Overview of Ganoderma lucidum Polysaccharides on Various Diseases by Regulating Intestinal Microbiota: what is new?

Three strands of monosaccharides with a complicated tertiary stereo structure and molecular weights varying from hundreds to millions make up the sugar chain of Ganoderma lucidum polysaccharides [1,2]. GLP is the primary ingredient in valuable Chinese medicine, as noted in the review of Ekiz et al. in recent decades, which has positive pharmacological effects in glycolipid metabolism-related, hepatic, cardiovascular, gastrointestinal, and cancer diseases, and has good prospects for clinical application [3]. All of the above diseases are currently encountering different problems in the development of single drugs, as the role of intestinal microbiota is gradually being emphasized, regulating intestinal microbiota has become a new idea for improving the diseases [4,5]. It has been shown that there is a correlation between the progression of diseases related to glycolipid metabolism, liver, cardiovascular, and gastrointestinal diseases, cancers, and intestinal microbiota [6-10]. Diseases linked to glycolipid metabolism in the intestinal microbiota, its component substances and metabolites can activate intestinal nerve endings' or intestinal epithelial cells' receptors. It can also enter the bloodstream and influence how the body uses glucose and fats [11]. Simultaneously, certain amino acids and their metabolites originating from the intestinal microbiota are closely related to insulin resistance, which can promote insulin secretion and reduce the risk of diabetes onset [12]. Studies related to Nonalcoholic Fatty Liver Disease (NAFLD) have found that improving intestinal dysbiosis improves liver steatosis, decreases lipid content, decreases serum amino acids levels, and inflammatory cytokines levels [13-17]. Reports on cardiovascular disease have shown that intestinal microbiota regulate lipid metabolism through the regulation of Bile Acids (BAs), Short-Chain Fatty Acids (SCFAs), and other effects on membrane protein receptors, such as GPCRs, thereby improving cardiovascular disease [18-23]. Intestinal microbiota, such as bifidobacteria, are associated with and even play a crucial part in Irritable Bowel Syndrome (IBS) disease progression and Inflammatory Bowel Diseases (IBDs) [24-27]. Intestinal microbiota can also be produced through the production of SCFAs [28]. Intestinal microbiota can also play an indirect role in cancer prevention by producing SCFAs, activating natural killer cells and lymphocytes, producing anti-inflammatory cytokines [29-31], and activating and regulating apoptotic proteins [32,33]. 

Through preliminary research, we found that GLP can regulate the structure of intestinal microbiota, increase the expansion of good bacteria while preventing the development of harmful ones, thus improving the intestinal microecological balance [34,35]. Secondly, GLP may have an impact on how the intestinal microbiome functions, for fact, by modulating metabolic pathways or signaling pathways, affecting the metabolic activity of the microbiota and related physiological functions [35,36]. By controlling the quantity of various microbiota in the digestive tract and altering intestinal variety, it may also be utilized to alter the proportion of each bacterial group, which may help treat certain illnesses. Although studies related to GLP and intestinal microbiota have been reported, no systematic review has been carried out. Since the extraction technology of GLP affects its biological activity, the pharmacological mechanism of GLP and its extraction method in controlling intestinal microbiota in various disorders will be the main topics of this research, which will act as a basis for advancing the research of GLP and the investigation of its potential targets.

• Polysaccharide extraction techniques 

Ethanol precipitation, deproteinization (Sevag method, proteolytic digestion by protease or trifluoroacetic acid), decolorization (activated charcoal, hydrogen peroxide, or resin method), dialysis, and division (affinity, cellulose columns, gel filtration, or ion exchange chromatography) were then used to further cleanse the collected basic polysaccharides [37-39]. Subsequent characterization of the components by spectroscopy, chromatography, or NMR followed by bioassays for bioactivity detection [34,40-43].

The majority of the useful polysaccharides found in edible mushroom herbs are soluble in water, which makes them amenable to extraction using physical procedures like being heated, ultrasound, microwave, etc [44]. One of the main difficulties in recovering polysaccharides is that structural complexity hinders their release from intracellular site locations and complex matrices. Both alkali or Acid Extraction (AE) and classical Hot- Water Extraction (HWE) call for high temperatures and protracted processing durations. These two significant drawbacks can affect the quality of the product in terms of decreased product quality and increased purification costs [45,46]. Thus, new and cutting-edge technologies that concentrate on the extraction of polysaccharides from edible mushrooms are required. These include Ultrasonic-Assisted Extraction (UAE), Microwave-Assisted Extraction (MAE), Enzyme-Assisted Extraction (EAE), Ultrasonic-Microwave Synergistic Extraction (UMSE), Subcritical Water Extraction (SWE), Pulsed Electric Field-Assisted Extraction (PEFAE), Aqueous Twin-Phase Extraction (ATPE), integrated extraction, and other innovative extraction technologies (e.g., nanoparticle technology, mixing, a vacuum condition extraction, and electrolytic oxidized water extraction) [47-52]. A few methods for extracting polysaccharides from edible mushrooms, including UMSE, PEFAE, and ATPE, have hardly ever been reviewed or addressed [37,53,54]. In addition, kinetic model predictions and simulations can extract information useful for industrial scale-up applications but rarely discussed in the literature. 

• GLP extraction techniques and biological activity 

GLP extraction processes, such as ethanol pretreatment, Hot Water Extraction (HWE), Ultrasound-Assisted Extraction (UAE), and novel methods like Phase Transition Extraction (PTE), significantly influence the structural and bioactive properties of the final product. These variations arise from differences in Molecular Weight (MW), monosaccharide composition, conformation, and glycosidic bonding, which are critical determinants of bioactivity (Table 1). 

