Table 2 lists the top 10 authors and their H-index and TC, of which Duan Jin-ao (n = 24), Jiang Shu (n = 17), Qian Da-wei (n = 16), Shang Er-xin (n = 16), Li, Xiao-bo (n = 15) ranked the top five in the Np. Duan Jin-ao from Nanjing University of Chinese Medicine had the most Np and H-index, and Tong Xiao-lin from China Academy of Chinese Medical Sciences had the most TC, indicating that their papers were of high quality and had a great impact on TCM/GM research. Notably, half of the authors were from Nanjing University of Chinese Medicine. Moreover, there were two authors from South Korea.

Figure 2A shows the annual scientific productivity of the top 20 authors. Most authors had published TCM/GM-related papers since 2014, and most authors’ influential papers were published in 2018 and 2019 (the darkest in the graph). Figure 2B shows the collaborations of the top 20 authors. Among them, the cooperation group with Duan Jin-ao as the core had the most collaborators, and most of the collaborators belong to the same institution (Nanjing University of Chinese Medicine), showing the tendency for cooperation within the institution.

Figure 3A shows the country distribution of papers. The papers were mainly from China (716), accounting for about 86.27% of total output, followed by USA (n = 58), South Korea (n = 44), Japan (n = 26) and Australia (n = 12) ( Table 3 ). More than 800 institutions were involved in this study, and the top 10 most productive institutions were shown in Table 3 , of which Nanjing University of Chinese Medicine (n = 63), Beijing University of Chinese Medicine (n = 59), Chinese Academy of Sciences (n = 47), Shanghai University of Traditional Chinese Medicine (n = 46) and China Academy of Chinese Medical Sciences (n = 43) were among the top five. The top 10 institutions all were from China, of which Chinese Academy of Chinese Medical Sciences had the most TC and Nanjing University of Chinese Medicine had the highest H-index.

Figure 3B depicts the partnership of the top 20 institutions in TCM/GM. Among them, Beijing University of Chinese Medicine and China Academy of Chinese Medical Sciences had the closest partnership. Figure 3C shows the annual scientific productivity of the top 10 institutions. We can see that Beijing University of Chinese Medicine had the most Np in the past two years. Figure 3D depicts the main funding agencies, which mainly were from China, especially the National Natural Science Foundation of China (accounting for 54%), indicating that China has strong support for research in related fields.

These papers were published in 241 journals. Table 4 shows the top 10 journals in the Np, of which Journal of Ethnopharmacology had the most Np (n = 82), followed by Frontiers in Pharmacology (n = 62), Evidence-Based Complementary and Alternative Medicine (n = 57) and Biomedicine & Pharmacotherapy (n = 32). The TC can show the importance of the journal, and the H-Index can evaluate the academic influence of journals. In the top 10 most productive journals, the Journal of Ethnopharmacology had the highest TC and H-index, followed by Frontiers in Pharmacology, and the Journal of Pharmaceutical and Biomedical Analysis. Figure 4 summarizes the annual Np and the cumulative Np in the top 10 journals. The cumulative Np in these journals was 376, accounting for about 37.94% of all papers, indicating that their excellent productivity.

Historical direct citation analysis can quickly identify the most relevant and cited significant papers in the development process of a field, draw a historical direct citation map according to the time series, and then trace the source year by year to analyze the historical development. Figure 5 shows the citation relationship of several classic papers, which appeared from 2009 to 2019. Two indicators, local citation score (LCS) and global citation score (GCS), were used to examine the research importance of the classic papers. LCS corresponds to the citations of a paper in the downloaded dataset, and GCS represents the times a paper had been cited by all papers in the WoS database ( Table 5 ).

