Metabolic syndrome (MS) is a dysbiosis of physiological metabolism caused by insulin resistance. MS manifests as a pathological state of metabolic disorders related to nutrition, including hyperglycemia, dyslipidemia, central obesity, and hypertension. An increasing amount of evidence indicates that the etiology of MS is associated with dysbiosis of the gut microbiota ^[1][2][3][147,148,149]. The HFD-induced dysbiosis of the gut microbiota may disrupt intestinal barrier function and increase endotoxin levels in the circulatory system. This leads to metabolic endotoxemia and induces MSs, such as insulin resistance, obesity, and even diabetes ^[4][150]. By generating enzymes such as CAZymes and proteases, the gut microbiota promotes the digestion of carbohydrates, such as DFs, and produces metabolites such as SCFAs that can be absorbed and used by the body. Studies have shown that changes in the gut microbiota and SCFAs are associated with the development of metabolic diseases ^[5][151]. According to experimental evidence, an increase in Firmicutes and a decrease in Bacteroides have been observed in obese individuals and mouse models ^[6][152]. Indeed, DFs from mushrooms can effectively improve diet-induced MSs in mice and rats (Table 13). For example, P. eryngii DFs reduced LDL cholesterol levels and body weight in HFD-fed mice by altering the abundance of SCFA-producing gut microbiota ^[7][116]. G. lucidum DFs reverse the HFD-induced dysbiosis of gut microbiota by reducing the proportion of Firmicutes/Bacteroides and the Proteobacteria level. They also maintain the integrity of the intestinal barrier and reduce metabolic endotoxemia ^[8][120]. F. velutipes DFs can alleviate lipid metabolism dysbiosis in obese mice by regulating the intestinal-flora-mediated AMPK signaling pathway ^[9][119]. In addition, other types of DFs from mushrooms can play a positive role in MSs by regulating the gut microbiota composition (Table 13). Thus, mushroom DFs appear to play a positive role in regulating dysbiosis in the intestine that is induced by metabolic disturbances and maintaining the integrity of the intestinal barrier, further highlighting the potential value of mushroom DFs as foods or drugs.