The structural characteristics of Ganoderma lucidum Polysaccharides (GLPs) directly govern their bioactivity. First, Molecular Weight (MW) plays a pivotal role: higher-MW GLPs (e.g., 1500 kDa from phase transition extraction, PTE) exhibit enhanced immunomodulatory and antioxidant effects due to improved receptor binding affinity and structural stability [41,55,56]. Second, sugar composition significantly influences bioactivity; galactose-rich GLPs (e.g., PTE-derived) demonstrate superior immune activity compared to glucose-dominant GLPs (e.g., hot water extraction, HWE), likely mediated by specific carbohydrate-protein interactions [41,56]. Third, conformational integrity is critical—triple-helix structures (retained in HWE and ultrasonic-assisted extraction, UAE) are essential for immune stimulation, whereas β-(1→6)-linkages disrupt helical stability, diminishing efficacy [41,55]. Finally, antioxidant capacity correlates with both MW and conformation, with PTE-derived GLPs outperforming UAE and HWE in scavenging free radicals and mitigating oxidative cellular damage [41,56]. These relationships underscore the importance of extraction method optimization to maximize therapeutic potential. For instance, a comparative study of HWE and UAE methods demonstrated that HWE extracts exhibited higher antioxidant activity (enhanced DPPH and hydroxyl radical scavenging) despite lower yields, likely due to preserved high-MW β-glucans [41]. Conversely, UAE’s smaller particle size and higher yield favor industrial scalability but may compromise conformational integrity, reducing immune-related bioactivity [41,57]. These findings underscore the need to balance extraction efficiency with structural preservation to optimize bioactivity. 

Emerging methods like PTE and PEF address traditional limitations (e.g., high temperatures, long processing times) by preserving structural features critical for bioactivity. For example, PEF’s low-temperature processing maintains antitumor efficacy by preventing thermal degradation of bioactive motifs [38]. Similarly, PTE’s ultra-high MW and galactose-rich composition enhance both antioxidant and immunomodulatory effects, making it a promising candidate for therapeutic applications [41,56]. 

Although GLP's physicochemical structures and physiological activities have been reported, the relationship between higher structures and biological activities remains unclear. Cutting-edge research has proven its excellent application prospects, such as antioxidant, anticancer, antitumor, antimutagenic, anti-HIV, anti-inflammatory, anticoagulant, anti-radiation, anti-fatigue, and antibiotic, antiproliferative, hypoglycemic, hepatoprotective, and antihypertensive effects; immune-modulating activity; and lowering of cholesterol and body fat [49,54,58-61]. The human intestinal tract cannot directly absorb GLP. Combined with previous studies, we hypothesized that GLP is likely to be broken down by the intestinal microbiota, which regulates the changes in the microbiota and thus plays a therapeutic or adjuvant role in treating or assisting diseases (Figure 1). 

Table 1: Impact of Extraction Methods on GLP Bioactivity. 

 Figure 1: GLP extraction and purification procedure.

• Diseases Related to Glycolipid Metabolism 

Diabetes: Type II Diabetes Mellitus (T2DM) is a prevalent long-term metabolic disease that affects over 90% of people with diabetes, including those who are extremely obese [63]. Studies have shown a substantial link among diabetes and issues with the intestinal microbiota. GLP, a biologically active substance, is important in regulating intestinal microbiota and has potential therapeutic effects on diabetes, that has recently received a great deal of attention from researchers [64,65]. The cotyledons and mycelium of Ganoderma lucidum contain polysaccharides, such as glycoproteins, (1 →3), (1 →6)-a/β-glucan, and water-soluble heteropolysaccharides [66], which are known to have hypoglycemic effects [3,67]. In diabetic mice, Ganoderma lucidum increased the activity of bacteria that produce SCFAs, like Blautia, Dehalobacterium and Lactococcus while decreased the amount of harmful microbes like Ruminococcus, Corynebacterium, Proteus and Aerococcus and increased the amount of anti-inflammatory microbes like Adlercreutzia and Rothia [7,68]. GLP extracted and concentrated from the mycelium of G. lucidum changed the proportion of dangerous microbes, like Ruminococcus and Aspergillus, while increasing beneficial microbes, such as Bacteroides, using a high-fat diet and the Streptozotocin (STZ) diabetes model in SD rats. This, in turn, restored the mice's blood glucose levels to normal. This study's microbiological and fecal metabolomics analyses revealed that GLP improved amino acid, carbohydrate, inflammatory substance, and bacterial toxin metabolism in the intestines of T2DM rats. Additionally, GLP restored intestinal microbiota diversity by increasing beneficial bacteria and decreasing harmful ones [7]. GLP was administered by gavage to an STZ diabetic rat model, and key genera analysis revealed that GLP dramatically increased the number of helpful bacteria, including Bifidobacterium spp., Turicibacter, Blautia, and E. faecalis and prevented the development of hazardous bacteria like Enterococcus, Dorea and Streptococcus spp. [67]. EGLS capsules were prepared with coated Ganoderma lucidum spore polysaccharide (GLS) applying a coating substance made of Resistant Starch (RS) [69]. In the SD rat diabetes model, EGLS intervention significantly reduced the number of Proteobacteria [69]. It enhanced the rats' glucose and lipid metabolic metrics, which were linked to increased insulin secretion, decreased adipogenesis, and increased glycogen synthesis [3,69]. GLP was chelated with chromium (III) to form a novel organochromium (GLP-Cr), which promotes insulin secretion on the one hand by decreasing harmful microbial phylotypes, such as the proportional quantity of Staphylococci. At the level of genus, it did, however, considerably raise the total number of intestinal probiotics such Weissella, Bifidobacterium, and Enterococcus. By reducing cholesterol and generating several secondary metabolites, such as SCFAs, vitamins, and extracellular polysaccharides, it also encourages the intestinal synthesis of n-butyric acid, propionic acid, and liver-beneficial acetic acid. Restructuring the intestinal microbiota to ameliorate metabolic diseases like diabetes and obesity [70]. Thus, GLP is an excellent candidate for treating type 2 diabetes. 

Hyperlipidemia: The hallmark of hyperlipidemia is high blood lipid levels, which includes triglycerides, total cholesterol, and LDL cholesterol [71,72]. Due to dietary and lifestyle changes, the prevalence of hyperlipidemia is rising rapidly. This disorder is commonly associated with NAFLD [72] and poses a serious risk of cardiovascular disease [73]. 