In 2009, a review paper titled “Traditional Chinese Medicine: Balancing the Gut Ecosystem” proposed that TCM plays an important role in restoring the gut ecological balance, and the multi-channel regulation of the human gut ecosystem may be a large part of the efficacy during TCM treatment (Li et al., 2009). In 2011, a review article showed that GM can induce comprehensive metabolism of herbal components and enhance the biological activity of ginsenosides (Wang et al., 2011). In 2013, a study showed that Chinese herbal formula can improve the GM in rats with non-alcoholic fatty liver disease (NAFLD) and return it to normal levels (Yin et al., 2013). In 2014, a clinical study showed that Ephedra sinica can exert an anti-obesity effect by regulating the GM of obese women (Kim et al., 2014). An in vitro study demonstrated that the presence of GM plays an important role in the gastrointestinal metabolism of the water extract of root of Scutellaria baicalensis (Xing et al., 2014). In 2015, an experimental study showed that Red Ginseng and Semen Coicis can improve the structure of GM, promote the growth of probiotics such as Bifidobacterium and Lactobacillus, and relieve the symptoms of ulcerative colitis (UC) (Guo et al., 2015). A clinical study showed that structure changes of GM (an increase in beneficial bacteria) induced by Gegen Qinlian Decoction (GQD) were associated with its anti-diabetic effect (Xu et al., 2015), which provided an important reference for TCM microecology research. In 2016, A review article on herb-microbiota interactions showed that TCM can play a role in promoting health and preventing diseases by affecting the structure of GM, and some herbal components can play their therapeutic roles through the GM-mediated biotransformation (Chen et al., 2016). Zhou et al. (2016) found that Ginseng polysaccharides can improve intestinal metabolism and absorption of ginsenosides, reinstate the disturbed GM, and promote the growth of Lactobacillus and Bacteroides. This study showed that even TCM polysaccharides that cannot be digested by the host can still indirectly promote the therapeutic effect, which endows TCM polysaccharides with new effects. Hussain et al. (2016) showed that Daesiho-tang reduced obesity in high-fat diet (HFD)-fed mice by altering gene expression and modulating GM. In 2017, a review article provided an overview of the molecular mechanisms underlying the interaction between TCM and GM (Xu et al., 2017). The other review article summarized herbal and functional foods for the prevention and treatment of cardiometabolic diseases by modulating GM and exerting prebiotic-like activities (Lyu et al., 2017). A study confirmed that Huangqin Decoction can improve dextran sulphate sodium (DSS)-induced colitis by altering the GM (Yang et al., 2017). An animal study demonstrated that the synergistic effect of metformin and Scutellaria baicalensis in lowering cholesterol levels by fecal excretion of bile acids (Han et al., 2017).

In 2018, an animal experiment showed Huang-Lian-Jie-Du Decoction (HLJDD) could improve hyperglycemia and restore the structure and function of dysregulated GM to a normal state by increasing short-chain fatty acids (SCFAs)-producing bacteria and reducing pathogenic bacteria in type 2 diabetes mellitus (T₂DM) rats, which provides new ideas for the study of the mechanism of TCM in the treatment of T₂DM (Chen et al., 2018). Gao et al. (2018) found that Qijian Mixture can effectively alleviate T₂DM, and this effect was related to the altered characteristics of metabolite profiles and GM. Wei et al. (2018) showed that Xiexin-Tang could significantly improve hyperglycemia, lipid metabolism dysfunction and inflammation in T₂DM rats, and some GM were closely related to T₂DM-related indicators. Subsequently, a clinical trial (Tong et al., 2018) showed that the TCM compound AMC can reduce the hyperlipidemia in patients with diabetes by changing the structure and diversity of the GM and regulating the probiotics of GM. A further animal experiment (Shen et al., 2018) demonstrated that Ginseng polysaccharides can alleviate DSS-induced colitis and enhance the systemic exposure of Rb1 by enhancing microbial deglycosylation and intestinal epithelial uptake of Rb1. The theory of “eighteen incompatible medicaments” in TCM is the most representative case of herbal-herbal interactions. Gancao and Gansui are one of the incompatible herbal pairs. Yu et al. (2018) showed that the Gancao-Gansui combination did not exacerbate gastrointestinal tissue or functional damage, but caused GM dysbiosis and increased the abundance of some rare genera such as Desulfovibrio and Mycoplasma. In 2019, a study (Wu et al., 2019) revealed the Parabacteroides goldsteinii plays a major role in the anti-obesity effect of polysaccharides isolated from Hirsutella sinensis. The other study (Sun et al., 2019) showed that an insoluble polysaccharide in sclerotia of Poria cocos can ameliorate hyperglycemia, hyperlipidemia and hepatic steatosis in mice by modulating GM. Two reviews (Feng et al., 2019; Yue et al., 2019) summarized the interactions between TCM and GM, including its theory, mechanism, and the future prospects and challenges of GM in TCM.

