways82. Concurrently, the influence of neuroendocrine regulatory networks on gut microbiota is increasingly being elucidated. Cohort studies on childhood psychological stress reveal that chronic stress states lead to a significant reduction in Bacteroides abundance alongside a marked increase in Roseburia abundance. These microbial shifts are strongly correlated with elevated cortisol levels, highlighting a direct link between neuroendocrine activation and dysbiosis83,84. Animal experiments further corroborate that chronic stress alters intestinal colonization resistance via hypothalamic-pituitary-adrenal (HPA) axis activation. This mechanism likely involves signaling through the vagus nerve within the gut-brain axis, affecting microbial colonization patterns and SCFA synthesis efficiency, providing a neurobiological explanation for the impact of psychological factors on microbiota homeostasis85,86. Notably, fungi such as Hericium erinaceus have been investigated for their active components (e.g., erinacines), which may promote the synthesis of nerve growth factor (NGF) and modulate stress responses via the gut-brain axis. This pathway could indirectly contribute to the amelioration of stress-associated dysbiosis87,88. The complex interplay between exogenous and endogenous factors in driving gut microbiota dysbiosis is illustrated in Fig. 2.

Fig. 2: Mechanisms of Gut Microbiota Dysbiosis.
Fig. 2: Mechanisms of Gut Microbiota Dysbiosis.The alternative text for this image may have been generated using AI.
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Exogenous factors (e.g., antibiotic overuse, high-fat/high-sugar diets, environmental pollutants) and endogenous factors (e.g., genetic susceptibility, intestinal barrier dysfunction, host metabolic disorders) synergistically disrupt the structural equilibrium of gut microbial communities. This dysbiosis is characterized by reduced abundance of beneficial bacteria (e.g., Bifidobacterium, Lactobacillus) and aberrant proliferation of opportunistic pathogens (e.g., Enterobacteriaceae, Desulfovibrio spp.). Such imbalance drives disease progression by: (1) compromising intestinal epithelial tight junction proteins (e.g., ZO-1, occludin); (2) inducing chronic low-grade inflammation via activation of pathways such as LPS-TLR4/NF-κB; and (3) altering microbial metabolite profiles (e.g., decreased SCFAs). These pathological changes collectively establish a “host metabolism-microbiome” vicious cycle, ultimately advancing diseases including IBD, metabolic syndrome, and colorectal cancer.

Edible Fungi

Overview and research progress of edible fungi

Definition and scope

This review adopts a broad definition of edible fungi, encompassing both mushrooms commonly used in daily diets and fungi with confirmed safety that are traditionally employed for health and medicinal purposes, such as Ganoderma lucidum and Phellinus linteus. These fungi synthesize diverse bioactive secondary metabolites and are widely distributed across six major taxonomic groups: Ascomycota, Basidiomycota, Zygomycota, Chytridiomycota, Glomeromycota, and Cryptomycota89,90. Their metabolites are functionally categorized into three classes: antibiotics (e.g., penicillin produced by Penicillium chrysogenum91) immunomodulators (e.g., polysaccharides from Ganoderma92), and toxins (e.g., aflatoxins biosynthesized by Aspergillus flavus93,94).Edible fungi, as a crucial source of natural bioactive molecules, possess immense development potential. Their integration with cutting-edge technologies such as multi-omics and synthetic biology holds great promise for novel drug discovery and gut microbiota modulation strategies.

Classification and functional profiling of edible fungi

Taxonomic and metabolic diversity

The edible fungi discussed in this review encompass traditionally defined medicinal mushrooms, such as Ganoderma lucidum, Trametes versicolor, and Phellinus linteus. Although these fungi are rarely consumed directly due to their tough texture and bitter taste, when administered as extracts or supplements, their bioactive components (e.g., polysaccharides, terpenoids) demonstrate considerable potential in gut microbiota regulation, hence their inclusion within the scope of this discussion. A summary of representative edible fungi, their core active components, functional mechanisms, and effects on gut microbiota is provided in Table 3.

Table 3 Representative Taxa of Edible Fungi and Their Functional Properties
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Core active ingredients and functional mechanisms

Edible fungi exert critical regulatory effects on gut microbiota composition and host health through their diverse bioactive metabolites. These components—including structura polysaccharides, terpenoids, peptides, dietary fibers, and other secondary metabolites95,96 —function via mechanisms such as immunomodulation, metabolic intervention, anti-inflammatory activity, and antioxidant effects97,98,99. This section will systematically analyze how representative constituents influence host health by directly or indirectly modulating the structure of the gut microbiota and its metabolic products.

