Gut microbiota: A magical multifunctional target regulated by medicine food homology species

Graphical abstract

Highlights

• •Gut microbiota's coevolution with hosts significantly impacts the regulation of human diseases.
• •Medicine food homology species are rich in bio-active substances, which have good medical and nutritional value.
• •Intaking medicine food homology species will affect the composition of gut microbiota and provide metabolites that affect host physiology.
• •The relationship between medicine food homology species–gut microbiota–individual health has been confirmed, but the underlying mechanisms remain far from clear.

Abstract

Background

The relationship between gut microbiota and human health has gradually been recognized. Increasing studies show that the disorder of gut microbiota is related to the occurrence and development of many diseases. Metabolites produced by the gut microbiota are responsible for their extensive regulatory roles. In addition, naturally derived medicine food homology species with low toxicity and high efficiency have been clearly defined owing to their outstanding physiological and pharmacological properties in disease prevention and treatment.

Aim of review

Based on supporting evidence, the current review summarizes the representative work of medicine food homology species targeting the gut microbiota to regulate host pathophysiology and discusses the challenges and prospects in this field. It aims to facilitate the understanding of the relationship among medicine food homology species, gut microbiota, and human health and further stimulate the advancement of more relevant research.

Key scientific concepts of review

As this review reveals, from the initial practical application to more mechanism studies, the relationship among medicine food homology species, gut microbiota, and human health has evolved into an irrefutable interaction. On the one hand, through affecting the population structure, metabolism, and function of gut microbiota, medicine food homology species maintain the homeostasis of the intestinal microenvironment and human health by affecting the population structure, metabolism, and function of gut microbiota. On the other hand, the gut microbiota is also involved in the bioconversion of the active ingredients from medicine food homology species and thus influences their physiological and pharmacological properties.

Introduction

Gut microbiota is a vast and complex ecosystem containing approximately 100 trillion microorganisms and is symbiotic with the host [1]. Research results have indicated that gut microbiota equals the number of human cells and has been dubbed a “forgotten organ” due to its multiple roles in human physiology [2]. These microorganisms bind closely to the intestinal mucosal epithelial cells and form a critical biological barrier to protect the intestinal mucosa from foreign pathogens [3]. Ingested plant polysaccharides and other dietary substances are degraded by the gut microbiota, which enhances the digestion efficiency of the host and simultaneously ensures a steady nutrient supply for the microorganisms. Moreover, extensive interconnections between the physiology of the microbial community and the host have been established due to millions of years of co-evolution, and they have extended beyond the degradation function [4]. The gut microbiota has developed a tactic to release large numbers of metabolites from different chemical categories to exert an extensive role in host organs, regardless of close to or far from the gastrointestinal lumen. These metabolites include but are not limited to, short-chain fatty acids (SCFAs) [5], bile acids (BAs) [6], [7], choline [8], [9], vitamins [10], tryptophan [11], [12], and indole derivatives [13], [14]. Besides, they associate with each other and host cells, thereby further influencing host health and disease states [15], [16], [17], [18]. Increasing pieces of evidence have shown that the imbalance of gut microbiota is related to the incidence of various diseases, including inflammatory bowel disease (IBD) [19], fatty liver [20], [21], obesity [22], [23], diabetes [24], [25], neurological disorders [26], [27], cardiovascular diseases [28], [29], etc. (Fig. 1, right). Although sharing a conserved set of core gut microbiota and core microbiome among individuals at the macro level may be necessary for correct gut function at the macro level, each one has a distinct and highly variable microbiota from an individual point of view [30], [31], [32]. In addition to host factors (such as age and genetics) [33], the composition and function of gut microbiota are also influenced mainly by changing environmental factors (Fig. 1, left), especially diet [34] and medications [35], [36]. Therefore, gut microbiota may be a multifunctional target regulated by easily ingested medicine food homology species.

Fig. 1.

Relationship between gut microbiota and human. Left: Multiple environmental factors, encompassing diet, antibiotics, pollution, physical inactivity, and disease, may engender perturbations in the gut microbiota. Right: Gut microbiota aberrations have been linked to a myriad of morbidities, spanning neuropsychiatric disorders, cardiovascular afflictions, gastrointestinal ailments, diseases arising from environmental and nutritional factors, endocrinopathies, and more. Figure created via BioRender.com.

The term “Medicinal Food Homology” (MFH) typically refers to species that are traditionally both food and Chinese medicine [37]. It also has various English expressions such as the homology of medicine and food, and the materials for both food and medicine. Globally, there are many concepts similar to MFH, such as functional foods and dietary supplements. Huang Di Nei Jing (475 BCE-221 BCE), the first monograph on medical theory in China, has recorded: “eating on an empty stomach as food and administering to the patient as medication”, which should be the earliest literal definition of the MFH theory. In about 500 CE, Sun Simiao, a medical scientist and pharmacologist at that time, systematically elaborated the theory of diet therapy for the first time and comprehensively expounded the method of combining food and medicine to treat diseases in Prescriptions Worth Thousand Gold for Emergencies [38]. Since modern times, people's health consciousness has gradually shifted from treatment to the combination of prevention and treatment, and medicinal plants with therapeutic effects have been integrated into the diet as dietary supplements, which belong to the category of alternative therapy. Modern pharmacological studies have demonstrated MFH species' preventive and therapeutic effects in various diseases, especially chronic diseases [39], [40], [41]. To ensure the safe and normative use of these species, the National Health Commission of the People's Republic of China has issued specific regulations on the MFH items. As of 2019, nearly a hundred kinds of Chinese medicine have been recognized as MFH species [42] (Fig. 2).

Fig. 2.

The history of MFH and some representative MFH species discussed in this review. Top: Key historical events in the development of MFH in China. Bottom: According to the taxonomy, these species are divided into nine groups: Liliflorae, Microspermae, Umbelliflorae, Rosales, Polyporales, Tubiflorae, Campanulales, Scitamineae, and others.

Increasing evidence shows a close interaction and relationship between MFH and gut microbiota, which can affect human health and disease processes. This review surveys the number of articles published on the MFH and gut microbiota over the past decade and finds that these fields have experienced vigorous development. However, so far, there are few articles to systematically review and analyze the regulation of MFH on gut microbiota and its influence on human health, which urgently needs replenishment. This review focuses on the research status of the regulation of MFH on gut microbiota and its effects on host health and discusses the interaction between MFH and gut microbiota. The content of the current review is deliberately confined to the critical selection of representative work, and it is not intended to be a comprehensive (encyclopedia) coverage covering all the examples that appear in the literature. According to the pathology catalog, this review is divided into digestive diseases, endocrine diseases, neurological and psychiatric disorders, cardiovascular diseases, environmental and nutritional diseases, etc. Finally, the research direction in this field has been prospected to encourage more researchers to pay attention to the effects of MFH on gut microbiota and human health and to provide new insights for treating clinical diseases.

Medicine food homology species treat diseases by regulating gut microbiota

Digestive system diseases

The digestive system is a functional group of digestive ducts and glands responsible for digestion, absorption, excretion, detoxification, and endocrinology. The interactions between gut microbiota, digestive system, and medicine food homology species are increasingly demonstrated to be essential for maintaining homeostasis and human health (Table 1).

Table 1.