Highly cited papers are one of the most valuable indicators in bibliometric methods, which usually are highly recognized. Table 6 lists the top 20 most cited papers in original research. Some papers have been outlined above, for instance, TCM can improve diabetes and insulin resistance (Xu et al., 2015; Liu et al., 2018; Tong et al., 2018; Wei et al., 2018), obesity (Kim et al., 2014; Wu et al., 2019), colitis (Guo et al., 2015; Yang et al., 2017) by adjusting the GM, here we analyze some other highly cited papers.

Highly cited papers mainly focused on the effect of TCM on GM to improve obesity and obesity-related diseases. A 2015 animal study (Chang et al., 2015) found Ganoderma lucidum could reduce obesity in mice by modulating GM, which had the highest TC. It pointed out a new direction for studying the mechanism of TCM, and has important guiding significance for TCM microecology research. Furthermore, oral administration of pomegranate peel extract can alleviate tissue inflammation and hypercholesterolemia in HFD-induced obese mice by modulating GM and promoting the growth of Bifidobacteria (Neyrinck et al., 2013). The effect of berberine on preventing obesity and insulin resistance in HFD-fed rats is partially mediated by the GM, which may reduce the exogenous antigen load of the host and increase the SCFAs level in the gut (Zhang et al., 2012). An insoluble polysaccharide from the sclerotium of Poria cocos can improve hyperglycemia, hyperlipidemia and hepatic steatosis by regulating GM (Sun et al., 2019). Fructooligosaccharides from Morinda officinalis can exert prebiotic effects on animal models of Alzheimer’s disease by targeting the microbiota-gut-brain axis (Chen et al., 2017). Moreover, probiotics combined with TCM had synergistic modulatory effects on GM, and TCM seems to act as a potential substitute for probiotics. A clinical trial (Lee et al., 2014) showed that co-administration of probiotics with herbal remedies had an effect on the GM in obese patients, resulting in significant reductions in body weight and waist circumference, which was important for the exploration of new prebiotics.

Several articles mentioned the relationship between GM and TCM in other aspects. For example, eugenol may enhance the mucosal barrier by increasing the thickness of the inner mucus layer through microbial stimulation, thereby preventing invading pathogens and diseases (Wlodarska et al., 2015). The metabolism of human GM plays an important role in the anti-inflammatory effect of traditional tannin-rich plant materials (Piwowarski et al., 2014). GM can play an important role in chemical prevention of colon cancer in Scutellaria baicalensis (Wang et al., 2015). Mushroom polysaccharides from Ganoderma lucidum and Poria cocos act as prebiotics to regulate GM composition, thus potentially contributing to the health promotion effect (Khan et al., 2018). Human GM has an impact on the metabolism and transformation of natural products, such as a study showing that intestinal bacteria play an important role in the metabolism and pharmacological effects of rhamnoglycosides (Bang et al., 2015).

Figure 6A shows the references with the most citations. In 2006, a mouse study (Turnbaugh et al., 2006) identified the GM as a contributing factor in the pathophysiology of obesity, which showed that obesity-associated GM had enhanced and transmissible ability to obtain energy from diet, and compared to ‘lean microbiota’, colonization of ‘obese microbiota’ in germ-free mice can result in a significantly greater increase in body fat. A clinical study (Ley et al., 2006) showed that the relative proportion of Bacteroides was reduced in obese people compared to lean people, and that this proportion increased with weight loss on two types of low-calorie diet. In 2010, Caporaso JG et al. (Caporaso et al., 2010) developed QIIME, which allows analysis of high-throughput community sequencing data. A 2012 clinical metagenome study (Qin et al., 2012) of the GM in T₂DM suggested that gut microbial markers may help to classify T₂DM. In 2015, Chang et al. (2015) verified Ganoderma lucidum could reduce obesity in mice by modulating the composition of GM. Xu et al. (2015) found that GQD could enrich the population of beneficial bacteria, such as Faecalibacterium, which is associated with its anti-diabetic effect. In 2017, a review article (Xu et al., 2017) provided a detailed description of the molecular mechanisms underlying the interactions between TCM and GM.