DF Source	Model	Gut Microbiota Regulation	SCFA Generation	Effect on Host	Reference
Pleurotus eryngii	HFD-induced obese rat	The relative abundances of Roseburia and Lactobacillus ↓, the relative abundances of Anaerostipes, Clostridium and Lactococcus ↑.	Increased the concentrations of total SCFAs.	Reduced BW gain, adipose tissue weight, FBG level; the expression of FASN and ACC.	[7][116]
Pleurotus eryngii	HFD-fed mice	The relative abundances of Methylobacterium and Lactobacillus ↑, the relative abundances of unidentified_Lachnospiraceae and Helicobacter ↓.	Increased the content of SCFAs, including acetic acid, propionic acid, and butyric acid.	Decreased the weight, promoted the proliferation of beneficial bacteria, reduced the risks of many chronic diseases.	[10][53]
Agaricus blazei Murrill	Hyperlipidemia rats	The ratio of Firmicutes/Bacteroidetes ↓; the abundance of Peptostreptococcaceae, Erysipelaceae, and Clostridium ↑.	Nm	Regulated dyslipidemia in rats with hyperlipidemia possibly by regulating imbalance in the intestinal microflora.	[11][117]
Hericium caput-medusae	One-day-old Arbor Acres male broilers	The count of Lactobacilli and Bifidobacteria ↑, the count of acecum Escherichia coli ↓.	Increased the concentration of propionic acid.	Decreased cholesterol content in broiler chickens.	[12][118]
Flammulina velutipes	Male C57BL/6 J mice	The relative abundance of some beneficial bacteria ↑, such as Akkermansia and Prevotellaceae UCG-001; the relative abundance of some harmful bacteria ↓, such as Lachnospiraceae NK4A136 group and Desulfovibrio.	Nm	Reduced the weight gain, triglycerides and total cholesterol, low-density lipoprotein cholesterol; increased the activity of enzymes related to scavenging ability of oxygen free radicals.	[9][119]
Flammulina velutipes	Mice	The relative abundance of Firmicutes ↓, the relative abundance of Bacteroidetes ↑; the ratio of Firmicutes/Bacteroidetes ↓.	Increased the concentrations of total SCFAs, acetic acid, propionic acid, and n-butyric acid.	Suppressed obesity and immune regulation.	[13][101]
Ganoderma lucidum	C57BL/6NCrlBltw genetic lineage mice	The ratio of Firmicutes/Bacteroidetes, Proteobacteria ↓.	Nm	Reduced body weight gain, chronic inflammation, and insulin resistance in obese individuals.	[8][120]
Poria cocos	C57BL/6J mice	The relative abundance of Lachnospiracea, Clostridium ↑.	Increased butyrate levels.	Activated the intestinal PPAR-γ pathway, modulated gut microbiota to improve hyperglycemia and hyperlipidemia.	[14][121]
Agaricus bisporus	Human	The relative abundance of Firmicutes ↑, the relative abundance of Bacteroidetes ↓.	Increased the concentrations of acetic acid and propionic acid.	Increased the relative abundance of beneficial bacteria, exhibited an effective prebiotic regulation function on human gut microbiota.	[15][105]
Cordyceps militaris	Liver and kidney injury induced by lead acetate in mice	The relative abundance of Clostridium and Bacteroidetes ↑, the relative abundance of Firmicutes ↓.	Nm	Reduced the Pb2+ content and organ index of liver and kidney in mice, had a protective effect on organs against damage in mice.	[16][122]
Pleurotus eryngii	C57BL/6 male mice	The relative abundances of Firmicutes ↓, Bacteroidetes ↑	Increased the concentrations of Acetate and Propionate.	Regulated the host immune function effectively.	[17][123]
Ganoderma lucidum	Chronic pancreatitis mice	The relative abundance of Bacteroidetes ↓ and that of Firmicutes ↑; at the genus level, the relative abundance of beneficial bacteria such as Lactobacillus, Roseburia, and Lachnospira ↑.	Nm	Indicated beneficial effects on pancreas fibrosis, and impeded an inflammatory response.	[18][124]
Dictyophora indusiata	Antibiotic-induced intestinal microflora disorder in mice	Beneficial bacteria ↑, including Lactobacilli and Ruminococcaceae; harmful bacteria ↓, such as Enterococcus, Bacteroides, and Proteobacteria.	Nm	Enhanced the restoration of gut microbiota and gut barrier integrity, reduce the inflammation and endotoxin levels in mice.	[19][125]
Coprinus comatus	Human	The relative abundances of Bacteroides and Bifidobacterium ↑, the ratio of Firmicutes/Bacteroidetes ↓.	Increased the production of propionic acid and butyric acid.	Demonstrated potential prebiotic effects.	[20][50]
Ganoderma lucidum	C57BL/6J mice	The relative abundances of Actinobacteria at the family level, and Leuconostoc, Lactobacillus spp. ↑.	Nm	Improved low-grade chronic inflammation, ectopic lipid accumulation, and systemic insulin sensitivity.	[21][126]
Hericium erinaceus	Mice	The relative abundance of Lachnospiraceae and Akkermansiaceae ↑, the relative abundance of Rikenellaceae and Bacteroidaceae ↓.	Nm	Promoted the production of NO, IL-6, IL-10, INF-γ, and TNF-α.	[22][127]
Auricularia auricular	ICR mice	The ratio of Firmicutes/Bacteroidetes ↓, the relative abundance of Porphyromoadaceae and Bacteroidaceae ↑.	Increased the concentration of total SCFAs and propanoic acid.	Increased microbial community diversity, and increased the immunoglobulin levels in mouse serum.	[23][128]
Ganoderma lucidum	DSS-induced colitis male Wistar rats	The relative abundance of Firmicutes, Paraprevotella, etc. ↑, the relative abundance of Proteobacteria, Escherichia, etc. ↓.	Increased total SCFAs, acetic acid, propionic acid, and butyric acid.	Enhanced the immunity and reduced inflammatory response and colonic cancer risk.	[24][129]
Ganoderma lucidum	BALB/C mice	The ratio of Firmicutes/Bacteroidetes ↓, the relative abundance of Alistipes ↑.	Nm	Demonstrated tumor-suppressing activity in mice.	[25][130]
Ganoderma lucidum	BALB/c mice	The relative abundance of Oscillospira and unknown genus of Desulfovibrionaceae ↓.	Nm	Prevented colon from shortening and reduced mortality by 30% of mortality in CRC mice.	[26][131]