Effects of medicine food homology species on digestive diseases via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Ginseng Radix Et Rhizoma	polysaccharide	↓Bacteroidetes; Verrucomicrobia; Proteobacteria ↑Akkermansia	↓inflammatory ↑autophagy; microbiota diversity	SD mice	200 mg/kg	IBD	[47]
Lycii Fructus	AA-2βG	↓Proteobacteria; Parabacteroides; Parasutterella; Clostridiaceae ↑Verrucomicrobia; Prevotellaceae; Helicobacteraceae	↑SCFAs; microbiota diversity	C57BL/6 mice (5 weeks old)	300 mg/kg	IBD	[48]
Lycii Fructus	arabinogalactan	↓Proteobacteria; Enterobacteriaceae ↑Ruminococcaceae; Muribaculaceae; Prevotellaceae; Rikenellaceae	↓inflammatory ↑SCFAs	male C57BL/6J mice (7 weeks old)	50 mg/kg	IBD	[49]
Polygonati Odorati Rhizoma	extract	↓Desulfobacterota; Campylobacterota ↑Muribaculaceae; Ruminococcus; Alloprevotella	↓H2S ↑SCFAs	male BABL/c mice (6–8 weeks old)	400 mg/kg	IBD	[50]
Ganoderma	polysaccharide	↓Oscillibacter; Desulfovibrio; Parasutterella; Alistipes ↑Bifidobacterium; Lactobacillus	↓inflammatory; tumorigenesis; ↑SCFAs; intestinal barrier	male C57BL/6 mice (5 weeks old)	300 mg/kg	CRC	[66]
Panacis Quinquefolii Radix	extract	↓Bacteroidetes; Verrucomicrobia ↑Firmicutes	↓inflammatory; harmful metabolites; tumor multiplicity ↑beneficial metabolites	male A/J mice (6 weeks old)	30 mg/kg	CRC	[67]
Jujubae Fructus	polysaccharide	↓Firmicutes ↑Bifidobacterium; Bacteroides; Lactobacillus	↓inflammatory ↑SCFAs; Metabolic functions	male C57BL/6 mice (6–8 weeks old)	1 g/kg	CRC	[68]
Jujubae Fructus	polysaccharide	↓Firmicutes; Cyanobacteria; Spirochaete; Deferribacteres; Mucoromycota ↑Bacteroidetes; Lactobacillaceae; Actinobacteria	↓gut dysbiosis ↑SCFAs	male C57BL/6 mice (6–8 weeks old)	1 g/kg	CRC	[69]
Lycii Fructus	Lycii Fructus	↓Alloprevotella ↑Akkermansia; Ruminococcaceae_UCG_014	↓inflammation; harmful metabolites ↑SCFAs; antioxidant capacity; beneficial metabolites	female C57BL/6 mice (4 weeks old)	1% of dry feed weight	ALD	[72]
Ganoderma	extract	↓Clostridium_sensu_stricto_1 ↑Ruminiclostridium_9; Prevotellaceae_UCG-001; Oscillibacter; Bilophila; Ruminococcaceae_UCG-009	↓harmful metabolites ↑SCFAs; metabolic function	male Kunming mice (6–7 weeks old)	100 mg/kg	ALD	[73]
Ganoderma	Ganoderic Acids	↓Helicobacter ↑Lactobacillus; Faecalibaculum; Romboutsia; Bifidobacterium	↓lipid metabolic	male Kunming mice (6 weeks old)	36 mg/kg	ALD	[74]
Astragali Radix	polysaccharides	↓Firmicutes ↑Bacteroidetes; Proteobacteria; Episilonbacteria	↓inflammation ↑intestinal integrity	male SD rats	200 mg/kg	NAFLD	[86]
Cassiae Semen	extract	↓Bilophila; Lactobacillus; Mucispirillum; Paraprevotella ↑Odoribacter; Rikenella; Desulfovibrio	↓inflammation; lipid accumulation ↑intestinal integrity	C57BL/6 mice	10 mg/kg	NAFLD	[87]
Rubi Fructus	extract	↑Turicibacter; Bifidobacterium	↓inflammation; liver fibrosis	male C57BL/6J mice (8 weeks old)	7.9 g/kg	liver fibrosis	[93]
Gardeniae Fructus	polysaccharides	↓Enterobacteriaceae; Enterococcaceae ↑Bacteroides	↓inflammation; bile acids ↑SCFAs; intestinal integrity	male C57BL/6 mice (8 weeks old)	400 mg/kg	Cholestasis	[96]

Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic relapsing disorder typically characterized by nonspecific inflammation and intestinal tissue damage [43]. The intestinal barrier is vital in maintaining intestinal homeostasis and is the primary defense against pathogen invasion [3]. Increasing evidence show that gut microbiota dysbiosis contributes to the initiation, development, and exacerbation of IBD [44]. According to reports, the overactive immune response is closely associated with an increase in lipopolysaccharide (LPS), a substance that makes up the cell walls of Gram-negative bacteria [45]. In addition, the primary intestinal metabolites, SCFAs, enhance the intestinal barrier, aid in nutritional absorption, and inhibit the growth of pathogenic microorganisms [46]. Thus, as an alternative therapy, targeting gut microbiota through the diet may be a new approach for IBD treatment in the future (Fig. 3).

Fig. 3.

Schematic representation of the proposed mechanism of medicine food homology species on ameliorating IBD and CRC. LPS from Gram-negative bacteria trigger an inflammatory cascade by activating the TLR4/NF-κB signaling pathway and releasing pro-inflammatory factors, thereby inducing an inflammatory response and increasing intestinal permeability. Persistent chronic intestinal inflammation eventually leads to cancer. Medicine food homology species reduced the release of toxic substances and the secretion of pro-inflammatory factors and repaired the intestinal barrier by regulating gut microbiota, thus decreasing the immune response, and playing the role of anti-IBD and CRC. Figure created via BioRender.com.

As a receptor of LPS, activated Toll-like receptor 4 (TLR4) recruits downstream signaling molecules to coordinate the secretion of inflammatory cytokines and oxidative stress response, thereby initiating IBD. Studies have shown that the edible herb Ginseng Radix Et Rhizoma can alleviate IBD. By lowering the abundance of Gram-negative bacteria, such as Bacteroidetes, Verrucomicrobia, Proteobacteria, etc., the concentration of LPS was decreased, resulting in the blocking of TLR4/Nuclear Factor-κB (NF-κB) pathway-associated proteins expression. Meanwhile, autophagy was stimulated to inhibit the activation of NF-κB, contributing to managing the inflammatory response in the intestine, which favorably connected with the restoration of Akkermansia by Ginseng polysaccharide [47]. Lycii Fructus is the most common dietary supplement with various pharmacological activities, such as antioxidant and immune promotion. In colon tissue, it has been shown that treatment with the active ingredient 2-O-β-D-Glucopyranosyl-L-ascorbic acid (AA-2βG) from Lycii Fructus can enhance the content of metabolites SCFAs and increase the mRNA expression level of G protein-coupled receptor 43(GPR43) and GPR41, two SCFAs receptors. Additionally, AA-2βG reduced Parabacteroides, Parasutterella, and Clostridium associated with the development and progression of IBD while increasing Helicobacteraceae, which protects against IBD [48]. Arabinogalactan, another bioactive ingredient from Lycii Fructus, has also been shown to be effective against IBD. It gave some gut bacteria that eat mucin O-glycans essential nutrients, lowering the amount of mucin 2 (MUC2) that some gut microbiota utilized and enhancing intestinal integrity [49]. Gas, a gut microbiota metabolite, can also influence how colitis develops. The administration of Polygonati Odorati Rhizoma extract modulated the gut microbiota in this article to lessen the harmful bacteria (such as Desulfovibrionaceae) linked to the gas generation of H₂S, which is poisonous in high quantities. Importantly, their research was the first to establish a link between intestinal gas production and key bacteria associated with ulcerative colitis [50].

In addition, many medicine food homology species can also participate in the treatment of IBD by regulating gut microbiota, including Crataegi Fructus [51], [52], Mel [53], Dioscoreae Rhizoma [54], Chrysanthemi Flos [55], Ziziphi Spinosae Semen [56], Curcumae Longae Rhizoma [57], Astragali Radix [58], [59], Ganoderma [60], etc. These species described above may serve as promising candidates to provide new therapeutic options for IBD.

Colorectal cancer

One of the most prevalent tumors, colorectal cancer (CRC) is responsible for 10% of all cancer diagnoses each year and all cancer-related deaths globally [61], [62]. In addition, CRC risk is higher in patients with long-standing IBD and gut microbiota disorders brought on by unhealthy lifestyle choices [63], [64], [65]. Therefore, it has become increasingly appealing to develop novel, potent, but low-toxicity reagents based on medicine food homology species for the prevention and therapy of CRC.