Figure 6B shows the top 20 references with the most bursts in this study. As shown in Figure 6B , most of the valuable burst references were from Nature and its sub-journals, showing the important inspiration of high-impact journals for TCM/GM research. In 2011, A review article (Han et al., 2011) mentioned that modulating GM may act as an anti-diabetic mechanism of berberine, providing a new explanation for the therapeutic effects of berberine. In 2012, two papers in Nature suggested that patients with T₂DM were characterized by the GM dysbiosis, a decrease in the abundance of some commonly butyrate-producing bacteria, and an increase in various opportunistic pathogens (Qin et al., 2012); there are functional interactions between the GM and host metabolism (Tremaroli and Bäckhed, 2012). A review article (Clemente et al., 2012) in Cell detailed the important role of human GM in host health and specified changes of GM associated with disease. In 2013, a study (Everard et al., 2013) showed that the abundance of Akkermansia muciniphila was reduced in obese and T₂DM mice, but prebiotic feeding normalized its abundance, which was associated with an improved metabolic profile. Two reviews (Shen et al., 2013; Zhao, 2013)explored the interrelationships between the GM, obesity and insulin resistance. In 2014, an article (Shin et al., 2014) showed that metformin treatment can increase Akkermansia, which may be associated with improved glucose homeostasis in diet-induced obese mice. Diet can rapidly and reproducibly alter the GM (David et al., 2014). In 2015, a study (Canfora et al., 2015) showed that GM metabolites SCFAs played an important role in control of body weight and insulin sensitivity. An experimental study (Feng et al., 2015) revealed that the GM can convert berberine into a form that can be absorbed by the gut. In 2018, a clinical study in Science suggested that dietary fiber can selectively boost GM to alleviate T₂DM. It can be seen that most of the papers come from the research on GM in modern medicine, especially the correlation study between GM and obesity, indicating that modern medicine has important enlightening significance for TCM research.

A total of 4049 keywords (1951 author’s keywords and 2118 keywords plus) were extracted from the imported papers. Figure 7A depicts the author’s keywords and keywords plus with the top 50 frequencies. Among author’s keywords, the most used keywords (exclude search terms) were “inflammation”, “ulcerative colitis”, “obesity”, “berberine”, “insulin resistance”, “type 2 diabetes”, “inflammatory bowel disease”, “irritable bowel syndrome”, “non-alcoholic fatty liver disease”, “metabolomics”, “metabolism”, “metabolites”, “pharmacokinetics”, “short-chain fatty acids”, “oxidative stress”, etc. Among keywords plus, the most used keywords (exclude search terms) were “inflammation”, “metabolism”, “metabolomics”, “expression”, “health”, “oxidative stress”, “obesity”, “chain fatty-acids”, “mechanisms”, “insulin-resistance”, “inflammatory bowel disease”, “antioxidant”, “flavonoids”, etc.

Through keywords with the most bursts detection, we can understand the development and changes of research hotspots, trends, and frontier dynamics within a certain period of time. A total of 20 burst keywords in this study were obtained, as shown in Figure 7B . The result showed that in the early days (before 2016), the effect of GM on the metabolism and biotransformation of TCM ingredients especially panax ginseng compounds K (one of the metabolites of ginsengoside) and flavonoids was the main focus. In the past few years (after 2016), the research focus was mainly on the effects of TCM on the GM of HFD-induced animal models, and the mechanism and clinical research of regulating GM imbalance to prevent and treat HFD-induced glycolipid metabolism diseases and inflammatory bowel disease (IBD). TCM/GM research had gone through the stage from pharmaceutical research to preclinical research, and finally to clinical research.