Fungal Polysaccharides

Fungal polysaccharides represent a class of highly abundant and widely studied bioactive components in natural fungi, with β-glucans serving as a prominent representative example. Their structural complexity arises from diverse glycosidic linkages, including α-1,3, β-1,3/1,6, among others. The unique (1 → 3)-β-D-glycosidic backbone with (1 → 6)-β-D-branched linkages100 forms a three-dimensional network structure, conferring a broad spectrum of bioactivities. For instance, polysaccharides from Lentinula edodes (lentinan), Tremella fuciformis, and Flammulina velutipes have been studied for immunomodulatory, antitumor, and anti-inflammatory biological activities, as observed in in vitro and animal studies.

Fungal polysaccharides enhance both innate and adaptive immune responses by activating macrophages, natural killer (NK) cells, and T lymphocytes101,102,103,104, thereby modulating the immune microenvironment within the context of gut microbiota regulation by edible fungi105. For example, lentinan alleviates intestinal inflammatory responses by inhibiting TLR4/MyD88-mediated NF-κB activation and blocking NLRP3 inflammasome assembly106,107,108. Studies have shown that lentinan increases the activity of antioxidant enzymes such as SOD, GSH-Px, and CAT in the intestines of Hucho taimen juveniles, inhibits lipid peroxidation, and reduces the expression of pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, thereby enhancing intestinal barrier function and alleviating chronic inflammatory conditions such as inflammatory bowel disease (IBD)109. Research on gut microbiota modulation has demonstrated that various edible fungal polysaccharides exhibit prebiotic effects and can alter microbial structure. Under experimental conditions, lentinan has been observed to increase the relative abundance of beneficial bacteria such as Lactobacillaceae, Lachnospiraceae, and Ruminococcaceae, while being associated with a reduction in taxa like Enterobacteriaceae and Fusobacteriota. It also restores the Bacillota/Bacteroidota balance and enhances the expression of intestinal barrier proteins (Occludin, ZO-1) in cyclophosphamide-induced immunosuppression models110. Flammulina velutipes polysaccharides can enhance gut microbial diversity, promote the proliferation of beneficial bacteria such as Prevotellaceae, and concurrently enhance the accumulation of short-chain fatty acids (SCFAs), further strengthening intestinal health. In vitro fermentation studies have observed that Tremella fuciformis polysaccharides modulate the microbiota, notably increasing the abundance of genera such as Phascolarctobacterium, Bacteroides, and Lachnoclostridium, and promoting the production of acetate, propionate, butyrate, and other SCFAs, indicating potential for improving intestinal microecology111.

Furthermore, fungal polysaccharides exert systemic regulatory effects via the “microbiota-gut-organ axis”. For instance, lentinan alleviates non-alcoholic steatohepatitis by modulating the microbiota-gut-liver axis112; pyranoglucan from Pleurotus pulmonarius prevents alcoholic liver disease by regulating the Nrf2/HO-1-TLR4/NF-κB signaling pathway and gut microbiota113; Tremella fuciformis polysaccharides alleviate atopic dermatitis by modulating immune responses and gut microbiota114. These effects collectively illustrate the multi-target and multi-level mechanisms of action of fungal polysaccharides in regulating gut microbiota and maintaining host health.

Bioactive Proteins and Peptides in Edible Fungi

Bioactive proteins in edible fungi are a class of proteins or peptides with specific biological functions, including lectins, ribosome-inactivating proteins, fungal immunomodulatory proteins (FIPs), and antimicrobial peptides, antioxidant peptides, among others115,116.

Fungal lectins can specifically recognize cell surface glycans, thereby modulating immune cell function117,118. For instance, Auricularia heimuer lectin (AAL) inhibits tumor proliferation by regulating the expression of JUN, TLR4, and MYD88119; Pleurotus eryngii lectin alleviates arsenic exposure-induced oxidative stress and apoptosis, impedes the downregulation of SOD2 mRNA expression, and reduces cell adhesion and proliferation120,121. Lentinula edodes lectin has been found to inhibit the growth of Staphylococcus aureus and Aspergillus niger, showing demonstrable effects in studies. These immunomodulatory and antimicrobial activities help ameliorate the intestinal inflammatory state, providing a favorable microenvironment for the colonization of beneficial bacterial communities122.