Ganoderma is one of the most popular and well-known mushrooms of MFH in China. Cancer caused by azoxymethane/dextran sulfate sodium (AOM/DSS) was dramatically reduced by dietary fiber Ganoderma polysaccharide (GLP). According to the findings, GLP consumption increased Firmicutes and decreased Bacteroidetes at the phylum level, which was related to SCFAs production and tumor susceptibility, respectively. In addition, GLP treatment inhibited tumorigenesis by increasing beneficial bacteria Bibifdobacterium and Lactobacillus and decreasing Desulfovibrio, Oscillibacter, and other bacteria positively related to CRC. Significantly, alterations in the levels of SCFAs, GPR43, Zonula Occludens-1 (ZO-1), LPS, and other factors demonstrate that GLP is crucial in preventing inflammation-related CRC carcinogenesis [66]. However, the exact mechanism of how the altered gut microbiota after GLP therapy affects the progression of CRC remains to be investigated. Panacis Quinquefolii Radix is metabolized by the gut microbiota into active components (e.g., compound K, 20S-protopanaxadiol) with anti-tumor potential, which can inhibit the release of cytokines and induce endogenous metabolite changes. Additionally, these components reduced Verrucomicrobia, a Gram-negative bacterium that promotes tumorigenesis [67]. In general, and particularly in China, Jujubae Fructus is regarded as a species with high nutritional value and pharmacological effects. Polysaccharides, as the main component of Jujubae Fructus, have significant gastrointestinal protective effects. It was reported that jujubae polysaccharides (JPs) increased the concentration of total SCFAs and changed the intestinal microbiota units, significantly increasing the abundance of beneficial bacteria, including Bifidobacterium, Bacteroides and Lactobacillus. Additionally, this study also revealed that JPs could alleviate metabolic dysfunction, which was related to specific gut microbiota [68], [69]. These findings suggested that Jujubae Fructus could reduce CRC-associated risks and be a valuable dietary therapeutic for CRC prevention.

Alcoholic liver disease

Alcoholic liver disease (ALD), brought on by prolonged excessive alcohol consumption, is one of the most common and poses a severe threat to human health and social development [70]. Several pathological characteristics of liver lesions, primarily fatty liver, alcoholic hepatitis, and alcoholic cirrhosis can be caused by ALD. In addition, increasing studies have suggested that excess ethanol and its metabolites, such as acetaldehyde, cause disorders of the gut microbiome homeostasis and the disruption of intestinal barrier permeability, leading to perturbations of the “gut-liver axis” and, finally, liver disease [71]. A promising ALD therapy strategy is focusing on the “gut-liver” axis.

In addition to its anti-IBD properties, which were already described, Lycii Fructus may also benefit the alcohol-induced liver injury. Lycii Fructus serves a protective role in the liver by reducing inflammation and enhancing antioxidant capacity, according to recent studies. On the one hand, Lycii Fructus boosted the levels of SCFAs that were positively correlated with Akkermansia and Ruminococcaceae_UCG_014, particularly butyrate, which is thought to be crucial for maintaining the integrity of the intestinal barrier by regulating the expression of tight junction proteins and mucin. Meanwhile, LPS biosynthesis was down-regulated by reducing Proteobacteria, thereby alleviating the subsequent inflammatory response caused by LPS translocation to the liver. On the other hand, glutathione (GSH), an endogenous antioxidant in hepatocytes, has been shown to delay or decrease apoptosis when GSH is blocked. Therefore, the effect of Lycii Fructus on GSH synthesis might be through regulating the growth of Akkermansia, thus improving its antioxidant capacity. Moreover, after L. barbarum intervention, toxic metabolites, such as phenylacetylglutamine, markedly decreased while helpful metabolites for treating ALD, including L-glutamic acid, pyroglutamic acid, vanillic acid, and retinol β-glucuronide were noticeably elevated. In addition to reversing the damage already done, the ability of Lycii Fructus pretreatment to resist the butyric acid drop caused by alcohol intake suggests that it also has disease-preventive effects [72]. Ganoderma could contribute to host health by increasing the abundance of Ruminiclostridium_9, Prevotellaceae_UCG-001, Oscillibacter, Ruminococcaceae_UCG-009, and others. It has been reported that these may be related to functions such as increasing the content of SCFAs, improving lipid metabolism, and inhibiting inflammation. Spearman correlation analysis showed that these bacteria were strongly correlated with a variety of liver metabolites, including caffeic acid [POS_13], erucic acid [POS_39], L-cystine [Neg_12], Ile-Ala [POS_8], etc. [73]. In another report, the active ingredient Ganoderma acids significantly reduced the level of pathogenic bacteria Helicobacter and exerted liver protection by regulating liver lipid metabolism by increasing the Lactobacillus, Faecalibaculum, and Romboutsia [74]. Although the opposite result was shown in Lv's work, the Lactobacillus level was reduced [75], which may be because the excessive abundance of Lactobacillus also disturbs lipid metabolism in the liver [76]. It was reported that the “gut-liver” axis could help Cornel iridoid glycoside (CIG) from Corni Fructus prevent ALD. Notably, the therapeutic efficacy of CIG (200 mg/kg) was superior to that of silymarin, suggesting that it can be an alternative hepatoprotective agent to prevent alcoholic liver injury. But further research is needed to determine the long-term effects of CIG in ALD models. [77]. Studies on medicine food homology species of Hippophae Fructus [78], Puerariae Lobatae Radix [79], Astragali radix, and related processed products [80], [81] have shown a growing role in preventing and alleviating of ALD through the gut microbiota.

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid metabolism dysfunction. Its mechanism mainly involves insulin resistance and increased oxidative stress, leading to hepatocyte steatosis and lipid peroxidation [82], [83]. The histological changes of NAFLD are similar to those of ALD, but there is no history of alcoholism in NAFLD patients. Even though pioglitazone, obeticholic acid, and vitamin E have all been tested in clinical trials, no drug has yet received therapeutic approval. [84]. In addition to exercise, dietary intervention is currently the only available therapy [85].

The SCFAs produced by the fermentation of indigestible dietary fiber can provide energy to the host. Studies have shown that SCFAs concentrations are higher in genetically obese or overweight models than in lean animal models, suggesting that microbial energy harvesting is increasing in obese patients. Although polysaccharides extracted from Astragali radix (mAPS) had no significant effect on SCFAs, it significantly reduced the protein expression of GPR41 and GPR43 in the liver and colon, which might be related to the down-regulation of Firmicutes/Bacteroidetes (F/B) ratio under mAPS intervention. These findings suggested that mAPS attenuated the progression of NAFLD partly by regulating host energy balance. In addition, decreased expression of GPR41 and GPR43 was correlated with decreased TLR4-NF-κB-NLRP3 signaling, perhaps exhibiting anti-inflammatory effects [86]. The seeds of Cassia obtusifolia L. and C. tora L. have a long medicinal history in China as a medicinal-edible substance known as Cassiae Semen (CS), with claims that it can ease constipation and have hepatoprotective benefits. In high-fat diet (HFD)-induced liver injury, Tang et al. revealed that CS extracts ameliorated lipid accumulation, intestinal barrier damage, liver damage, and inflammation. Importantly, fecal microbe transplantation (FMT) recapitulated the pharmacological effects of CS, and the efficacy was impaired by antibiotic-induced dysbiosis [87]. In addition, by combining the cholesterol-lowering probiotics DM9054 and 86,066 with anthraquinone from Cassia obtusifolia L., the development of HFD-induced NAFLD was effectively prevented and the effect of co-administration was more pronounced than that of either agent administered alone [88]. Moreover, Amomi Fructus [89], Poria [90], Crataegi Fructus [91], Puerariae Lobatae Radix and its components [92] play a preventive and therapeutic role in NAFLD by regulating gut microbiota and triggering related signals.

Others

Liver disease also includes other subtypes, such as liver fibrosis, cirrhosis, etc. These are often driven by inflammation or environmental factors. Rubi Fructus (RF), the dried fruit of Rubus chingii Hu., is a well-known herb for nourishing the liver and has been documented in many monographs such as “Kai Bao Ben Cao” and “Ben Cao Fa Ming”. Liu et al. revealed that supplementation with RF extract could effectively ameliorate CCl₄-induced liver fibrosis while simultaneously modulating the gut microbiota. Correlation analysis indicated that the regulatory effect of RF on intestinal microbiota and its beneficial effects on liver fibrosis were related, among which Bifidobacterium and Turicibacter were the most pertinent bacterial genera, and were closely related to pharmacodynamic parameters, including alanine aminotransferase, aspartate aminotransferase, etc. [93]. Cholestasis can also cause liver damage and progression to liver fibrosis without proper treatment. Gardeniae Fructus, an herb commonly used to treat liver disease [94], is also a constituent in many classic anti-cholestatic prescriptions [95]. For the first time, Ma et al. showed how polysaccharides from Gardeniae Fructus modulated gut microbiota to alleviate cholestatic liver damage. The decreased bile acids levels, the reduced hepatic inflammation mediated by the TLR4/NF-κB pathway, and repaired intestinal barrier were proven to be involved in this process. However, how the polysaccharide from Gardeniae Fructus regulates gut microbiota to reduce bile acid accumulation in the liver requires further investigation [96]. In addition, Portulacae Herba was reported as a supplementary dietary therapeutic strategy to alleviate liver and kidney injury associated with food-source toxic metal Cd exposure by increasing the beneficial bacteria Akkermansia and Faecalibaculum [97].