An animal meta-analysis study that included 49 articles showed that Ganoderma lucidum had a lowering effect on TG, TC, LDL-C, HDL-C, and VLDL levels and that different doses of Ganoderma lucidum had varying degrees of efficacy on the lipid profile; however, there is still a great deal of uncertainty about the mechanism of action and its effects on metabolism [74]. It was discovered that giving resistant starch-coated Ganoderma lucidum spores (EGLS) orally to T2DM rats for 28 days increased the expression of genes related to glucose and cholesterol homeostasis (Insig1, Insig2), synthesis of glycogen (GS2 and GYG1), oxidization of lipids (Acox1), and lipogenesis inhibition (ACC, Fads1). The control of hypoglycemia and hypolipidemic processes in the liver of rats with diabetes was impacted in a synergistic manner by the reduction of Aspergillus colonies and the enhancement of dysfunctional intestinal microbiota [69]. In hyper-cholesterolemic rats, research using Ganoderma lucidum polysaccharide peptide (GLPP) revealed that oral GLPP treatment dramatically decreased blood levels of TG, TC, FFA, and LDL-C, relieved dyslipidemia, and inhibited hepatic lipid buildup and steatosis [75]. Spearman correlation analyses revealed that serum and liver lipid levels were positively correlated with Allobaculum, Phascolarctobacterium, Psychrobacter, Enterorhabdus, Blautia, and Roseburia and negatively correlated with Jeotgalicoccus, Ignavigranum, Sporosarcina, Bacteroides, Anaerovorax, Parasutterella, Alistipes, and Alloprevotella [75]. GLPP also affected the relative abundance of functionally pertinent intestinal microbiota phylotypes [75]. Those findings imply that GLPP may ameliorate lipid metabolism disorders by the intestinal microbiota's composition and regulating genes implicated in the metabolism of hepatic lipids and cholesterol [75]. 

The GLP extract maintained TC and LDL-C at lower amounts than the model group, according to data from mice given a high-cholesterol diet [3,76]. The incorporation of GLP extract significantly raised the levels of Lactobacillus spp. at the genus level, according to 16S RNA sequencing of the intestinal microbiota, indicating that these microbes could additionally be contributing to decreasing serum cholesterol [77]. The glucan in the extract may induce an increase a rise in the percentage of Lactobacillus spp. and potentially other genera, like Paramycetes spp. and Mucispirillum spp., thereby increasing the microbiota abundance [76], which may be one of the mechanisms by which the Gl extract prevents hypercholesterolemia [76]. 

Atherosclerosis: Atherosclerotic Cardiovascular Disease (ASCVD) is a major global cause of mortality and illness [78,79], characterized by connective tissue growth, calcium carbonate, fatty acids, and cholesterol deposition, collagen and proteoglycan accumulation, arterial wall hardening and thickening, arterial thinning, and reduced arterial flexibility [80]. Numerous pieces of evidence indicate a significant correlation between intestinal dysbiosis and ASCVD. Endothelial dysfunction, lipid accumulation, foam cell accumulation, and systemic chronic inflammation are all consequences of intestinal dysbiosis that might result in ASCVD [81-83]. Related studies have shown that GLP can cure ASCVD by boosting the levels of certain SCFAs, modifying intestinal microbiota dysbiosis and directly slowing the disease's progression [84]. In a study related to GLP and T2D, it was found that GLP increased butyric and valeric acids, SCFAs enhanced IL-10 expression, activated Treg cells, and lowered the synthesis of IL-1β and IL-6, two pro-inflammatory cytokines, which restored the disordered metabolic pathways and repaired the aberrant colony function to its typical level in T2DM rats [7]. 

Hyperlipidemia is one of the leading causes of atherosclerosis [73], and GLP has greatly helped treat ASCVD by protecting blood vessels and lowering blood lipid levels. A prospective study of Ganoderma lucidum polysaccharide peptide (GLPP) found significant reductions in the levels of CEC, EPC, TNF-α, and IL-6 in patients with stable angina pectoris and high-risk patients, as well as reductions in the levels of NO, LDL, and total cholesterol, showing the favorable vascular protective and lipid-lowering effects of GLPP [9]. A consistent trend has also been shown in GLPP studies in hypercholesterolemic rats, where the optimal dose of GLPP was 300 mg/kg [85]. Based on reports of Ganoderma lucidum polysaccharide peptides, their antioxidant properties [86-88], inhibition of inflammatory responses [89], and promotion of cholesterol reversal [9,85] inhibit hyperlipidemia and hold promise as an adjunctive therapeutic agent for ASCVD. Atherosclerosis is categorized as an aging disease; thus, growing older is a separate risk factor for atherosclerosis development [90]. According to an analysis of extrinsic factors from the vascular system, aging influences myeloid cell growth, causes some myeloid clones to proliferate, and alters myeloid cell function, all of which contribute to ASCVD by inducing inflammation, including the possible involvement of IL-6 [91]. Enhanced concentrations of the inflammatory cytokine IL-6 in the aorta are linked to aging among intrinsic vascular factors [91]. This creates a beneficial feedback cycle with impaired vascular mitochondrial function, which results in decreased vascular mitochondrial function and impaired mitochondrial autophagy, which speeds up the formation of atherosclerosis [91]. A review introduced a new concept of the anti-aging mechanism of GLP, providing new perspectives on its potential to treat ASCVD [92]. In addition, Guo et al. found that black Ganoderma lucidum polysaccharides (PSG) could inhibit mitochondrial dysfunction by activating autophagy to reduce ROS levels, resulting in anti-aging [93]. Therefore, it is worthwhile to investigate how GLP can be used therapeutically to treat ASCVD by correcting mitochondrial dysfunction and activating autophagy. 

On the one hand, GLP affects the level of SCFAs, such as butyrate, through the regulation of intestinal microbiota, thus regulating inflammation-related pathways, cells, and inflammatory factors, achieving anti-inflammatory effects, and improving ASCVD. In addition, GLP can directly protect blood vessels through its own antioxidant and anti-inflammatory effects, lowering blood lipids and inhibiting plaque formation by promoting reverse cholesterol transport, activating autophagy, restoring mitochondrial dysfunction to achieve anti-vascular aging effects, and improving atherosclerotic disease directly from these three aspects. 

• Liver Diseases 

Nonalcoholic fatty liver disease: NAFLD is a common liver condition that damages the liver by generating inflammation and steatosis in more than 5% of the liver cells [94]. It has been shown that intestinal microbiota can differentiate between Alcoholic Liver Disease (AFLD) and NAFLD [95], that there is a correlation between the composition of fecal microbiota and disease activity scores, and that the relative abundance of the four species of Lactobacillus, Desulfovibrio, Ruminiclostridium, and Turicibacter can be used as surrogates for assessing the severity of NAFLD and thus further help to differentiate nonalcoholic steatohepatitis (NASH) from NAFLD, indicating that intestinal microbiota may be used as a possible NAFLD diagnostic marker [95]. 