Fungal Immunomodulatory Proteins (FIPs) are a class of low-molecular-weight proteins, represented by FIP-fve isolated from Flammulina velutipes. FIP-fve promotes T-cell proliferation and IL-2 release by activating the MAP2K3/p38α (MAPK14) signaling pathway and notably induces interferon-γ (IFN-γ) production, a process that can be blocked by the p38 MAPK inhibitor SB203580123,124. In an obese asthma model, FIP-fve alleviated airway hyperresponsiveness and reduced levels of inflammatory cytokines such as IL-6 and IL-33, demonstrating its potential in metabolic-immune cross-regulation125. Notably, the FIP-fve-mediated Th1-type immune dominant response can suppress the over-proliferation of opportunistic pathogens in the gut and influence microbial community structure by modulating the cytokine network. The Agaricus bisporus lectin-like protein LSMT, which shares structural similarity with Clostridium botulinum HA-33 and Clitocybe nebularis lectin, possesses the potential to penetrate intestinal epithelial cells and is thus suitable for the development of oral drug delivery systems. Pleurotus eryngii protein improves intestinal homeostasis by modulating lipid and terpenoid metabolism, reducing pro-inflammatory bacteria (e.g., Escherichia, Shigella), activating cholesterol metabolism pathways, and promoting IL-10 secretion126. This process is accompanied by an increase in the relative abundance of beneficial bacteria such as Lactobacillus. Bioactive peptides from Hericium erinaceus exhibit good absorbability and immunomodulatory functions in gastrointestinal models127, and can promote the proliferation of beneficial microorganisms like Akkermansia. Selenium-chelating peptides from Grifola frondosa can be effectively absorbed by Caco-2 cells and regulate the expression of cell cycle and apoptosis-related proteins, suggesting their potential as selenium supplements128. Their antioxidant activity also helps mitigate the adverse effects of oxidative stress on the gut microbiota.

Synergistic effects of fungal secondary metabolites

Secondary metabolites from edible fungi not only possess intrinsic bioactivity but also exert influence on host health through synergistic interactions between components or indirectly through modulation of the gut microbiota, thereby forming a multi-target and networked regulatory system. This synergistic effect is particularly evident in the regulation of intestinal microecology. Multiple studies have revealed the synergistic potential of specific fungal metabolites in improving the intestinal environment. For instance, compounds 10–12 isolated from Morchella sextelata exhibit significant anti-inflammatory activity (inhibiting nitric oxide production), while compounds 7 and 9 demonstrate antioxidant capacity superior to that of vitamin C129. Anti-inflammatory and antioxidant activities are crucial for maintaining intestinal barrier integrity and suppressing gut inflammation; the synergy of these components helps create a stable intestinal microenvironment for beneficial bacterial communities. Similarly, secondary metabolites such as phenolic acids and vitamins, abundantly found in Boletus spp., serve as functional food ingredients that indirectly protect intestinal health through their synergistic antioxidant effects130.

Fungal polysaccharides are one of the core components regulating gut microbiota, and their effects are often involve synergy with microbial metabolites. Research on Flammulina velutipes residue polysaccharide and its metabolites (FVRP) serves as a representative case. In an immunosuppressed mouse model, FVRP was observed to alleviate intestinal injury and improve antioxidant and immune parameters. Furthermore, it appeared to provide intestinal protection and immunomodulation by concurrently modulating the gut microbiota (e.g., promoting Prevotellaceae and reducing Lachnospiraceae), increasing short-chain fatty acid (SCFA) levels, and reversing cyclophosphamide-induced alterations in 32 endogenous metabolites. Fecal microbiota transplantation experiments confirmed that the effects of FVRP largely depend on its broad regulation of the gut microbiota and associated metabolites131.

Secondary metabolites from Grifola frondosa demonstrate synergistic regulatory potential targeting different diseases. Among its isolates, heptadecanoic acid, uridine, and adenosine can synergistically inhibit α-glucosidase (relevant to diabetes); ergosterol compounds possess anti-proliferative (anti-tumor) activity; while ergosterol and methyl linoleate can synergistically inhibit the enterovirus EV71. Molecular docking results indicate that these active compounds can stably bind to target proteins via various molecular interactions. This multi-target synergistic mechanism provides a basis for their ability to improve health by modulating the intestinal environment or directly acting on intestinal pathogens132.

Hericium erinaceus is an excellent model for studying the synergistic effects of fungal secondary metabolites, particularly their impact on health via the gut-brain axis. Its key neuroactive component, Erinacine A, is extensively metabolized in the liver, and the five identified metabolites provide a basis for assessing its bioavailability and safety133. During simulated gastrointestinal digestion, Hericium erinaceus polysaccharides (HEP) undergo a reduction in molecular weight and release free monosaccharides, thereby enhancing the growth-promoting effect (prebiotic activity) of its digestion products on probiotics such as Lactiplantibacillus plantarum. These probiotics then ferment HEP, producing SCFAs including acetate and butyrate. This series of events suggests a potential cycle whereby fungal polysaccharides influence gut microbiota metabolism to increase the production of beneficial metabolites like SCFAs, which may contribute to intestinal health134.Furthermore, various secondary metabolites isolated from Hericium erinaceus (e.g., erinaroll K, hericerin A, erinacone F) have been confirmed to possess anti-inflammatory activity, effectively inhibiting the production of inflammatory factors such as TNF-α, IL-6, and NO in macrophages135. Concurrently, the metabolite complex system from Hericium erinaceus and Ganoderma lucidum can activate the aryl hydrocarbon receptor (AhR) signaling pathway and upregulate the expression of various proteins related to proliferation, autophagy, and antioxidation in hippocampal neurons, demonstrating neuroprotective potential136. AhR is a key molecular bridge connecting gut microbiota metabolism (e.g., tryptophan metabolites) with host immune and neurological functions. Studies on aged frail mice showed that standardized Hericium erinaceus extract (containing multiple known active components) improved motor ability, alleviated cerebellar degenerative changes, and reduced systemic inflammation and oxidative stress, fully demonstrating the synergistic anti-aging effects of its multiple metabolites acting through multiple pathways, including the gut-brain axis137 A review of Agaricus subrufescens and other Agaricus species points out that they produce up to 70 natural products with various activities such as anticancer and immunomodulation. The synergistic action of these components forms an important foundation for their development as functional foods138.