Environmental and nutritional diseases

Nutritional diseases

Obesity is an over-nourishing disease defined as the accumulation of body fat and has become a serious global health problem [98]. Given the negative impact of obesity on individual health and the economy, it is urgent to explore new ways to prevent and treat obesity. Here, several medicine food homology species exert their anti-obesity activity by regulating gut microbiota and related signals (Table 2).

Table 2.

Effects of medicine food homology species on environmental and nutritional diseases via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Dendrobii Officinalis Caulis	extract	↓Bilophila ↑Muribaculum; Akkermansia; Bifidobacterium	↓inflammatory; oxidant stress; ↑intestinal barrier; glucose homeostasis; SCFAs	male C57BL/6 mice (6 weeks old)	1 g/kg	Obesity	[99]
Ganoderma	extract	↓the ratio of F/B; Proteobacteria; Escherichia	↓inflammatory ↑intestinal barrier	male C57BL/6N mice (8 weeks old)	8 % WEGL	Obesity	[100]
Citri Reticulatae Pericarpium	Polymethoxyflavone	↓Proteobacteria; F/B; Acetatifactor; Bilophila ↑Akkermansia; Allobaculum	↓BAs metabolism ↑SCFAs;	male C57BL/6J mice (6 weeks old)	0.5% extract	Obesity	[101]
Lycii Fructus	polysaccharide	↓Proteobacteria ↑Lactobacillus	↓inflammatory ↑SCFAs	male C57BL/6 mice	50 mg/kg	Obesity	[102]
Glycyrrhizae Radix Et Rhizoma	total flavonoids	↑Lactobacillus; Muribaculum; Roseburia; Anaerotruncus;	↓inflammatory ↑SCFAs	male C57BL/6 mice (6 weeks old)	135 mg/kg	ADR	[103]
Poria	polysaccharides	↓Proteobacteria; Cyanobacteria; Ruminococcaceae; Helicobacteraceae ↑Erysipelotrichaceae; Prevotellaceae	↓inflammatory ↑intestinal barrier	male C57BL/6 mice (6–8 weeks old)	7.6 mg/kg	ADR	[104]
Amomi Fructus	volatile oil bornyl acetate	↓Escherichia; Bacteroides; Helicobacter ↑Lactobacillus; Bifidobacterium;	↓inflammatory ↑intestinal barrier	male SD rats (8 weeks old)	32 mg/kg 8 mg/kg	ADR	[105]
Codonopsis Radix	polysaccharides	↓Escherichia coli ↑Lactobacillus	↑immunity	SPF BALB/c mice (8 weeks old)	200 mg/kg	ADR	[106]
Lycii Fructus	AA-2βG	↓Proteobacteria; Deferribacteraceae ↑Muribaculaceae	↑immunity; amino acid metabolism and biosynthesis	BALB/c mice (5 weeks old)	100 mg/kg	ADR	[109]
Ginseng Radix Et Rhizoma	Ginsenoside Rg1	↑B. vulgatus	↓tryptophan metabolism; 5-HT; 5-HTR1B; 5-HTR2A	female BALB/c mice (6 weeks old)	200 mg/kg	ADR	[111]

Dendrobii Officinalis is an edible medicinal plant and several studies revealed that D. officinale and its components exert the therapeutic effects on metabolic syndrome. By targeting gut microbiota and host metabolism, D. Officinale dietary fiber (DODF) effectively alleviated obesity-related symptoms in obese mice. The gut microbiota of obese mice was restructured as indicated by increased Akkermansia, Bifidobacterium, and Muribaculum and decreased Bilophila. In addition, metabolic phenotypes were changed following DODF administration, as seen by upregulation of energy metabolism, an increase in acetate and taurine, and a reduction in serum low-density/very low-density lipoproteins (LDL/VLDL). These indicated that DODF might be utilized as a prebiotic for managing obesity (Fig. 4) [99]. Furthermore, water extract of Ganoderma mycelium (WEG) has been shown to effectively reduce body weight, inflammation, and insulin resistance in HFD mice. Combined with the fecal transplants experiment, WEG not only reversed the gut dysbiosis, including the drop in the F/B ratio and the level of endotoxin-producing Proteobacteria, but it also maintained the intestinal barrier integrity and reduced metabolic endotoxemia. Further experiments suggested that high molecular weight polysaccharides (4300 kDa) isolated from WEG exhibited similar anti-obesity and microbiota-modulating actions, illuminating the underlying material foundation [100]. Dysregulation of BAs may lead to obesity. Citri Reticulatae Pericarpium extracts dose-dependently alleviated HFD-induced growth of Acetatifactor and Bilophila, bacteria involved in BAs metabolism [101]. In addition, Polysaccharides from Lycii Fructus (LBPs) could be used as prebiotics to ameliorate obesity by altering the genus-specific gut microbiota (Proteobacteria and Lactobacillus) and SCFAs metabolism [102].

Fig. 4.

The protective effects of DODF in obesity. DODF remodeled the metabolic phenotype of the host by reshaping gut microbiota, thus enhancing insulin signaling pathway and liver glycogen synthesis and alleviating systemic inflammatory responses and oxidative stress. Figure created via BioRender.com.

Adverse drug reactions

Therapeutic drug injury, also known as adverse drug reactions, is the effect of drugs that have nothing to do with the therapeutic effect and are detrimental to the body when the drug treats the disease. Consequently, we have explored some medicine food homology species which can alleviate the damage caused by these drugs (Table 2).

Intestinal inflammation is the most common adverse drug reaction. Although irinotecan (CPT-11) is an effective chemotherapeutic agent for solid tumors, severe gastrointestinal toxicity significantly limits its anticancer effects. Duan et al. reported total flavonoids of Glycyrrhiza uralensis (TFGU) could correct the whole intestinal microbial imbalance and fecal metabolic disorder in CPT-11-induced colitis mice. It mainly call-backed SCFAs-producing bacteria, including Muribaculum, Roseburia, Anaerotruncus, and Lactobacillus, and corrected Bacteroides and Clostridium, which were closely related to β-glucuronidase. In addition, TFGU could also increase the abundance of the Lactobacillus and butyrate-producing bacteria Roseburia, both of which are conducive to balancing the intestinal environment in colitis [103]. Poria extract showed an excellent protective effect on intestinal injury caused by cisplatin. It could mainly alleviate the imbalance of intestinal microflora induced by cisplatin, which significantly reduced pathogens such as Helicobacteraceae and promoted the growth of probiotics such as Erysipelotrichaceae and Prevotellaceae [104]. The chemotherapeutic 5-fluorouracil (5-FU) can produce common toxic side effects, such as intestinal mucositis. The volatile oil from Amomi Fructus and its active component, bornyl acetate, have been proven to effectively reduce the number of pathogenic bacteria (including Escherichia, Bacteroides, Helicobacter, etc., increase probiotics (including Lactobacillus, Bifidobacterium) and alleviate intestinal mucositis caused by 5-FU [105].

Cyclophosphamide (CTX) is a common cancer chemotherapeutic drug in clinics that can cause immunosuppression and intestinal mucosal damage when used in large doses. Zou et al. found that polysaccharides from Codonopsis Radix (CRP) could regulate the imbalance and inhibit the growth of Escherichia coli by promoting the growth of Lactobacillus. CRP has a significant protective effect on immunosuppression, especially on mucosal immune damage caused by CTX, and is a potential source of innate immune regulation. A subsequent study on the changes in immune indexes further confirmed that the intestinal immune system might be the active target site of polysaccharides isolated from Codonopsis Radix [106], [107]. In the immunosuppressive model of C57BL/6 mice induced by CTX, Huang et al. found the co-treatment with Panacis Quinquefolii Radix polysaccharide and ginsenoside (AGP_AGG) could alleviate the side effects of CTX by regulating intestinal flora and related metabolism. Research showed that the increase in the beneficial bacteria Lactobacillus, Bifidobacterium, Parasutterella, Lachnospiraceae, etc., were positively correlated with the curative effect of AGP_AGG [108]. AA-2βG also showed regulatory and immunomodulatory effects on intestinal and colonic microflora in mice in similar models. Especially in the microflora of the mouse colon and small intestine, the relative abundance of Muribaculaceae increased significantly, although the interaction between AA-2βG and mouse lipids needs further investigation [109]. Recently, Sun et al. found that the active fraction from Polygonati Rhizoma (PSE30 and PSE75) could enhance the immunity by improving intestinal microorganisms and activating macrophages in the immunosuppressive mouse model constructed by CTX. The preliminary study showed that PSE75 could call back the CTX-induced increased abundance of Bacteroidales, Lachnospiraceae, Lachnospiraceae, and Lachnospiraceae and increase the relative abundance of Lactobacillus, Desulfovibrio, and Enterorhabdus, indicating that PSE75 is expected to be an excellent immune booster [110].