The intestinal tract is the largest immune organ of the human body, and it is involved in immune and inflammatory reactions ^[27][153]. Although DFs cannot be completely digested in the intestine, they are decomposed into various metabolites through enzymes produced by intestinal microorganisms. Some microbial metabolites, such as tryptophan metabolites and SCFAs, interact with host cells through the intestinal barrier, thereby affecting the immune response ^[28][154]. An increasing number of studies have shown that SCFAs can inhibit the expression of inflammatory factors or alleviate inflammation by promoting histone acetylation or activating GPRs ^[29][155], activating peroxisome-proliferator-activated receptors ^[30][156], inhibiting the NF-κB signaling pathway ^[31][157], facilitating T-cell apoptosis ^[32][158], increasing antimicrobial peptide production ^[33][159], and downregulating the expression of signal transduction and activating transcription factor-3 ^[34][160]. Relevant studies have also reported that DFs from mushrooms can promote SCFA production and the growth of intestinal microorganisms to stimulate the host immune response and regulate the differentiation, maturation, and function of immune cells (Table 13). Vlassopoulou et al. ^[35][161] found that supplementation with mushroom β-(1→3, 1→6)-d-glucan is well tolerated and promotes health through the potentiation of the immune system. In addition, F. velutipes DF may affect immune function regulation by mediating the gut microbiota ^[13][101]. H. erinaceus DFs can regulate the gut microbiota composition and immune activity through the NF-κB, MAPK, and PI3K/Akt pathways ^[22][127]. G. lucidum DFs change the diversity of the gut microbiota and significantly alleviate pancreatitis symptoms in mice by reducing the levels of lipase, interferon-γ (IFN-γ), and TNF-α and increasing SOD levels and total antioxidant activity ^[18][124]. A. auricular DFs may affect intestinal nutritional metabolism and immune regulation by changing the composition of the gut microbiota ^[23][128]. G. lucidum DFs not only regulate the gut microbiota composition and SCFA production but also participate in the regulation of gene expression in KEGG pathways related to different types of inflammation ^[24][129]. Thus, these studies indicate that DFs from different mushrooms may be associated with different immune regulatory pathways. This immune regulation can be attributed to the diversity of the gut microbiota and SCFA production, which may act as signaling molecules for mediating and maintaining the host’s immune system.

The gut microbiota affects the metabolism and endocrine and immune systems of the host. The gut microbiota is associated with the occurrence of many diseases, including inflammatory bowel disease, nonalcoholic fatty liver disease, type 2 diabetes, and neurodegenerative diseases ^[36][37][38][162,163,164]. Importantly, increasing evidence shows that the gut microbiota can affect tumor occurrence, tumor progression, and the response to treatment ^[39][19]. For example, Helicobacter pylori induces gastritis and canceration by producing toxic factors such as cytotoxin-associated gene A and vacuolating cytotoxin A ^[40][165]. A study investigating the gut microbiota of patients with early lung cancer reported that Akkermansia muciniphila may cause lung cancer ^[41][166]. The decrease in the abundance of Lactobacillidae and Bifidobacteriaceae in colorectal cancer (CRC) patients is related to colon and rectal tumors, respectively ^[42][167]. In patients with multiple polypoid adenoma and intramucosal carcinoma, significant changes in the microbiome and metabolome have been observed. The relative abundance of Fusobacterium nucleatum spp. increased during the progression of intramucosal carcinoma to the more advanced stage, while the abundance of Atobobium parvulum and Actinomyces odontolyticus significantly increased in patients with multiple polypoid adenoma and/or intramucosal carcinoma ^[43][168]. Moreover, the gut microbiota is closely correlated with the effect of chemotherapy and immunotherapy ^[44][45][169,170]. For example, the gut microbiota can alleviate chemotherapy-induced adverse reactions in CRC patients ^[46][171]. Butyric acid, a metabolite of the gut microbiota, can directly improve the antitumor cytotoxic effect of CD8⁺ T cells in vitro and in vivo in an ID2-dependent manner by promoting the IL-12 signaling pathway. Butyric acid can also promote the antitumor efficacy of oxaliplatin ^[47][172]. L. rhamnosus GG-induced cGAS/STING-dependent type I interferon can enhance the response to immune checkpoint inhibitors ^[48][173].

DFs from mushrooms play an anticancer/antitumor role by regulating the gut microbiota composition and diversity, and this role has attracted increasing attention (Table 13). For example, G. lucidum polysaccharide can reverse the proportion of Firmicutes/Bacteroides and increase the levels of Alistipes, resulting in the production of SCFAs, and Helicobacter and Riskenella, which are related to immunosuppression and carcinogenesis ^[25][130]. Moreover, G. lucidum DFs can alleviate CRC by altering special intestinal microorganisms ^[26][131]. Thus, these studies indicate that mushroom DFs inhibit tumor growth or metastasis by regulating the gut microbiota composition and diversity; furthermore, immunomonitoring mediated by gut microbiota-produced metabolites such as SCFAs may be beneficial. However, the exact anticancer/antitumor mechanism of mushroom DFs remains unclear.

Because of their strong water absorption and swelling capacities, DFs from mushrooms, especially IDF, can promote intestinal peristalsis, increase stool volume, increase the frequency of bowel movements, and avert constipation, thereby preventing and treating gastrointestinal diseases. Feeding constipated rats with A. polytricha DFs increased the wet weight of their stool and intestinal propulsion rate, thereby indicating high constipation-relieving activity ^[49][73]. Furthermore, DFs from mushrooms have antioxidant capacity and can eliminate free radicals from the body. For example, DFs extracted from Boletus edulis have significant reducing power and chelating activity and strong antioxidant activity ^[50][174].