Impact of Edible Fungi on Gut Microbiota and Bacterial Metabolites

Modulation of gut microbiota by edible fungi

In modern lifestyles, dietary habits and medical practices are profoundly reshaping gut microbial ecosystems139,140. Extensive research indicates that long-term consumption of high-fat diets, overreliance on antibiotics, and frequent intake of processed foods—seemingly mundane behaviors—severely disrupt gut microbiota. For instance, high-fat diets reduce the abundance of Saccharomyces cerevisiae in murine intestines141. Such disruptions manifest as structural imbalances in gut microbiota, including elevated Bacillota/Bacteroidota ratios and opportunistic pathogen proliferation (e.g., Escherichia coli)142,143,144. These changes increase intestinal permeability (“leaky gut”), fostering chronic inflammation and triggering immune-metabolic disorders such as obesity and diabetes145,146,147.

Edible fungi such as shiitake (Lentinula edodes), reishi (Ganoderma lucidum), and lion’s mane (Hericium erinaceus) contain compounds that are studied for their roles in supporting gut health148,149,150. Rich in polysaccharides, dietary fibers, and secondary metabolites, these fungi modulate gut microbiota by restructuring microbial communities and enhancing the metabolic activity of beneficial bacteria151,152. Clinical trials reveal that dietary supplements derived from edible mushrooms (e.g., shiitake, Lentinula edodes) promote SCFA production and correlate with increased IgA levels. Populations consuming fungi-rich diets exhibit notably higher gut microbiota diversity compared to those on standard diets153, underscoring fungi’s pivotal role in gut health and offering novel strategies for microbiome maintenance.

Animal studies have shown that edible fungi can regulate the gut microbiota. In azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse models, β-glucans isolated from shiitake mushrooms (Lentinula edodes), a common edible fungus, demonstrated beneficial effects by rebuilding the mucosal barrier, increasing SCFAs secretion, and reshaping microbial structure---specifically enriching Bacteroidota while reducing Pseudomonadota154. These findings highlight how fungal polysaccharides not only restructure microbiota but also promote ecological resilience of beneficial taxa155.

Similarly, in mouse studies, Auricularia polysaccharides have been observed to lower the Bacillota/Bacteroidota ratio and are associated with increased fecal microbial diversity156. Collectively, edible fungi achieve dynamic gut homeostasis through a “Microbiota-Metabolite-Host” triad; for instance, shiitake β-glucans selectively enrich Bacteroidota and suppress Pseudomonadota, thereby improving microbial composition while enhancing intestinal barrier function via SCFAs. Understanding this dual mechanism suggests potential relevance to strategies for addressing chronic inflammatory diseases. The holistic mechanisms by which edible fungi and their bioactive components regulate gut microbiota and improve host health are depicted in Fig. 3.

Fig. 3: Mechanisms of fungal regulation of gut microbiota.
Fig. 3: Mechanisms of fungal regulation of gut microbiota.The alternative text for this image may have been generated using AI.
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Illustrates the holistic process through which edible fungi modulate intestinal health via bioactive components such as polysaccharides. The left panel depicts gut microbiota dysbiosis and pathogenic bacterial colonization within the outline of the human intestinal tract, along with the introduction of fungal components. The right panel zooms in on cellular and molecular mechanisms, demonstrating how these components bind to receptors (e.g., TLR4, TLR2), activate immune pathways (such as NF-κB and NLRP3), regulate inflammatory cytokines (including TNF-α and IL-6), enhance short-chain fatty acid (SCFAs) production, and involve epigenetic mechanisms—such as histone acetylation and DNA methylation. These processes collectively contribute to enhanced immune function, moderated inflammation, preservation of intestinal barrier integrity (e.g., through mucins and E-cadherin), and inhibition of intestinal epithelial cell apoptosis.