Drug abuse is an undesirable behavior that violates medical use and social norms and can easily cause physical, emotional, mental, or sensory damage. Morphine dependence is a persistent brain disease caused by the opioid morphine, which causes significant physical and mental damage to abusers. Ginsenoside Rg1, an herbal-based dietary supplement derived from Ginseng Radix Et Rhizoma, was shown to be helpful in protection against morphine dependence. Significantly increased B. vulgatus after ginsenoside Rg1 administration inhibited tryptophan metabolism and reduced serotonin (5-HT) and 5-hydroxytryptamine receptor 1B (5-HTR1B)/5-hydroxytryptamine receptor 2A (5-HTR2A) levels, thus inhibiting excitatory nerve conduction and alleviating morphine dependence. This seminal evidence suggested that ginsenoside Rg1 intervention in gut microbiome-tryptophan metabolism-serotonin signaling in morphine disease may be a novel strategy for treating drug dependence [111].

Neurological and psychiatric disorders

Neurological and psychiatric disorders are a widespread group of chronic diseases that cause severe mental and physical health problems for patients. Many studies have highlighted the vital role of gut microbiota in the occurrence and development of these diseases. Biological products produced by gut microbiota act as messengers through the gut-brain axis [112]. Thus, many medicine food homology species have been shown to alleviate neurological and psychiatric disorders by targeting gut microbiota to regulate the gut-brain axis (Table 3).

Table 3.

Effects of medicine food homology species on neurological and psychiatric disorders via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Poria	extract	↓Cyanobacteria; Proteobacteria; Roseburia; Bacteroides; Deferribacteraceae, Enterobacteriales ↑Lactobacillus	↓Aβ plaques; secondary BAs; BMAA; inflammatory	male APP/PS1 mice	1.2 g/kg	AD	[116]
Astragali Radix	flavonoids	↑Roseburia; Lactobacillus; Allobaculum	↓AGEs; Aβ protein ↑SCFAs	male C57BL/6J mice (10 weeks old)	50 mg/kg	AD	[117]
Gastrodiae Rhizoma	extract	↓Rikenelleos-RC9 ↑Bacilli; Lactobacillus johnsonii; Lactobacillus murinus; Lactobacillus reuteri.	↓P-TauThr231 levels	SPF mice (8 weeks old)	300 mg/kg	AD	[118]
Astragali Radix	polysaccharide	↓Osscillospira; Mucispirillum ↑Lactobacillus; Sutterella	↓metabolic disorders ↑SCFAs	male C57BL/6J mice	600 mg/kg	AD	[120]
Panacis Quinquefolii Radix	Panacis Quinquefolii Radix	↑Akkermansia muciniphila; Lactobacillus	↑SCFAs	Human (18–40 years old)	200 mg/day	AD	[119]
Sojae Semen Praeparatum	Semen Sojae Praeparatum	↓Bacteroides ↑Ruminococcaceae_UCG-008	↓SCFAs; ↑5-HT; GABA; BDNF; NE	male SD rats	0.97 g/kg	Depression	[127]
Cistanches Herba	extract	↓Bacteroides ↑Ruminococcus	↓SCFAs ↑5-HT; GABA; BDNF; NE	male SD rats	400 mg/kg	Depression	[128]
Poria	triterpenoids extracts	↓ [Prevotella; Allobaculum; Ochrobactrum	↓palmitoylcarnitine; enoxolone ↑taurocholic acid; citric acid; creatine	male SD rats	15 g/kg	Depression	[129]
Poria	polysaccharide	↓Blautial ↑Ruminococcus; Prevotella;	↓inflammatory	male Wistar rats (8 weeks old)	100 mg/kg	Anxiety	[138]

Neurological disorders

As the most common neurodegenerative disease, Alzheimer's disease (AD) has a complex pathogenesis. Extracellular deposition of amyloid beta protein (Aβ) and intracellular neurofibrillary tangles of tau protein are typical pathological markers [113], [114]. In addition, in pathological conditions, various factors, such as most secondary BAs and endotoxins, can promote the generation of reactive oxygen species and induce neuroinflammation, thereby causing brain damage [115]. The later stages of AD are accompanied by increasingly severe cognitive impairment and no effective therapeutic drugs. The gut microbiota is known as “the second brain “. There is mounting evidence that the microbiota-gut-brain axis has a role in regulating the progression of AD (Fig. 5c), such as butyrate, a metabolite of gut microbes, can cross the blood–brain barrier (BBB) to reduce Aβ aggregation. Therefore, “drugging the microbiome “may be a new strategy for neurological disease treatment.

Fig. 5.

Scheme illustrating the role of Poria in AD treatment. (a) Regulation of gut-brain axis with Poria intervention. (b) In the dysregulation of gut microbiota, the increase of harmful bacteria and pro-inflammatory factors in the gut leads to increased intestinal and blood–brain barrier permeability. The ensuing peripheral immune response over activates the microglia and weakens their ability to clear damaged neurons and proteins. In addition, harmful secretions (such as BMAA) are produced by the corresponding bacteria and accelerate the formation of Aβ plaques. All these adverse factors were reversed with the Poria intervention. (c) The homeostatic gut interacts with the brain through neural, metabolic, endocrine, and immune pathways. Figure created via BioRender.com.

Due to its unique advantages, traditional Chinese herbal medicine has shown significant effects on various diseases with complex mechanisms, especially in the field of neuroprotection. Poria, a conventional herbal and dietary supplement, dramatically reduced the abundance of Roseburia and Bacteroides, which can convert primary BAs into secondary BAs and thus help to alleviate AD-related pathologies by restoring BA homeostasis. Meanwhile, Cyanobacteria, which produces toxic amino acids (β-N-methylamino-L-alanine, BMAA) that misfold Aβ protein, has also been significantly inhibited in reducing Aβ plaques. Deferribacteraceae, Enterobacteriales, and Proteobacteria produce endotoxins and induce neuroinflammation, resulting in excessive activation of microglia and astrocytes and thus leading to a decrease in Aβ proteins clearance. All these harmful bacteria were reduced after the Poria intervention. Moreover, the abundance of Lactobacillus, a probiotic that produces the neurotransmitter γ-aminobutyric acid (GABA), was increased (Fig. 5b) [116]. In another study, decreased levels of advanced glycosylation end products (AGEs) in serum also contributed to retard deposition of Aβ protein in the brain, as the increased abundance of Roseburia and Lactobacillus by flavonoids from Astragali Radix [117]. Notably, Gastrodiae Rhizoma, a medicine food homology species, improved the cognitive impairment in AD mice by reducing the intraneuronal accumulation of hyperphosphorylated Tau^Thr231 in a dose-dependent manner. Increased abundance of Lactobacillus johnsonii, Lactobacillus murinus, Lactobacillus reuteri, etc., and reversed Rikenelleos-RC9 might be a possible mechanistic connection between gut microbiota dysregulation and P-Tau^Thr231 levels in AD progression [118]. SCFAs, especially butyrate, were significantly increased after intervention with Panacis Quinquefolii Radix and Astragali Radix, which linked with the observed increase in Allobaculum, Akkermansia mucinphila and Lactobacillus, etc. [119], [120].

Psychiatric disorders

Depression is a pervasive and incapacitating mental disorder that has become one of the most concerning diseases [121]. The pathogenesis of depression is extremely complex. Decreased levels of monoamines in the brain's nervous system are among the most accepted hypotheses, such as GABA, norepinephrine (NE), and serotonin (5-HT) [122], [123]. Brain-derived neurotrophic factor (BDNF) is a key neuronal substrate for regulating depressive-like behavior, and levels of BDNF in the hippocampus and serum are downregulated by severe psychological stress and mood disorders [124], [125], [126].