GLP can influence metabolism of lipids and inhibit inflammatory answers via adjusting the composition and usage of the intestinal microbiota, resulting in a positive effect on NASH [8]. The findings of a research on the combined benefits of chitosan (PC) and GLP on high-fat-fed hamsters showed that PC significantly attenuates hyperlipidemia by lowering serum levels of low-density lipoprotein cholesterol, total cholesterol, and total triglycerides [96]. Interestingly, the research discovered also that PCs regulate the makeup of the intestinal microbiota, and that specific bacterial abundance is negatively correlated with lipid profiles. This highlights the potential of polysaccharides to ameliorate lipid metabolism disorders by modulating intestinal microbiota [96]. GLPP's potential as a treatment for NAFLD was examined using a mouse model, which showed that GLPP regulates bile acid metabolism and attenuates hepatic fibrosis through the FXR-SHP/FGF pathway, suggesting that GLPP might provide protection for liver health by affecting bile acid metabolism [97]. Research on GLP's function in reducing oxidative stress and hepatic steatosis in db/db mice has demonstrated that GLP reduces hepatic steatosis via the nuclear factor e2-related factor-2/heme oxygenase-1 pathway, indicating that GLP may be used as a treatment for NAFLD [98]. 

The above literature suggests that GLP can potentially ameliorate NAFLD, mainly by controlling the contents and roles of intestinal microbiota. Thus, it affects lipid metabolism and inflammatory responses by modulating related pathways, like bile acid metabolism, to reduce hepatic fibrosis and by acting directly on its own, such as combating oxidative stress and ameliorating hepatic steatosis. 

Acute liver injury: Acute liver injury is a serious condition that might result from several causes, including the use of certain medications, viral infections, and chemical-induced injury [99-101]. In the last several years, the role of GLP in ameliorating acute liver injury by regulating the intestinal microbiota has become a key academic issue. 

Firmicutes/Bacteriophages (F/B) can disrupt intestinal homeostasis and trigger fatty liver injury [99,102,103]. The mycelium of Ganoderma lucidum can lower the F/B ratio, lower the amount of Aspergillus that carries endotoxins, preserve the intestinal barrier, and lower metabolic endotoxicosis [104], inhibit TLR4 signaling, and reduce inflammation, thus reducing inflammation-induced acute liver injury. Additional studies have suggested that GLP may lessen the severity of acute CCL4 liver injury by enhancing the wide range of the intestinal microbiota [105,106]. The treatment group had higher species abundance of the phylum Mycobacterium anisopliae and lower species abundance of the phyla Rickettsia, Microbacterium and Ascomycetes than the model group [105]. At the genus level, the treatment group decreased the abundance of Mucispirillum, Anaerotruncus, Intestinimonas, Pseudoflavonifractor and Oscillibacter, Marvinbryantia, Clostridium-XlVa, Clostridium-XVIII, Clostridium-XlVb compared to the model group, increased the number of Alloprevotella, which controls numerous metabolic processes for carbohydrates and effectively promotes polysaccharide degradation, as well as promotes the development of intestinal epithelial cells in mice to fend off damage from oxidative stress, thereby maintaining intestinal barrier integrity, ameliorating mucosal inflammation, and liver damage brought on by CCL4 [105]. In another study, Ganoderma lucidum spore powder (GLSP) reduced the acute liver injury's severity through modulating the diversity and function of intestinal microbiota [106]. According to the findings, GLSP reduced blood levels of AST and ALT induced by liver injury; reduced the release of TNF-α, IL-1β, and IL-18, three inflammatory factors; ameliorated damaged hepatocytes; modulated the diversity of intestinal microecological communities; and decreased the concentrations of dangerous bacteria including E. coli-Shigella and Aspergillus phyla, which further supports GLP's function in preserving intestinal health and shielding the liver from injury [106]. 

• Colitis 

GLP offers a new approach to treating colitis, an inflammatory bowel disease characterized by an inflammatory response and tissue damage in the intestinal mucosa [107,108]. A study examining the impact of a water-soluble extract of Ganoderma lucidum mycelium (MAK) medium on mice with colitis induced by trinitrobenzene sulfonic acid (TNBS) revealed that GLP may be able to modulate the inflammatory response, and that the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse Peritoneal Macrophages (PMs) improved colitis [10]. This is further supported by a study by Nagai et al., which explored the preventive effect of MAK on indomethacin-induced ileitis in mice [109]. This research emphasized the anti-inflammatory effects of MAK and its ability to induce GM-CSF, which play an important part in alleviating inflammation. These findings underline the potential of GLP to modulate inflammatory factors through immune mechanisms. 

It has been found that the intestinal microbiota of patients with colitis is structurally abnormal and enriched with pathogenic bacteria. As a prebiotic, GLP significantly affects the intestinal microbiota by modulating butyric acid abundance and indoleamine 2,3-dioxygenase (IDO) activity, and it is essential for promoting intestinal health in general(6). GLP promotes host health by increasing the beneficial bacteria Bifidobacterium and Lactobacillus, and decreasing Oscillibacter, Desulfuricans, Parasutterella, Alistipes and other bacteria [110]. This shows that GLP significantly affects colitis by regulating the abundance of the intestinal microbiota. 

• Tumor 

The anticancer research has focused a lot of emphasis on polysaccharides because of their low toxicity and immunomodulatory properties [111], with most GLP research focusing on the effects on disease progression through immune function and intestinal microbiota [3,111-114].