Based on the frequency of two or more keywords appearing at the same time, clustering analysis is carried out. This study treated each clustered keyword as a category, then merged it into the cluster with the highest similarity, finally classified all individuals into a category base on same color. Figure 7C shows the clustering results in TCM/GM, which can be divided into three categories.

Metabolic diseases such as obesity, T₂DM and hyperlipidemia are associated with GM dysfunction. TCM such as berberine has shown considerable efficacy in the treatment of metabolic disorders by modulating GM (Yang et al., 2021; Zhang et al., 2021). (1) Obesity and Lipid Metabolism: Human GM associated with obesity has been studied earlier (Ley et al., 2006; Tremaroli and Bäckhed, 2012; Zhao, 2013; Shin et al., 2014). Some studies showed that TCM such as Celastrol (Hua et al., 2021), Ganoderma lucidum (Chang et al., 2015) and Daesiho-Tang (Hussain et al., 2016) can attenuate HFD-induced obesity by remodeling GM to inhibit lipid absorption. Moreover, Liu et al. (2019) showed that Coix seed can be used as a prebiotic preparation to reduce body weight and prevent obesity-related metabolic disorders. Wu et al. (2021) found that Bupleurum radix extract can improve the impaired lipid metabolism in HFD-induced obese mice through regulation of GM-mediated FGF21 signaling pathway. Er-Chen Decoction has a beneficial effect on obesity, especially lipid metabolism disorder, which is related to the regulation of GM (Zhao et al., 2021). A meta-analysis showed that oral TCM preparations could improve lipid metabolism disorders in patients by regulating GM (Gong et al., 2022). (2) T₂DM and Insulin Resistance: Many herbal monomers and formulations can pass the “bacteria-mucosal immunity-inflammation-diabetes” axis to improve glucose metabolism and treat diabetes (Gao et al., 2017; Zheng et al., 2020). Cao et al. (2019) found that Jinqi-Jiangtang Tablet may improve the insulin sensitivity of T₂DM mice by improving the GM and promoting the production of SCFAs. Zheng et al. (2020) showed that Bu-Zang-Tong-Luo Decoction has a beneficial effect on diabetic hindlimb ischemia by remodeling the structure of GM. Wang et al. (2019) reported that Ophiopogon japonicus tuber polysaccharide can be used as a new type of functional food to prevent diabetes-related GM dysbiosis and metabolic disorder. Berberine can ameliorate liver injury-induced glucose and lipid metabolism disorders by alleviating ER stress in hepatocytes and regulating GM (Yang et al., 2021). A meta-analysis showed that TCM could regulate GM and improve glucose metabolism in T₂DM patients (Zheng et al., 2021). (3) NAFLD: GM is an important target for the TCM treatment of NAFLD (Ma et al., 2017). For instance, Ginsenosides can improve NAFLD through the comprehensive regulation of GM, inflammation and energy homeostasis (Liang et al., 2021). Gypenosides can modulate GM to attenuate disease progression in mice with NAFLD (Huang et al., 2019). Sheng-Jiang Powder (Li et al., 2020) and GQD (Guo et al., 2018) can alleviate HFD-induced steatohepatitis and improve NAFLD by regulating GM. A review detailed the significance of GM in the pathogenesis of NAFLD and the current status of TCM treatment of NAFLD by regulating GM (Li and Hu, 2020).