Sojae Semen Praeparatum (SSP), a traditional edible herb, showed an antidepressant effect in a chronic unpredictable mild stress (CUMS)-induced mice model. Specifically, this species enhanced the population of the Ruminococcaceae_UCG-008 to slow the depression-related drop in GABA and BDNF. Meanwhile, 5-HT, BDNF, and NE levels were noticeably rising while Bacteroides was reducing [127]. Contrarily, Cistanches Herba demonstrated the exact opposite regulatory impact of SSP on Bacteroides and Ruminococcus while also being able to raise 5-HT levels in the hippocampal region in the same paradigm as described above [128]. Qin et al. also observed that triterpenoids extract from Poria could increase intestinal microbial diversity in CUMS rats and exert antidepressant effects by reducing the abundance of Prevotella, Allobaculum and Ochrobactrum to regulate pathways such as inflammation, energy metabolism, and immunity [129]. In addition, growing preclinical evidence points to the gut-brain axis through the vagus nerve as a critical role in the bidirectional communication between gut microbiota and the brain [130], [131]. For instance, subdiaphragmatic vagotomy stopped the manifestation of depressive-like behavior in rodents [132], [133], [134], [135], [136]. It's apparent that the MFH species are highly correlated with the vagal pathway in the aspect of combating psychiatric disorders, but the underlying mechanism awaits further investigation.

Anxiety is another psychiatric disorder that often accompanies depression. The core symptoms of the disease are excessive nervousness and worry, accompanied by symptoms such as insomnia, which seriously affect the quality of patients’ life [137]. Poria has been widely used to treat restlessness as an ancient medicine and modern functional food. Ye et al. demonstrated that Poria exerted anxiolytic effects by reducing Blautial and increasing Ruminococcus and Prevotella, which were associated with decreased inflammatory response in a rat model of anxiety induced by chronic sleep deprivation [138]. In addition, Lilii Bulbus and Ziziphi Spinosae Semen are traditional Chinese herbs used for treating insomnia for thousands of years. Modern studies revealed that these species ameliorated the disturbance of gut microbiota caused by insomnia and significantly regulated the gut microbiota-related metabolites, thus showing therapeutic effects through the microbe-gut-brain axis [139], [140].

Cardiovascular diseases

Atherosclerosis (AS) is a risk factor for cardiovascular diseases, which has become the leading cause of death worldwide [141]. Various factors can predispose to AS, particularly dyslipidemia. Natural species have unique advantages in regulating these indicators (Table 4). In the current study, the active ingredient, ginsenoside Rc (GRc), alleviates AS by modifying the gut microbiota and fecal metabolites. At the genus levels, the relative abundances of the beneficial bacteria Muribaculaceae, Lactobacillus, Ileibacterium, and Bifidobacterium increased significantly under the GRc intervention. In contrast, the abundance of the harmful bacteria Faecalibaculum, Oscillibacter, and Eubacterium_coprostanoligenes_group decreased. These changes were closely related to a variety of metabolites involved in the metabolism of taurine and purine, ATP binding cassette (ABC) transporters, the biosynthesis of primary BAs and arginine, the tricarboxylic acid (TCA) cycle, and other pathways [142]. Circulating trimethylamine N-Oxide (TMAO), derived from the oxidation of trimellitic anhydride (TMA) by liver-secreted flavin monooxygenase 3 (FMO3), can be used as a predictive signal for the early stages of AS, which can influence cholesterol metabolism and oxidative stress. Ginkgolide B (GB) is a naturally occurring chemical derived from Ginkgo Semen that has been identified as a therapy for AS. The mRNA and protein expression of FMO3 were dramatically suppressed by GB therapy, leading to a decrease in TMA and TMAO concentrations, which were linked to the altered gut microbiota in HFD mice. Increased Bacteroides and decreased Helicobacter might contribute to the anti­atherosclerotic effects of GB [143]. 7α-hydroxylase (CYP7A1) is a specific rate-limiting enzyme. Polyphenol extract and essential oil from Tsaoko Fructus altered the abundance of Allobaculum, Desulfovibrio, and Ruminococcus_2, the gut microbiota associated with CYP7A1, and upregulated the expression of CYP7A1 at both the mRNA and protein levels, thus exhibiting cholesterol-lowering effect by converting cholesterol into BAs and excreting them out [144]. Additionally, intervention with Ganoderma and its active ingredient could also ameliorate dyslipidemia by selectively promoting the growth of specific benign bacteria (Prevotella and SCFAs producers) [145], [146].

Table 4.

Effects of medicine food homology species on cardiovascular diseases via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Ginseng Radix Et Rhizoma	ginsenoside Rc	↓Faecalibaculum; Oscillibacter; Eubacterium_coprostanoligenes_group ↑Muribaculaceae; Lactobacillus; Ileibacterium; Bifidobacterium	↓uric acid; adenine; fumaric acid; malic acid; citric acid; cholesterol ↑L-glutamine; ABC Transporter; BAs; FXR; TGR	male C57/BL6 ApoE−/−mice (7 weeks old)	40 mg/kg	AS	[142]
Ginkgo Semen	Ginkgolide B	↓Helicobacter ↑Bacteroides	↓TMA; TMAO; cholesterol ↑FMO3	male C57/BL6 ApoE−/− mice (8 weeks old)	30 mg/kg	AS	[143]
Tsaoko Fructus	Polyphenol extract/ essential oil	↓Allobaculum, Desulfovibrio ↑Ruminococcus_2	↓cholesterol ↑CYP7A1	male Golden Syrian hamsters (8 weeks old)	1000 mg/kg 200 mg/kg	AS	[144]
Ganoderma	extract	↓Turicibacter; Clostridium XVIII ↑Prevotella; Alloprevotella; Ruminococcus	↓blood lipid levels ↑SCFAs	male Wistar rats	150 mg/kg	AS	[145]
Ganoderma	Ganoderic acid A	↑Alistipes; Bacteroides	↓blood lipid levels ↑SCFAs	male SPF Kunming mice (6 weeks old)	75 mg/kg	AS	[146]

Endocrine diseases

Diabetes is a metabolic disorder in which hyperglycemia results from inadequate insulin production and/or action. According to 2021 data from the International Diabetes Federation, it makes diabetes prevention and treatment are a global priority, with 537 million people living with diabetes [147]. Growing evidence suggests that the gut microbiota is crucial in controlling host physiology and metabolism, and its dysbiosis is associated with the progression of diabetes [148], [149]. Therefore, targeting the gut microbiota and its metabolites has become a required field in diabetes prevention and treatment (Table 5).

Table 5.

Effects of medicine food homology species on endocrine diseases via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Lycii Fructus	polysaccharides	↓Allobaculum; Dubosiella; Romboutsia ↑Bacteroides; Ruminococcaceae_UCG-014; Mucispirillum; Intestinimonas; Ruminococcaceae_UCG-009	↓inflammatory; ↑SCFAs; insulin	male SPF C57BL/6 mice (6 weeks old)	200 mg/kg	Diabetes	[150]
Lycii Fructus	polysaccharides	↑Allobaculum	↓inflammatory ↑intestinal barrier	male C57BL/6 mice (5 weeks old) Caco-2 cells	200 mg/kg 200 μg/kg	Diabetes	[154]
Portulacae Herba	extract	↓Firmicutes	↓BCAAs	male C57BL/6J mice (3 weeks old)	200 mg/kg	Diabetes	[158]
Siraitia Fructus	mogrosides	↓Lachnospiraceae_UCG-004; Desulfovibrio; Escherichia Shigella ↑Elusimicrobium,	↓blood glucose; insulin resistance; 1β-hydroxycholic acid ↑SCFAs	male SD rats	20 mg/kg	Diabetes	[155]
Mori Folium	extract	↓Romboutsia; Oscillatoriales_cyanobacterium ↑Alloprevotella; Parabacteroides; Muribaculaceae	↓inflammatory; blood glucose; insulin resistance	Male C57BJ/6J mice (8 weeks old)	250 mg/kg	Diabetes	[156]

LBPs altered the gut microbiota composition in diabetic mice, specifically increasing SCFAs-producing bacteria Ruminococcaceae_UCG-014 and Intestinimonas. Then, the increased SCFAs promoted insulin secretion and improved insulin sensitivity by directly activating the GPCRs (GPR41 and GPR43) receptor to increase the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) by intestinal L cells [150]. In addition, increased intestinal permeability and chronic inflammation due to intestinal barrier dysfunction are thought to be responsible for impaired islet β cell function and insulin signaling [151], [152]. SCFAs exert a protective effect on the intestinal barrier by promoting epithelial cell proliferation, increasing MUC2 gene expression, and promoting tight junction assembly [153]. Here, SCFAs were elevated, and LPS was decreased by altering the specific gut microbiota after LBPs intervention, thereby repairing the intestinal barrier, alleviating the inflammatory response, and relieving blood glucose levels in diabetic mice [150], [154]. The disturbance of gut microbiota in diabetic mice was restored by Siraitia Fructus (SF) intervention. The relative abundance of Elasimicrobium negatively correlated with fasting glucose and insulin resistance was significantly increased, while Lachnospiraceae_UCG-004 positively correlated with these factors was reduced. Additionally, the inhibition effect of SF and its component on opportunistic pathogens Desulfovibrio and Escherichia Shigella might contribute to diabetes treatment [155]. Mori Folium also alleviated diabetes by mediating the host–microbial metabolic axis. The bacteria Alloprevotella, Parabacteroides, Muribaculaceae, Romboutsia, and Oscillatoriales_cyanobacterium associated with lactic acid and other metabolites were all reversed under Mori Folium intervention [156]. Serum-branched-chain amino acids (BCAAs) levels have been reported to be associated with insulin resistance [157]. Portulacae Herba extract intervention reduced the biosynthesis of BCAAs, which was mainly associated with the phylum Firmicutes, thereby reducing the level of serum BCAAs and alleviating the progression of diabetes [158].