Fungal modulation of SCFAs production

Edible fungi generate diverse metabolites during fermentation, including polysaccharides (e.g., β-glucans), polyphenols, and enzymes, which profoundly enhance the synthesis of SCFAs by reshaping gut microbiota composition. SCFAs—primarily acetate (C2), propionate (C3), and butyrate (C4)—account for over 90% of total microbial fermentation products derived from dietary fibers157.

The synthesis of SCFAs is intricately linked to specific metabolic pathways of gut bacteria. Acetate is primarily generated via the acetyl-CoA pathway by Bifidobacterium and Bacteroides through the fermentation of glucose or fructose. Propionate production occurs via the succinate pathway (involving Bacteroides) or acrylate pathway (involving Bacillota), predominantly mediated by Pseudomonadota and Propionibacterium158. Butyrate synthesis relies on the butyrate kinase pathway (e.g., Faecalibacterium prausnitzii) or butyryl-CoA: acetyl-CoA transferase pathway (e.g., Roseburia), with Bacillota (e.g., Ruminococcus) playing a central role159,160. These mechanisms not only provide a theoretical foundation for fungal interventions in metabolic diseases but also pave the way for developing precision therapies targeting SCFAs signaling, whose potential in tumor microenvironment modulation will be further discussed.

SCFAs exert critical physiological functions in the host. They suppress pathogenic bacteria, such as Escherichia coli, by lowering intestinal pH161. Immunologically, butyrate promotes regulatory T-cell differentiation by activating G protein-coupled receptors (GPR41/GPR43) or HDACs162. In energy metabolism, propionate drives hepatic gluconeogenesis163, while acetate provides acetyl groups for β-oxidation in peripheral tissues164,165. Extensive studies confirm that SCFAs act as “microbe-host” signaling molecules, deeply influencing immune-metabolic pathologies (e.g., obesity, diabetes), IBD, and neurodegenerative diseases166,167,168. For example, butyrate alleviates colitis by enhancing intestinal barrier function169,170.

Edible fungi are considered to influence SCFA levels through several proposed mechanisms. First, fungal polysaccharides, such as β-glucans from Ganoderma lucidum, can serve as fermentable dietary fibers for the gut microbiota, providing substrates for SCFA synthesis171. Second, fungal components may reshape microbial composition by promoting the growth of certain beneficial bacteria (e.g., Bifidobacterium and Lactobacillus) that are known to produce SCFAs. For instance, Phellinus polysaccharides have been observed in studies to increase the abundance of Bacteroides, Pseudomonadota, and Butyricimonas while reducing taxa like Escherichia, Morganella, and Enteromonas; these shifts are associated with changes in butyrate, bile acid, and purine metabolism172. Similarly, Tremella yeast polysaccharides have shown prebiotic activity by stimulating specific strains of Lactobacillus and Bifidobacterium, which may indirectly support SCFA production173. Third, fungal secondary metabolites, including terpenoids and polyphenols, can modulate bacterial enzymatic activity in experimental models. Some terpenoids have been found to enhance the activity of bacterial enzymes involved in SCFA synthesis, such as butyrate kinase, potentially accelerating their production. Fourth, edible fungi might indirectly affect SCFA levels by influencing host physiology. Certain fungal components are thought to regulate intestinal motility and secretions, which could create a more favorable environment for microbial fermentation and thereby potentially increase SCFA yields. These interconnected mechanisms suggest a potential link between fungal intake, microbial metabolism, and host physiology.

Gut microbiota-mediated effects of edible fungi on metabolic diseases and cancer

Role of edible fungi in metabolic diseases via gut microbiota modulation

Metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD), have emerged as critical global health challenges174,175,176. Recent studies reveal that the pathogenesis of these conditions is closely linked to gut microbiota dysbiosis177,178,179. Gut microbiota regulates metabolic homeostasis by modulating host energy metabolism, immune responses, and signaling molecule synthesis180,181. For instance, shifts in the abundance of Bacteroidota and Bacillota correlate with weight gain and insulin resistance182; while SCFAs—such as acetate, propionate, and butyrate—produced from microbial fiber fermentation, activate G protein-coupled receptors (GPR41–GPR43) or HDACs to regulate intestinal barrier integrity, inflammation, and glucose/lipid metabolism183,184,185,186. Fungal polysaccharides ameliorate obesity by remodeling microbiota through PPARγ signaling, elucidate the molecular mechanisms by which fungal polysaccharides improve obesity via the “microbiota-metabolite-host” axis.