Lower gastrointestinal diseases are also a hotspot in TCM/GM research, TCM can regulate GM to treat IBD (mainly UC), irritable bowel syndrome (IBS) and Colorectal cancer (CRC) (1). UC: GM dysbiosis is closely related to UC, and TCM can alter the composition of GM to treat UC by enriching beneficial bacteria or SCFA-producing bacteria and reducing pathogenic bacteria (Feng et al., 2022). For example, Rhubarb Peony Decoction can restore Th17/Treg balance by regulating GM to improve UC (Luo et al., 2019). Li-Zhong Decoction can improve UC by regulating GM and its metabolites. The combined treatment of probiotics and TCM can inhibit intestinal inflammation and reduce adverse events for UC (Hu et al., 2022). (2) IBS: Li et al. (2018) showed that Tong-Xie-Yao-Fang could reduce colonic serotonin levels and alleviate the symptoms of IBS by beneficially affecting GM. Chen et al. (2017) found that Wu-Ji-Wan may relieve IBS by regulating the GM and stabilizing the intestinal mucosal barrier. (3) CRC: Lv et al. (2019) showed that GQD can enhance the efficacy of PD-1 in CRC by remodeling the GM and tumor microenvironment. A further study (Li et al., 2020) showed that GQD can modulate the GM to enhance the immunity of CRC patients and protect the intestinal barrier function. Sui et al. (2020) found that YYFZBJS ameliorated CRC progression in mice by remodeling GM and inhibiting regulatory T cell generation.

GM dysbiosis and altered metabolites can result in the promotion of endotoxin-mediated promotion of metabolic inflammation, destruction of the intestinal mucosal barrier, and decreased host anti-oxidative stress capacity, which are the main reasons for the link between GM and host diseases (Everard et al., 2013). However, excitingly, the interactions between TCM and GM may break this link by intervening in inflammation, metabolism, oxidative stress, and IMB. Many review articles (Xu et al., 2017; Feng et al., 2019; An et al., 2019; Lin et al., 2019; Zhang et al., 2019; Zhang et al., 2020; Gong et al., 2020) had outlined the interactions between TCM and GM ( Table 7 ), including: (a) TCM can regulate the composition of GM and restore the balance of GM, such as increasing anti-inflammatory and SCFAs-producing bacteria and reducing pathogenic bacteria; (b) TCM can regulate the metabolism of GM by increasing the level of SCFAs, regulating bile acid (BA) metabolism, reducing the production of trimethylamine N-oxide (TMAO) and the release of inflammatory factors (Li et al., 2021); (c) GM can transform TCM compounds into metabolites and components with different bioavailability and bioactivity/toxicity and in turn improve the composition of GM; (d) GM can mediate interactions between multiple chemicals in TCM.

The specific mechanism of TCM regulating GM to treat diseases is complex, specifically, including the following aspects in our current research (Wu et al., 2019): (1) Anti-inflammatory: Inflammation regulation is the key to the efficacy of TCM/GM interaction. TCM can regulate the composition of GM and reduce inflammation caused by GM dysbiosis. For instance, berberine can modulate GM and inhibit the activation of TLR4 signaling pathway and the release of NLRP3 inflammasome and its cytokines (Zhao et al., 2022). GM plays an important role in anti-inflammatory function of berberine and luteolin (Cao et al., 2021; Franza et al., 2021). Kai-Xin-San can suppress the neuronal inflammation by regulating GM (Cao et al., 2020). Bofutsushosan can alter the GM by increasing Akkermansia muciniphila, and help reduce diet-induced inflammation (Fujisaka et al., 2020). Furthermore, the metabolism of GM also plays an important role in the anti-inflammatory effect of TCM (Piwowarski et al., 2014; Jang et al., 2019). (2) Anti-oxidative stress: There is growing evidence that some bacteria, such as Lactobacillus, Bifidobacterium and Akkermansia, and the bacterial metabolite butyrate have potential anti-oxidant properties, and as mentioned above, TCM can promote their increase. In addition, probiotics can reduce the level of intestinal oxidative stress through their own antioxidant enzymes and anti-oxidant metabolites, and some TCM such as mushroom polysaccharides from Ganoderma lucidum and Poria cocos (Khan et al., 2018), Fructooligosaccharides from Morinda officinalis (Chen et al., 2017) and Astragalus polysaccharides (Li et al., 2009) have probiotic-like effects and can play this function. (3) Protecting the intestinal barrier: The intestinal mucosal barrier (IMB) is the first line of defense against the invasion of commensal bacteria and pathogenic microorganisms. Under the influence of HFD, inflammatory stimulation, oxidative stress and other factors, the structure and function of IMB may be damaged, which may lead to intestinal injury (leaky-gut). Defects in IMB function are important factors leading to the development of diseases such as IBD. Some TCM can improve the IMB function by adjusting GM (Cao et al., 2019). For instance, Eugenol may enhance the IMB by increasing the thickness of the inner mucus layer through microbial stimulation, thereby preventing invading pathogens and diseases (Wlodarska et al., 2015). Scutellaria-Coptis (Zhang et al., 2020), Ginsenosides (Liang et al., 2021) and GQD (Li et al., 2020) can alleviate IMB damage by inhibiting inflammation and regulating GM.