Others

Medicine food homology species targeting the gut microbiota regulate various diseases (Table 6). For example, chronic nonbacterial prostatitis (CNP) is a common urological disease with a high incidence and low cure rate. Previous studies have demonstrated that Poria polysaccharides (PPs) effectively relieved CNP by regulating the gut microbiota [159], [160]. Parabacteroides, Fusicatenibacter, and Parasutterella, as well as their metabolites haloperidol glucoside acid and 7-ketodeoxycholic acid, were significantly enriched by PPs in colonic epithelium, altering the expression of several critical genes in colon epithelium. Meanwhile, the ratio of dihydrotestosterone to estradiol (DTH/E2) was regulated, prostate inflammation was eventually suppressed, and CNP was reduced. Among them, haloperidol glucuronide and 7-ketodeoxycholic acid could be the signaling molecules of the “gut-prostate” axis to alleviate CNP [161]. These results provide new guidelines for treating CNP using natural-derived species to target the gut microbiota.

Table 6.

Effects of medicine food homology species on other diseases via gut microbiota.

Species	Category of Active Ingredient	Microbiota Findings	Mechanism	Animals	Dose	Disease	Ref.
Poria	polysaccharides	↑Parabacteroides; Fusicatenibacter; Parasutterella	↓inflammatory; Cyp1a1; Hsd17b7 ↑Pla2g2f; Alox15; DTH/E2	male SD rats (7–8 weeks old)	250 mg/kg	Chronic nonbacterial prostatitis	[161]
Astragali Radix	polysaccharides	↓Bifidobacterium_pseudolongum ↑Lactobacillus_johnsonii	↓MDSC ↑immunity; CD8 T cells; L-glutamate; creatine	male C57BL/6 mice (5–6 weeks old)	200 mg/kg	Malignant melanoma	[162]
Poria	extract	↓Desulfovibrio; Mucispirillum ↑Lactobacillus; Bifidobacterium	↓inflammatory; putrescine ↑intestinal barrier	female (BALB/c mice (4 weeks old)	700 mg/kg	Breast cancer	[163]
Eucommiae Folium	extract	↑Lactobacillus bulgaricus	↑SCFAs; gut microbiota diversity	male SAMP6 mice (16 weeks old)	3.0 g/kg	osteoporosis	[164]
Poria	poricoic acid A	↓Escherichia_Shigella; Blautia; Enterorhabdus; Parasutterella	↓inflammatory; polyamine metabolites; glycine-conjugated compounds;	male SD rats	10 mg/kg	chronic kidney disease	[165]

Malignant melanoma is an invasive skin cancer characterized by high mortality and poor prognosis. Myeloid-derived suppressor cells (MDSCs) can interfere with antitumor activity by impairing the tumor-killing effect of CD8 T cells. Administration of Astragali Radix polysaccharides (APs) significantly decreased the number of MDSCs and the expression of the MDSCs-related molecule while increasing the number of CD8 T cells. It was shown that the ability of MDSCs to inhibit CD8 T cells from killing tumor cells was weakened. Subsequent FMT and antibiotic (ABX) interference experiments demonstrated that this function was achieved by regulating the gut microbiota. L-glutamate and creatine, which were negatively correlated with Bifidobacterium_pseudolongum and positively correlated with Lactobacillus_johnsonii, were significantly upregulated under APs intervention. All these data revealed the therapeutic capacity of APs to inhibit tumor growth, which was related to the degenerative immunosuppressive efficiency of MDSCs and depended on the remodeling and metabolic function of the gut microbiota [162].

Medicine food homology species also show profound and extensive effects targeting the gut microbiota. Poria improved dysbacteriosis in breast cancer mice by boosting the beneficial bacteria Lactobacillus and Bifidobacterium and decreasing the sulfate-reducing bacteria Desulfovibrio and the inflammatory-associated bacteria Mucispirillum, etc. [163]. In vivo studies in the senescence-accelerated mouse model proved that Eucommiae Folium extract supplementation promoted the growth of Lactobacillus bulgaricus, increased the concentration of SCFAs in feces and serum, and exhibited anti-osteoporosis activity [164]. As a new dietary and therapeutic strategy, Poria supplementation could delay the development of chronic kidney disease by regulating the gut microbiota and its metabolites [165].

Bioconversion of active constituents by gut microbiota

The gut microbiota is not only regulated by ingested substances but also has the tremendous capability to convert the active ingredients of these species into diverse xenobiotics. The metabolization of the azo drug Prontosil into sulfonamide with significant antimicrobial activity by azo reductase is a classic example of microbiome-driven activation of precursor drugs [166]. Oral administration is the dominant use in medicine food homology species, which inevitably leads to direct contact and interaction between the gut microbiota and these species. The essence of the conversion of these natural-derived active components by gut microbiota is chemical reactions that occur when enzymes produced by gut microbiota modify the structure of these exogenous substrates. The modified structures show altered physicochemical and biological properties that enhance the therapeutic efficacy and increase the biological diversity of ingested natural products [167], [168]. Compared with the modification of these natural products by chemical synthesis, the biotransformation of gut microbiota has unique advantages: 1) Most of the reactions driven by the gut microbiota secreted catalytic enzymes are challenging to complete by chemical synthesis; 2) Enzymatic reactions are highly selective, especially without the need to protect the groups that do not participate in the conversion; 3) The reaction conditions of biotransformation are relatively mild, which can maximize the protection of the active ingredients from the damage of external conditions, such as high temperature and pressure [169], [170], [171]. The biotransformation of gut microbiota mainly includes demethylation, deprenylation, deglycosylation, dihydroxylation, and acetylation, and some representative examples are listed below (Fig. 6).

Fig. 6.

Modification of bioactive ingredients from medicine food homology species by gut microbiota.

Demethylation and deprenylation

Furanocoumarins are bioactive ingredients in foods and herbs and exhibit various pharmacological activities, including anti-inflammatory, anti-cancer, neuroprotection, and so on [172]. However, oral administration of furanocoumarins may also be phototoxic. Furanocoumarin ingestion and subsequent exposure to ultraviolet have been reported to cause photosensitive dermatitis [173]. In addition, furanocoumarins inhibit the drug-metabolizing enzyme CYP3A in the liver, which prolongs the drug's duration of action and leads to serious adverse effects [174]. Angelicae Dahuricae Radix contains a variety of furanocoumarins, including xanthotoxin, bergapten, imperatorin, and isoimperatorin, etc. In the current study, the Co O-methyltransferase expressed by the gut microbe Blautia sp. MRG-PMF1 lysed the methyl aryl ether and converted xanthotoxin and bergapten to the products xanthotoxol and bergaptol, respectively. Importantly, the prenyl aryl ether group was cleavaged in the same way. Deprenylation of imperatorin and isoimperatorin by gut microbial conversion also resulted in the products described above [175]. These demethylated and deprenylated phenolic metabolites with better solubility can be excreted rapidly with urine and thus serve as its detoxification mechanism [176] (Fig. 6a).