Research has demonstrated that GLP improves the diversity and abundance of intestinal microbiota and the intestinal microenvironment, indirectly exerting preventive and anticancer effects [115]. For example, in a mouse model of Azoxymethane/Dextran Sulfate Sodium (AOM/DSS), GLP led to microbiome dysbiosis and increased production of SCFAs [113]. The F/B ratio rose with GLP treatment, and the model and GLP groups' genus levels revealed notable differences between Lactobacillus and Bifidobacterium species. GLP treatment raised the relative abundance of Bacteroides acidifaciens and Alistipes finegoldii at the species level while dramatically decreasing the relative abundance of Lactobacillus reuteri and Bifidobacterium pseudolongum. At the species level, Alistipes finegoldii was positively or negatively correlated with the development of colorectal cancer (CRC) [113]. A related study found that GLP consumption by rats with colitis significantly reduced the DAI composite score which is utilized to gauge the severity of DSS-induced colitis in an animal model and produced significantly more SCFAs in the cecum [116]. Production of SCFA in the small intestine and cecum increases some bacteria, such as Ruminococcus, as well as a decrease in pathogens, such as Escherichia-Shigella [116]. SCFAs and altered intestinal microbiota further regulate the expression of 11 genes associated with inflammation, resulting in reduced inflammatory responses, enhanced immunity, and increased colon cancer risk [116,117]. 

In addition, Guo et al. discovered that water-soluble polysaccharides extracted from Ganoderma lucidum could inhibit colonic inflammation and tumorigenesis by controlling intestinal microbiota and immune cell function and improving the intestinal barrier [113]. Furthermore, Li et al. investigated how Ganoderma lucidum spore polysaccharides could lessen intestinal barrier disruption brought on by paclitaxel [118]. These polysaccharides were found to inhibit apoptosis by reversing microtubule polymerization, validating their protective effects on the intestinal barrier and their potential to modulate the intestinal's mechanical, immune, and biological barrier functions [118]. Through the promotion of cuprocyte proliferation, mucin 2 (MUC2) secretion, and tight junction (TJ) protein (occludin and zonula occludens-1(ZO-1)) production, as well as the reduction of circulating lipopolysaccharide (LPS) levels, GLP can successfully restore intestinal mucosal barrier health [113]. 

The anti-cancer effects of GLP primarily involve direct enhancement of the tumor immune environment by boosting host immunity, stimulating T lymphocytes and NK cells, and activating macrophages. Indirectly, GLP regulates intestinal microbiota to correct bacterial dysbiosis, modulate metabolism such as SCFAs, and influence inflammatory pathways to reduce inflammation and enhance immunity. Additionally, GLP protects intestinal barrier function, thereby inhibiting colitis and tumor progression. Additionally, it safeguards the intestinal barrier function, thereby preventing colitis and tumor development. The findings endorse GLP's role in immune-enhancing therapies related to chemotherapy, highlighting the pivotal interaction between GLP and intestinal microbiota in immunological function, disease progression, and overall health (Figure 2 & Table 2). 

 Figure 2: GLP ameliorates some diseases through intestinal microbiota.

Table 2: Regulation of intestinal microbiota by GLP in different diseases.

• GLP regulates the abundance and diversity of intestinal microbiota 

GLP can significantly alleviate disease symptoms by modulating the quantity and variety of intestinal microbiota and restoring the structure of the intestinal microbiota [120-122]. Intestinal microbiota are the typical microorganisms in the human intestinal, and some researchers have divided them into three groups according to their function in the human intestinal: probiotics, neutrophils, and pathogenic bacteria [123]. Studies on IBDs have shown that dysbiosis, or a reduction in microbial diversity, occurs when the abundance of certain pathogenic bacteria, like Enterobacteriaceae, Proteobacteria, Veillonellaceae, Clostridium, Ruminococcus gnavus, and Desulfovibrio increases while the abundance of some beneficial bacteria, like Lachnospiraceae, Eerysipelotrichales, and Bifidobacteria decreases [122,124]. IBD symptoms will be lessened by bacterial structural restoration as well as an increase in enterobacteria diversity and abundance [122,124]. GLP treatment of AOM/DSS-induced colitis in mice resulted in changes in the composition of CRC-associated enterobacteria, with an increase in the F/B ratio, a significant increase in the relative abundance of Lactobacillus reuteri and Bifidobacterium pseudolongum, as well as of Bacteroides acidifaciens and Alistipes finegoldii, and a decline in the relative abundance of Desulfovibrio and Alistipes [113]. Research has demonstrated that GLP reduces pathogens (e.g., Escherichia-Shigella) in rat models of colitis [116]. The composition of the intestinal microbiota in the state of T2DM is modulated by GLP, according to correlative studies. As the F/B ratio increases, there is a decrease in harmful bacteria such as Ruminococcus, Proteus, Coprococcus, while levels of Parabacteroides and Bacteroides, members of Bacteroidetes spp., increase [7]. In a study on chronic pancreatitis, Ganoderma lucidum mycelial polysaccharide (GLPS3) greatly increased the thick-walled phylum's relative abundance at the phylum level in research on chronic pancreatitis, while lowering the anaplastic phylum's relative abundance [125]. At the level of genus, GLPS3 significantly increased the corresponding abundances of Lachnospiraceae , Roseburia spp., and Lactobacillus spp. [125]. GLP was found to mediate the intestinal microbiota of the phyla Firmicutes, Verrucomicrobia Proteobacteria and Bacteroidetes in a CCL4 mouse model of acute liver damage [105]. In particular, it increased the abundance of Alloprevotella and decreased the abundance of Mucispirillum, Anaerotruncus, Clostridium -XVIII, Intestinimonas, Pseudoflavonifractor, Oscillibacter, Marvinbryantia, Clostridium-XlVa and Clostridium-XlVb [105]. A study examining the anti-metastatic effects of GLP peptides on sleep-fragmented B16-F10-luc-G5 melanoma mice found elevated Bacteroides levels and reduced levels of Parvibacter, Christensenellaceae, Desulfovibrio and Odoribacter [126]. GLP increases intestinal microbiota abundance, which, on the one hand, prevents and improves illness, making the intestinal microecology more stable and conducive to disease prevention, and by raising beneficial bacteria and lowering pathogenic bacteria and pathogens (Figure 3). 