Recent research highlights the therapeutic potential of bioactive components from medicinal fungi in alleviating metabolic disorders by reshaping gut microbiota or enhancing SCFAs biosynthesis187. For example, Ganoderma lucidum rich in polysaccharides and triterpenoids, demonstrates potent anti-obesity effects in animal models. An 8-week intervention with Ganoderma polysaccharides (GLP) notably reduced the abundance of Parabacteroides, Bacteroides and Lachnospiraceae incertae sedis, lowered TNF-α and IL-6 levels, restored IL-10 production, and modulated key signaling pathways. In mice, GLP treatment reduced HFD-induced weight gain, fat accumulation, hyperlipidemia, and hepatic inflammation, and improved glucose tolerance188. Research on Phellinus and Ganoderma suggests that their bioactive components may contribute to metabolic improvement through a dual mechanism involving (1) modulation of microbial metabolism (e.g., enhancing butyrate synthesis) and (2) interaction with host immunometabolic pathways (e.g., associated with stimulated GLP-1 secretion189). This multidimensional regulatory strategy overcomes the limitations of conventional single-target therapies, offering innovative approaches for personalized treatment of diabetes and obesity. By simultaneously addressing gut microbiota dysbiosis and host metabolic dysfunction, edible fungi exemplify a holistic paradigm for precision medicine, bridging microbial ecology to clinical therapeutics.

Gut microbiota-mediated antitumor effects of edible fungi

The intricate relationship between gut microbiota and tumorigenesis has become a pivotal focus in oncology, with specific pathogenic bacteria directly or indirectly driving tumor progression190,191. For instance, the FadA adhesin produced by Fusobacteriota corrig (a pathogenic bacterium) stimulates proliferation in human colon cancer cell lines (HCT116, DLD1, SW480, HT29) in a time-dependent manner. Its interaction with E-cadherin promotes bacterial adhesion and invasion via clathrin-mediated endocytosis. Short-term exposure of HCT116 cells to FadAc (the active FadA complex) impairs E-cadherin’s tumor-suppressive activity, reduces β-catenin phosphorylation, and activates Wnt signaling through nuclear translocation, while enhancing NF-κB and oncogenes like Myc and Cyclin D142. Conversely, certain commensal bacteria exhibit antitumor potential. For example, combined use of Lactobacillus plantarum and Bifidobacterium lactis suppresses tumor growth in GL261 glioma mouse models by inhibiting the PI3K–AKT pathway, notably reducing tumor volume and improving survival rates192. Additionally, Bifidobacterium longum enhances NK cell activity and upregulates pulmonary expression of IFN-γ, IL-2, IL-12, and IL-18, demonstrating antiviral and antitumor properties193.

Preclinical studies suggest that bioactive metabolites from edible fungi may influence tumor development by modulating the composition of the gut microbiota. For instance, Flammulina velutipes polysaccharides alleviate cadmium-induced intestinal damage in mice by modulating gut inflammation and microbial composition. They increase Bacteroides abundance, reduce Desulfovibrio and Clostridium populations, and restore SCFAs levels (acetate, propionate, isobutyrate, butyrate, isovalerate, and valerate), thereby enhancing microbial metabolic function194 In co-culture systems, Agaricus blazei polysaccharides have been shown to significantly activate CD8+ T cells in co-culture systems, enhancing their colorectal cancer-killing capacity. In vivo studies further reveal that Agaricus blazei polysaccharides inhibit intraperitoneal tumor growth, remodel the tumor microenvironment (TME) by increasing ω-3 polyunsaturated fatty acids, and promote T-cell-mediated immune regulation195.

Similarly, polysaccharides from Inonotus obliquus mycelia (IOP) ameliorate dextran sulfate sodium (DSS)-induced ulcerative colitis in mice by reducing colon oxidative stress markers (e.g., MDA, MPO, NO), increasing IL-10 secretion, and suppressing pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). IOP also lowers the Bacillota/Bacteroidota ratio while enriching Bacteroides and Lactobacillus, suggesting potential as potential as a therapeutic agent for colitis-associated colorectal cancer80. These findings underscore the dual role of edible fungi in targeting both dysbiotic microbiota and oncogenic pathways, offering novel strategies for cancer prevention and adjuvant therapy.

Molecular mechanisms of edible fungi in epigenetic regulation of gut microbiota

Within the gut ecosystem, edible fungi not only reshape microbial composition through metabolites but also exert profound interventions in host-microbiota interactions via epigenetic regulation, a pivotal bridge connecting environmental factors and host gene expression. Epigenetic mechanisms, such as DNA methylation and histone modifications, are central to the dynamic interplay between gut microbiota and the host. Microbial-derived molecules like SCFAs and tryptophan metabolites can remodel host cell functions through these pathways, influencing disease progression. Recent studies suggest a mechanism by which Phellinus linteus polysaccharides may increase butyrate levels through enrichment of Butyricimonas spp. In this proposed model, butyrate, acting as an HDAC inhibitor, induces H3K27 acetylation in intestinal epithelial cells, potentially activating the Foxp3 locus and enhancing regulatory T-cell differentiation. In parallel, Ganoderma-derived triterpenoids (e.g., ganoderic acids) have been observed to inhibit DNMT1, which is associated with reduced DNA methylation at pro-inflammatory gene loci such as IL-6. These complementary actions have been proposed to synergistically support intestinal barrier function. This tripartite regulatory network—encompassing microbial metabolites, epigenetic modifications, and immune responses—provides a molecular rationale for the multi-target properties of fungal components.