Deglycosylation

Many complex natural products are usually in glycosylated forms, such as ginsenosides. After oral administration of Ginseng, the major ginsenosides are metabolized to deglycosylated products by the gut microbiota before absorption into the bloodstream. The biotransformation of Ginsenoside Rb1 with Bifidobacterium led to the deglycosylated metabolite Rd. And compound K with anticancer and antidiabetic activities was also obtained after subsequent continuous deglycosylation [177]. In addition, deglycosylated metabolites possess potent pharmacological activity compared to basic ginsenosides. For example, the 20(S)-protopanaxatriol (PPT) obtained from the deglycosylation of Rg1 has a stronger anti-fatigue activity than the original saponin [178]. Calycosin-7-O-β-D-glucoside (CG) has been investigated intensively as the major isoflavonoids in Astragali Radix and has been reported to possess extensive pharmacological properties. It was reported that aglycone calycosin was obtained from the deglycosylation of CG by Bacteroides sp.13 isolated from human gut bacteria [179]. Importantly, it has a more vital antiviral ability than the corresponding glycoside [180] and can protect PC12 cells from glutamate-induced injury, while CG cannot [181]. These results indicate that the deglycosylation of natural products with gut microbiota is critical to finding new therapeutic molecules with more potent and diverse pharmacological activities (Fig. 6b).

Dehydroxylation and acetylation

Dehydroxylation is also one of the main metabolic ways of natural products by gut microbiota. For example, Formononetin is a well-known phytoestrogen used to prevent and treat breast, prostate, and colon cancers and osteoporosis [182], [183]. It was reported that Bacteroides sp.58 from human intestinal bacteria could dehydroxylate calycosin and convert it into Formononetin. In addition, the acetylation of calycosin was accomplished by strain Clostridium sp.21–2 [179] (Fig. 6c).

Conclusion and future perspectives

To sum up, as a “forgotten organ”, the gut microbiota plays a crucial role in regulating human health. Targeting the gut microbiota by medicine food homology species to affect the host favorably is the dawn of disease prevention and treatment. This review summarizes the interaction between MFH species and gut microbiota and its effects on human health from a macro point of view. The changes in the composition and metabolites of gut microbiota and the conversion of natural active components after MFH species intervention have proved these interactions. According to the results of literature research, species from Rosales are the most abundant in regulating the involvement of gut flora in host pathophysiology (Fig. 7a). In addition, the statistical results also revealed that saccharides are the most widely studied and widely used (Fig. 7b). These results provide a direction for further searching for MFH species and active ingredients.

Fig. 7.

Distribution of (a) medicine food homology species and (b) bioactive ingredients from medicine food homology species.

As this review shows, from the initial practical application to more mechanism studies, the relationship between MFH–gut microbiota–human health has evolved into an irrefutable interaction. But obviously, there are still a lot of challenges:

• (I)The category of MFH species needs to be further clarified. This may require screening and research performed by various countries and regions in combination with the actual local situation, as each region has different dietary sources and habits that must be taken into account, and drastic changes in diet can upset the body's balance and even lead to more complex health problems. In addition, medical institutions or the government should constantly update the standards and catalogs of MFH since they are a continuous development process.
• (II)Most existing studies only establish the association among MFH, gut microbiota, and disease phenotype, but it is not causal. Future research should further clarify the causal relationship among MFH, gut microbiota, and therapeutic effect, especially at the cellular and molecular level, which is helpful for the transformation from experimental research to clinical application.
• (III)Although it has been proven that the regulation of gut microbiota is an effective method for disease treatment. How to define healthy gut microbiota, quickly detect and analyze, and select appropriate MFH for individuals are worthy of in-depth study because there are significant differences in individuals' gut microbiota. Besides, eating habits, living environment, and other factors are individual independent variables. Therefore, a new method of observation and analysis may be proposed to achieve detailed communication and more insights into diet, gut microbiome population, and their relationship with host health, thus obtaining personalized healthy diet guidance and disease treatment for human beings [184].
• (IV)Nowadays, the discoveries related to the role of MFH, gut microbiota, and human disease state are exploding. Efforts should be made to integrate, process, and analyze this massive data to transform it into useful and applicable knowledge [185]. This may require new methods such as omics analysis [186], [187], [188], [189] and machine learning [190], [191]. These methods are expected to accurately predict the disease state and find appropriate treatment means by using more samples across the population and time.
• (V)Explaining the advantages of the MFH theory in managing gut microbiota requires an advanced theory and a broader perspective, both of which are made possible by the rapid development of modern means. This requires continuous cooperation in various areas, such as traditional Chinese medicine, neurology, microbiology, and life sciences, to develop comprehensive and relevant approaches to identify the mechanisms of action that are still based on observations. At the same time, more efforts should be made to translate these findings into improved human health [192], [193], [194], [195], [196].

Looking ahead, the knowledge and experience accumulated by studying the effects of MFH on gut microbiota will open a new field to prevent and treat human diseases. It is hoped that the treatment of complex diseases and the regulation of gut microbiota can find more “overlap” in MFH, and more clinicians will regulate the microbiota through MFH and use it as an alternative for disease prevention and diagnosis.

Compliance with ethics requirements

This article does not contain any studies with human or animal subjects.

CRediT authorship contribution statement

Wei-Fang Zuo: Writing – original draft, Writing – review & editing, Visualization. Qiwen Pang: Writing – original draft, Writing – review & editing, Visualization. Lai-Ping Yao: Writing – review & editing, Formal analysis. Yang Zhang: Formal analysis, Visualization. Cheng Peng: Funding acquisition. Wei Huang: Conceptualization, Funding acquisition. Bo Han: Conceptualization, Supervision, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Wei-Fang Zuo was born in Sichuan Province, China, in 1997. She obtained her Master's degree from Chengdu University of Traditional Chinese Medicine in 2022. She is now pursuing her Ph.D. at the same university under the supervision of Prof Bo Han and Prof Wei Huang. Currently, her main research interests are synthesizing and modifying active compounds in traditional Chinese medicine and elucidating the pharmacological mechanisms and metabolic processes of bioactive substances.

Qiwen Pang was born in 1996 in Sichuan Province, China. In 2019, he received his Bachelor's degree in Pharmaceutical Engineering from Jiangxi University of Science and Technology, College of Pharmacy. Now, he is a postgraduate student in the School of Pharmacy at Chengdu University of Traditional Chinese Medicine. His research interests are structural modification, activity screening, and mechanism investigation of active ingredients of traditional Chinese medicine and natural products.

Laiping Yao received her Bachelor's degree in Traditional Chinese Medicine from the School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, College of Science and Technology in 2022. Now, she is pursuing her Master's degree at the College of Pharmacy, Chengdu University of Traditional Chinese Medicine. Her main research interests are the discovery and structural modification of bioactive components in traditional Chinese medicine.

Yang Zhang was born in 2001 in Chongqing Municipality, China. He enrolled at Chengdu University of Traditional Chinese Medicine in 2019. Now, he is pursuing his Bachelor's degree in Chinese Pharmacy at the College of Pharmacy, Chengdu University of TCM.

Cheng Peng was born in 1964 in Sichuan, China. He graduated from Chengdu University of Traditional Chinese Medicine with a degree in Chinese medicine and received his Ph.D. in 1996. He joined the Chengdu University of Traditional Chinese Medicine in 1986 and became a professor in 1999. He is currently the Vice President of the Chengdu University of Chinese Medicine and the Director of the State Key Laboratory of Southwest Specialty Chinese Medicine Resources. His research interests are based on the discovery of active ingredients in traditional Chinese medicine and natural products, the investigation of the relationship between toxicity and therapeutic efficacy, and the study of the mechanism of action and biotransformation of bioactive molecules in the intestinal microbiota. He has received many awards, including the National Science and Technology Progress Award, and is a member of the Chinese Pharmacopoeia Commission.

Wei Huang was born in Chengdu, China in 1980. She received her B.S. and M.S. degrees from West China College of Pharmacy, Sichuan University, in 2003 and 2006, respectively, and her Ph.D. degree in Chinese medicine from Chengdu University of Traditional Chinese Medicine in 2010. Currently, she is a professor at the College of Pharmacy, Chengdu University of Chinese Medicine. Her main research interests are chemical modification, structure-activity relationships, and potential molecular mechanisms of active ingredients in traditional Chinese medicine and natural products.

Bo Han received his Ph.D. degree from the West China School of Pharmacy, Sichuan University, in 2010. In 2017–2018, he was a visiting scientist at RNA Institute, State University of New York, USA. Since 2015, he has worked as a Professor at the State Key Laboratory of Southwestern Chinese Medicine Resources at Chengdu University of TCM. His interest is in the design, synthesis and modification of lead compounds based on biologically active compounds discovered from traditional medicinal plants and the study of their pharmacological efficacy and mechanism of action.