• Regulation of GLP-related functional metabolites 

The metabolism of natural polysaccharides, such as GLP, is primarily facilitated by carbohydrate enzymes (CAZymes) encoded by the intestinal microbiota in the digestive tract [127]. At the same time, genes for related metabolic enzymes can also be regulated. The degradation of GLP produces a number of functional metabolites like SCFAs, lactic acid, pyruvic acid, and ethanol, along with gases like H2, CO2, CH4, and H2S, which further exert biological activities to regulate the organism [128,129]. Among them, butyric acid in SCFAs is rich in bioactivities, which not only directly reduces pro-inflammatory factor secretion but also increases useful metabolites [130]. Additionally, it is an activator of GPR41, GPR43, and GPR109a, triggering G protein-coupled receptor signaling in intestinal epithelial cells and induces Treg cell and T cell differentiation [131,132]. In addition, butyric acid modulates the development and activity of macrophages and dendritic cells and reduces the secretion of inflammatory cytokines [133]. GLP in a rat model of T2DM caused by food and STZ interferes at the genus level with members of the phylum Thick-walled Bacteria associated with the production of SCFAs, including Allobaculum, Veillonella, Ruminococcus, Coprococcus, Blautia, Dehalobacterium, Lactococcus and Aerococcus, thereby modulating the immune response, maintenance of energy homeostasis, and pathogen invasion of the organism [7]. Through LXRα-ABCA1/ABCG1 signaling, GLP facilitates reverse cholesterol transport and raises CYP7A1 and CYP27A1 expression, two enzymes in charge of producing Bas [134]. In order to control lipid metabolism, BAs activate FXR to suppress the production of CD36 [97], a crucial protein that allows long-chain fatty acids to enter the liver and inhibits obesity and triglyceride accumulation [135]. By activating GPR43 in the fat tissue in response to alterations in the makeup of the intestinal microbiota and elevated SCFA production, GLP could influence metabolism and prevent obesity [136]. The over-accumulation of free fatty acids in the liver was suppressed by GLP-Cr, which also significantly regulated the levels of some biomarkers involved in α-linolenic acid metabolism, fatty acid biosynthesis, steroid hormone biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, and primary bile acid metabolism [97]. GLP-Cr also regulated the mRNA levels of genes encoding crucial liver enzymes involved with glucose and lipid metabolism [97]. These results imply that GLP might exert biological activity through the regulation of functional metabolites or related metabolic enzymes, thereby improving the health of the organism and intervening in the disease process (Figure 3). 

• GLP protects the mechanical and immune barriers of the intestinal 

GLP can be efficacious by interacting with intestinal microbiota with the intestinal barrier [137]. Intestinal barriers are broadly categorized into biological, mechanical, chemical, and immune barriers [138]. Biological barriers are formed by specialized commensal microbiota in the intestinal that adhere to or bind to the intestinal mucosa [138]. The chemical barrier consists of gastric juice, bile, mucus, mucin, mucopolysaccharides, various digestive enzymes, lysozymes, and other substances secreted by the gastrointestinal tract [138]. Intestinal permeability is maintained and altered by physical barriers, sometimes referred to as intestinal mucosal mechanical barriers and immunological barriers [139]. The intestinal mucosal mechanical barriers primarily consist of mucosal epithelial cells and their intercellular junction complexes, predominantly adherens and tight junctions. Occludin and claudin are two proteins that comprise tight junctions and preserve the mechanical barrier's integrity [140]. The intestinal immune barrier comprises two components: one is composed of three parts, includes intestinal lymphoid tissue, various immune cells such as T cells and B cells, and their secretion of secretory immunoglobulin (sIgA) [141-144]. The other is innate immunity, composed of intestinal microbiota, which acts by stimulating the body to produce self-limiting humoral mucosal immunity [145]. The immune barrier acts primarily as an immune defence against invading antigens which are able to penetrate the intestinal mechanical barrier [146]. High-Fat Diet feeding decreased the production of the tight junction components ZO-1 and occludin, but supplementation with aqueous extraction of Ganoderma lucidum my-celium (WEGL) restored these effects, suggesting that WEGL enhances intestinal barrier integrity in HFD-fed animals [104]. By reversing the polymerization of micro tubules and inhibiting apoptosis, Ganoderma lucidum spore polysaccharide (SGP) further prevented intestinal barrier damage caused by paclitaxel. This was demonstrated by a decrease in endotoxemia and an increase in tight junction proteins, such as zonula occludens-1 (ZO-1), E-cadherin, β-catenin, and occludin, which contribute to the protective effect of the intestinal mechanical barrier [118]. GLP, by increasing the number of cuprates, MUC2 secretion, and tight junction protein expression, forms a seal between neighboring epithelial cells, reduces intestinal permeability, maintains the integrity of the mucosal epithelial barrier, and maintains the immune barrier [113]. According to related research, GLP boosted the proliferative response of T and B cells, speeded up the recovery of splenic natural killer cells and natural killer T cells in immunosuppressed mice, increased the activity of cytotoxic T lymphocytes, NK cells, and lymphokine-activated killer cells, and prompted phagocytosis and cytotoxicity in macrophages [147]. GLIS, a bioactive proteoglycan found in Ganoderma lucidum, is a novel B-cell stimulating factor that activates B-lymphocytes and promotes the growth of mice spleen lymphocytes, boosting the percentage of B-cells by three to four times [148]. Increased B-cell size and surface expression of CD71 and CD25 lead to increased secretion of sIgA. In the intestinal immune response, sIgA is essential because it stops harmful bacteria from attaching to intestinal epithelial cells. On the other hand, it binds to bacteria to form antigen-antibody complexes presented to macrophages [148]. The immune system of cancer patients often fails to control tumor growth due to immunogenic defects in tumor cells, and GLP can promote the proliferation of lymphocytes induced by B16F10 melanoma cells, upregulate the expression of CD69, and promote the production of IFN-γ, which has an antitumor effect by enhancing the host's immune function [149]. Related studies have demonstrated that GLP can exert pharmacological effects by protecting the mechanical and immune barriers of the intestinal (Figure 3). 

Effect of GLP on Serum LPS and Chronic Inflammation 

It has been documented that LPS causes chronic inflammation by activating the TLR4/NF-κB signaling pathway, which is linked to a number of illnesses, such as intestinal dysbiosis, cancer, cardiovascular disease, and T2DM [150]. Studies have shown that GLP can ameliorate metabolic inflammation and related diseases by attenuating the inflammatory responses induced by LPS through multiple mechanisms, including inhibition of inflammatory factor expression, modulation of macrophage polarization, control of intestinal microbiota, and protection of intestinal barrier function [151]. 