SCFAs, the core metabolites of microbial fiber fermentation, serve as key epigenetic signaling molecules. For example, in studies, Ganoderma polysaccharides have been observed to selectively enrich butyrate-producing bacteria such as Ruminococcaceae, Lachnospiraceae, and Blautia. These changes in microbial composition are associated with increased intestinal butyrate levels149,196. Butyrate exerts anti-inflammatory effects through dual mechanisms: (1) HDACs to induce hyperacetylation of histone H3K9, activating anti-inflammatory genes (e.g., IL-10, Foxp3); and (2) suppressing NF-κB signaling via HDAC8 modulation, synergistically promoting regulatory T-cell differentiation and intestinal barrier enhancement186,197,198,199. In DSS-induced colitis models, Kai-xin Peng et al. demonstrated that butyrate upregulates Slc26a3 expression by inhibiting HDAC activity, an effect mimicked by pan-HDAC inhibitors200. In a study by Guo-qiang Fan et al. using RAW 264.7/Caco-2 co-cultures, butyrate was shown to suppress macrophage pyroptosis and enhance the levels of tight junction proteins (ZO-1, occludin) in intestinal epithelial cells201. In separate findings, Phellinus polysaccharides have been observed to enrich Bacteroides, an effect concurrent with increased propionate production202. Meanwhile, Tremella extracts have been reported to inhibit LPS-induced phosphorylation of the IKK–NF-κB and MAPK pathways. Their administration is also associated with an increased abundance of Phascolarctobacterium, Bacteroides, and Lachnoclostridium, along with elevated levels of acetate, propionate, butyrate, and valerate111,203. As pivotal microbial metabolites, SCFAs play an indispensable role in epigenetic regulation. Edible fungi, through their bioactive components, precisely modulate gut microbiota to enhance SCFAs synthesis, thereby improving intestinal ecology. Despite progress in understanding fungal-mediated epigenetic regulation, deeper mechanistic insights remain a critical challenge.

Considerations for translation: dosage, safety, and regulatory landscape

Despite promising preclinical evidence, translating these findings into tangible human health benefits requires addressing several challenges, notably concerning dosage and safety. Currently, most supporting data originate from animal studies, and extrapolating effective doses to humans must carefully consider the form of consumption (e.g., whole mushroom versus standardized extract).

For instance, β-glucans from different sources exhibit distinct functionalities. Cereal-derived β-glucans, primarily used for metabolic benefits like cholesterol reduction, are often administered at high, gram-level doses in dietary interventions. In contrast, mushroom-derived β-glucans, known for their immunomodulatory properties, are typically incorporated into functional foods or nutritional supplements at significantly lower doses204. This fundamental difference underscores that the future of edible fungi lies in strengthening their role in food-based applications and clinical nutrition, rather than pursuing purely pharmacological development. Furthermore, regulatory frameworks vary globally, with many regions classifying mushroom-based products as functional foods or dietary supplements, which subjects them to different regulatory standards and evidence requirements compared to pharmaceuticals. The established adequate intake level, regardless of source, is 200 mg/day, with an acceptable upper limit of 1000 mg/day.

Regarding safety and human efficacy, clinical studies provide preliminary evidence of variable quality. A pooled analysis of 17 RCTs indicated that Ganoderma lucidum supplements (200–11,200 mg/day) significantly reduced Body Mass Index (BMI), yet the quality of evidence for all outcomes was very low205. Subchronic toxicity tests showed no signs of pulmonary toxicity with oral Ganoderma lucidum extract doses up to 1200 mg/kg/day206. In one clinical study, a Ganoderma lucidum polysaccharide extract (1800 mg, three times daily) led to disease stabilization in some cancer patients with good tolerability207. Case reports have also reported on the safety and potential benefits of Ganoderma lucidum powder in pediatric patients208, as well as its ability to reduce serum HBV DNA levels in hepatitis B patients209.