GLP dramatically reduced the generation of inflammatory factors brought on by LPS. For instance, it dramatically decreased the release of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 macrophages by 60.5%, 32.1%, and 46.1%, correspondingly [113]. In addition, GLP was able to downregulate the expression of inflammatory markers: IL-1β, iNOS, and COX-2 in intestinal HT-29, RAW264.7, and NCM460 cells stimulated by LPS [113]. At the same time, GLP can regulate the polarization status of macrophages to improve disease progression [152]. Specifically, GLP inhibited LPS-induced macrophage polarization toward the M1 phenotype and reduced IL-1β, NO, and ROS production. GLP promoted macrophage polarization to the M2 phenotype by upregulating IL-10 levels and mannose receptor (MR) expression in LPS-treated cells [152]. 

In addition to the direct effects described above, GLP reduces serum LPS levels by protecting intestinal barrier function and modulating intestinal microbiota. Tight junction protein expression, MUC2 secretion, and the number of high-level glandular cells all showed a substantial improvement in intestinal barrier function following GLP [153]. Furthermore, by increasing the number of small intestine cuprates and immunoprotein A-secreting cells and lowering intestinal permeability and serum D-lactate levels, GLP promotes recovery in small intestinal villus damage [153]. Additionally, the intestinal microbiota's dysbiosis brought on by LPS is alleviated and short-chain fatty acid synthesis is increased, which regulates the intestinal microcirculation [84]. This improves lipid metabolism diseases by accelerating bile acid metabolism and showing a significant rise in Bacillus mimeticus. In addition, GLP can significantly increase the number of helpful bacteria (e.g., Brucella abortus and Dehalobacterium) and decrease the variety of dangerous bacteria (e.g., Ruminococcus and Bacilli ), thus improving intestinal health [84]. 

Through these mechanisms, GLP can significantly reduce serum endotoxin levels and attenuate the systemic inflammatory response induced by LPS, suggesting its potential medicinal value in the management of illnesses linked to persistent inflammation [154] (Figure 3).

 Figure 3: Pharmacologic mechanism of GLP through intestinal microbiota.

Drug-Drug Interactions (DDIs) occur between two or more drugs when used concurrently or sequentially, and such interactions may alter the pharmacodynamic or pharmacokinetic properties of the drugs, thereby affecting their efficacy and safety [155]. Pharmacokinetic interactions are mainly related to the absorption, distribution, metabolism, and excretion of drugs, which affect the concentration and duration of action of drugs in the body [156,157]. Pharmacodynamic interactions are primarily concerned with the pharmacological effects of drugs, which affect their efficacy and adverse effects [156,157]. 

Intestinal microbiota can influence drug metabolism and absorption, thereby altering drugs' pharmacokinetic and pharmacodynamic properties and mediating DDIs [158]. The intestinal microbiota can influence drug transportation in vivo through various mechanisms, thus regulating their efficacy and toxicity. The main mechanisms include: the intestinal microbiota interacts directly with drugs to change their chemical structure to reduce toxicity and enhance efficacy; the intestinal microbiota regulates the permeability of the intestinal barrier in both directions to promote the absorption of non-toxic drugs and inhibit the absorption of toxic components; the intestinal microbiota regulates transporter protein expression and function in both directions, which selectively promotes the absorption of effective components or inhibits the absorption of toxic elements [159]. The intestinal microbiota can play a crucial role in preserving medication homeostasis and minimizing adverse effects. This paper discusses the possible synergistic effects of GLP with other drugs from the perspective of intestinal microbiota mediating drug medication. 

GLP can synergize with a variety of drugs, including hypoglycemic, anti-inflammatory, and antitumor drugs, via controlling the intestinal microbiota, enhancing the efficacy of drugs, and reducing their side effects [105]. The processes that underlie these synergistic benefits include boosting the formation of short-chain fatty acids, enhancing intestinal barrier function, lowering the expression of inflammatory markers, and increasing the number of good bacteria while decreasing the quantity of dangerous bacteria [159]. For example, GLP was found to significantly reduce tumor growth and size while improving intestinal dysbiosis when combined with paclitaxel [160]. This is demonstrated by a rise in the number of helpful bacteria, like Bacteroides and Ruminococcus, and a fall in the number of dangerous bacteria, including Desulfovibrio and Odoribacter. Modifying intestinal microbiota and tumor metabolism may have this synergistic impact [160]. 

Further exploration of the specific mechanisms of these synergistic effects and the creation of novel combination therapeutic approaches are fresh approaches to better illness management, as exemplified by leonurine (Leo) and an H2S donor called SPRC. When combined with GLP, Leo may exhibit significant synergistic effects through the modulating effect of the intestinal microbiota, which has important clinical application prospects. Among Leo's multiple biological activities are uterine contraction, antioxidant, anti-inflammatory, apoptotic regulator, anticancer, and more [161]. GLP regulates intestinal microbiota, raising the quantity of helpful bacteria and lowering the amount of dangerous bacteria, which boosts immune system activity and increases the effectiveness of anti-tumor medications [113]. When Leo is combined with GLP, it may significantly improve the dysbiosis of intestinal microbiota, boost the production of SCFAs, inhibit TLR4/MyD88/NF-κB signaling, reduce serum LPS content, significantly improve the function of intestinal barriers, reduce inflammatory factors in the body, and enhance the antitumor effect [113]. In recent years, it has been found that SPRC can synergize with various drugs by controlling the intestinal microbiota, improving the efficacy of drugs, and reducing side effects [162]. GLP increases the F/B ratio and reduces the number of dangerous bacteria like such as Desulfovibrio [113]; SPRC acts as an H2S donor and further enhances this modulation by modulating the production of H2S by intestinal microbiota [163], and the combination of the two may significantly ameliorate intestinal dysbiosis. GLP repairs intestinal barrier dysfunction and enhances intestinal barrier integrity through upregulation of intercellular junction protein synthesis (e.g., Occludin, Claudin-1, and E-cadherin), thereby reducing the occurrence of endotoxemia [113]; H2S produced by SPRC can further enhance this effect and preserve the intestinal barrier's integrity [164], thus inhibiting tumorigenesis and significantly improving tumor size and number [113,165]. GLP mitigates inflammation by lowering IL-1β, iNOS, and COX-2 levels and inhibiting TLR4/MyD88/NF-κB signaling [113]. Additionally, H2S from SPRC further reduces these inflammatory mediators, enhancing the anti-inflammatory effects [166]. GLP reduces macrophage infiltration and inflammatory marker expression, modulating immune cell function [113], while SPRC amplifies this effect by altering the intestinal microbiota and enhancing immune function [164]. The combination of GLP with Leo or SPRC may have better prospects for clinical application in treating inflammatory bowel disease, antitumor aspects, and so on. To cure diseases more successfully, future research should investigate the precise processes underlying these synergistic effects and create fresh therapeutic approaches (Figure 4). 