Furthermore, regulatory frameworks for mushroom products vary globally, influencing their market access. In the EU, mushroom extracts may be classified as Novel Foods if there is a lack of evidence for their significant consumption within the EU prior to May 1997, thus requiring a pre-market safety assessment. In the US, mushroom-based dietary supplements must meet GRAS standards, with health claims regulated. In Asia, mushrooms like Ganoderma lucidum are often integrated into functional foods210,211. For example, in Japan and China, certain polysaccharides (e.g., lentinan) are used in nutritional support for health maintenance, reflecting their role in traditional diets and modern functional foods. This underscores the spectrum from food to nutritional applications, rather than emphasizing pharmaceutical uses212. However, the European Medicines Agency (EMA) and the US FDA have not approved PSK or PSP, citing only a limited number of ongoing or completed clinical trials. Although more clinical trials have emerged in recent years (e.g., for adjuvant COVID-19 treatment)213, trials in the mushroom field remain scarce and limited, often hampered by shortcomings in study design.

This analysis demonstrates that the distinction between edible and medicinal mushrooms is not absolute but exists on a spectrum. Many mushrooms consumed as food (e.g., Agaricus bisporus, Lentinula edodes) contain bioactive compounds (e.g., β-glucans, triterpenoids) that confer health benefits beyond basic nutrition, aligning with their traditional use in functional foods and nutraceuticals. As mentioned, lentinan from Lentinula edodes is approved in Japan and China as a pharmaceutical adjuvant for treating gastric and colorectal cancer, exemplifying its dual identity as both a food-derived component and a drug. This overlap is further illustrated by the fact that, because the same mushroom species can be consumed as a whole food or processed into extracts for therapeutic purposes, with the dosage and form of application ultimately determining its classification.

Conclusion and outlook

In summary, this review systematizes the growing body of preclinical evidence suggesting that edible fungi and their bioactive components have the potential to act as modulators of the gut microbiota. The mechanisms discussed, such as reshaping microbial communities and promoting SCFAs production, provide a rational basis for this potential. However, it is paramount to reiterate that these promising effects are primarily observed in animal and cell studies. These beneficial effects are mediated through core mechanisms including reshaping microbial communities, promoting SCFAs production, and enhancing intestinal barrier function. The multifaceted nature of edible fungi, from dietary staples to sources of bioactive compounds, suggests potential new avenues for dietary strategies to support gut health. However, realizing this potential in evidence-based human applications requires a concerted effort to bridge the identified gaps, particularly through rigorous clinical trials. Future work must focus not only on mechanistic exploration but also on addressing the translational challenges outlined in this review, such as establishing human dose-response relationships and validating efficacy in targeted populations. For instance, fungi like Ganoderma lucidum are consumed as functional foods in Asian cultures for their nourishing properties, highlighting the continuum from dietary to health-promoting uses. Future work should focus on establishing dose-response relationships in humans, optimizing processing technologies, addressing region-specific regulatory frameworks, and ultimately translating these findings into safe and effective dietary strategies.

While we adopted an inclusive perspective based on shared mechanisms, it is crucial to reaffirm that their paths to human application are distinct, involving vastly different dosage regimens, safety profiles, and regulatory pathways (as detailed in Section 4.5). This distinction means that findings from studies on concentrated extracts cannot be directly translated into dietary advice for whole mushrooms, and vice versa.

This inherent difference constitutes a significant limitation of the current evidence base, complicating cross-extrapolation of findings. Therefore, future research must not only validate efficacy in human trials but also explicitly define the product matrix (e.g., whole mushroom, specific extract type, standardization) and its intended use (food, supplement, or drug). Dose-response relationships need to be established specifically for each form. Furthermore, navigating the complex and regionally varied regulatory landscapes is essential for the rational development and credible marketing of fungal-based health products. Well-designed clinical trials that account for these factors are urgently needed to bridge the gap between mechanistic promise and tangible human health benefits.

In regions like the European Union, many medicinal mushroom extracts may be classified as Novel Foods, requiring pre-market safety evaluation by the European Food Safety Authority (EFSA). Health claims are strictly regulated and demand substantial scientific evidence. In the United States, mushroom products marketed as dietary supplements must be safe (Generally Recognized as Safe, GRAS), and any structure/function claims are closely monitored by the FDA, with disease risk reduction claims being extremely rare. Conversely, in regions such as Japan and China, specific mushroom polysaccharides (e.g., Lentinan) are approved as pharmaceutical adjuvants for cancer treatment. These regulatory disparities highlight that the same fungal species can exist on a spectrum from food to drug, where its classification depends largely on formulation, dosage, and claimed benefits, rather than constituting an absolute dichotomy. Navigating these diverse regulatory frameworks is essential for the rational development and global marketing of fungal-based health products.

Although this review has summarized these advances, limitations and challenges remain, such as the need for more human trials. The diverse applications of edible fungi—from whole foods to processed nutritional products and potential clinical uses—represent a promising research avenue. Future studies should focus on processing techniques (e.g., extraction and formulation), efficacy validation across food, supplement, and therapeutic contexts, legal considerations, and integrated strategies that leverage the multifaceted nature of fungi. This approach is crucial for translating practical benefits for global health.