Figure 4: GLP regulates intestinal microbiota directly or through interaction with drugs to respond to a variety of diseases.

This study focused on different GLP extraction techniques and their effects on various diseases of the intestinal microbiota. Although recent reviews, like the one by Ekiz et al., have thoroughly outlined Ganoderma lucidum's wide range of medicinal potential in treating viral infections (like COVID-19) and metabolic disorders, our research concentrates on the mechanical function of its polysaccharides in regulating intestinal microbiota and their synergistic effects with pharmaceutical agents. Our study, in contrast to other research, emphasizes the crucial role intestinal microbiota-mediated pathways play in bridging the gap between polysaccharide bioactivity and treatment effects in chronic illnesses. In addition to adding to the body of current research, this focused approach offers fresh perspectives on how to best optimize Ganoderma lucidum-based combination treatments—a topic that was not sufficiently covered in previous reviews. 

The current manuscript reveals that by controlling the quantity of intestinal microbiota, preserving the digestive tract's immunological and mechanical barriers, and using intestinal microbiota to control functional metabolites, GLP may have disease-preventive benefits. For example, in diabetes, GLP exerts hypoglycemic effects by lowering cholesterol, mainly by producing SCFA-associated bacteria. GLP modifies host cholesterol and levels of cholesterol in hyperlipidemia by modulating lipid-synthesis-associated microbes. By changing the intestinal microbiota to reduce the production of inflammatory substances, GLP prevents ASCVD. On the other hand, it directly functions as an anti-inflammatory, antioxidant, anti-aging, and cholesterol-transport monopharmacological agent. GLP preserves the mucosal barrier of the intestine in models of NAFLD and acute liver injury primarily by broadening the variety of the intestinal microbiota, controlling the abundance of intestinal bacteria, and reducing liver damage by controlling the metabolism of bile acids and carbohydrates to control lipid metabolism. GLP alleviates intestinal inflammation in colitis by regulating SCFA-producing bacteria and influencing immune responses and inflammatory states. In tumors, GLP may be involved in controlling the host's immunological response. In contrast, GLP improves intestinal microbiota, protects the intestinal barrier function, produces SCFA bacteria, and regulates immune and anti-inflammatory effects, thus inhibiting tumorigenesis. Notably, GLP simultaneously alleviates the chronic inflammatory state in many diseases by lowering serum LPS levels. 

Importantly, preclinical and clinical studies underscore GLPs’ safety profile. Acute toxicity tests in mice (up to 5000 mg/kg) and subchronic studies in rats (2.0–8.0 g/kg/day for 30 days) revealed no mortality, organ toxicity, or mutagenic effects [167,168]. Clinical trials corroborate low toxicity, though rare allergic reactions and interactions with anticoagulants warrant caution in sensitive populations [169]. As a natural product with multiple biological activities, GLP shows excellent potential for drug combination applications, especially in generating synergistic effects by regulating the intestinal microbiota (Figure 4). 

The composition of intestinal microbiota varies greatly depending on the interference of different factors, including between individuals, under different pathological conditions, and between rodents and humans. Therefore, to obtain data supporting the regulation of intestinal microbiota by GLP under human pathological conditions, further large-scale multicenter clinical trials are needed for GLP to become a new drug. Future studies should prioritize validating GLPs’ therapeutic applications in oncology (e.g., immune enhancement and chemotherapy support), metabolic disorders, and cardiovascular diseases, while optimizing dosing regimens to address bioavailability challenges [86,112]. 

Our study has provided preliminary insights into the secondary metabolites of GLP and their roles in intestinal microbiota regulation. GLP is metabolized by intestinal microbiota into bioactive substances like SCFAs, which are vital for intestinal health and metabolic regulation. However, current research, including ours, has limitations. The exact metabolic pathways and mechanisms of GLP in the intestinal remain unclear, and the specific functions of these metabolites in immune and metabolic regulation are not fully understood. Moreover, individual variability, dosage, and timing of GLP administration can significantly impact metabolic outcomes, areas that require more in-depth investigation. Future studies should focus on elucidating these metabolic pathways, clarifying the roles of GLP-derived metabolites, and exploring how different factors influence GLP metabolism. This will help fill the existing knowledge gaps and provide a more comprehensive understanding of GLP' effects in vivo. 

GLP has a promising future as a combination of multiple biological activities. However, GLP has low bioavailability and poor drug-forming properties. However, the continuous development in the field of pharmacy, new dosage forms, new drug delivery systems, and new drug carrier technologies such as microcapsules and nanoparticles bring the hope of further development of many natural products represented by GLP with good biological activity but insufficient bioavailability, which can improve their bioavailability while targeting the target organs more accurately. GLP-related products may have a promising application in the areas of immunomodulators, anti-inflammatory agents and medications to prevent metabolic disorders. Emerging drug delivery systems, coupled with GLPs’ established safety profile, position them as ideal candidates for combination therapies in clinical settings. In the decades to come, multi-dose GLP drugs should be developed while conducting multicenter cooperative clinical trials to accumulate more evidence-based evidence. Further exploration and development of GLP-mediated intestinal microbiota regulation in various diseases will complement the pharmacological mechanism of GLP drugs, discover more indications, and bring reference and inspiration to the development of other natural polysaccharides.

All authors thank the Macau Science and Technology Development Fund (FDCT 0012/2021/AMJ, 0001/2024/RDP, 0001/2024/AKP, 0092/2022/A2, 0144/2022/A3); the Shenzhen-Hong Kong-Macao Science and Technology Fund (Category C: SGDX20220530111203020); and the Laboratory of Drug Discovery from Natural Resources and Industrialization.

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