TCM/GM-related metabolites are key factors in the curative effect of herbal medicines (Wang et al., 2019). Metabolomic analysis is an ideal method to identify changes in TCM/GM-related metabolites (Shen et al., 2018). The interactions of TCM and GM can lead to the increase or decrease of certain metabolites and the production of new metabolites or the disappearance of certain metabolites (Feng et al., 2019). The metabolites mainly include three categories (Feng et al., 2018): (a) metabolites that are transformed from TCM by the GM, such as compound K and baicalein; (b) metabolites that are secreted by the host and modified by GM, such as secondary bile acids; (c) metabolites that are synthesized by GM de novo, such as SCFAs and polysaccharide A.

Herbal compounds can be transformed by the GM (type a metabolites) or metabolized into other types of metabolites in a new scaffold (type c metabolites). On the one hand, GM is involved in the metabolism and biotransformation of TCM components such as flavonoids and ginsenosides by producing specific enzymes, such as reductase and hydrolase (Dey, 2019; Zhang et al., 2020; Xie et al., 2020). TCM-related metabolites mediated by GM can have better bioavailability and bioactivity than their parent compounds. For example, human GM can efficiently metabolize baicalin with minor anti-tumor effect to baicalein with potent anti-tumor effect (Wang et al., 2015). Some metabolites of herbal ingredients influenced by GM were demonstrated to be more cytotoxic to tumor cells than non-metabolites (Kim et al., 2008) and have higher anticomplementary and antimicrobial activity (Xing et al., 2014). The GM can convert berberine to a more easily absorbed but inactive metabolite dihydroberberine through enzymatic catalysis, which is then oxidized back to berberine and incorporated into the blood to exert pharmacological activity (Feng et al., 2015). In fact, under fermentation by the GM, TCM can be metabolized into various metabolites with a wide range of bioactivities to affect its efficacy and toxicity (Piwowarski et al., 2014; Lin et al., 2021). On the other hand, GM-related metabolites influenced by TCM can have a wide range of effects on the therapeutic or side effects of TCM. SCFAs are the major de novo metabolites associated with TCM and the most well-studied in TCM/GM over the past decade (Feng et al., 2018). SCFAs can regulate gut hormone production, gut integrity, energy homeostasis, appetite, and immune function (Canfora et al., 2015). The therapeutic effect of TCM can be partially achieved by affecting SCFAs (Zhang et al., 2012; Zhang et al., 2021). For example, after using Scutellariae radix, Coptidis Rhizoma and their combination, SCFAs-producing bacteria were significantly enriched in T₂DM rats, while secondary bile acid-producing bacteria were significantly decreased (Xiao et al., 2020). Xiexin Tang (Wei et al., 2018; Zhang et al., 2021) and HLJDD (Chen et al., 2018) can significantly ameliorate the GM of T₂DM rats, increasing the abundance of SCFAs-producing and anti-inflammatory bacteria. Moreover, berberine (Wang et al., 2017), Poria cocos (Sun et al., 2019) and Indigo Naturalis (Sun et al., 2020) can increase the abundance of butyrate-producing bacteria and promote the production of butyrate (a SCFA fermented by the GM), which may explain their therapeutic efficacy.

Notably, low oral bioavailability and bioactivity are a perplexing problem for some TCM. GM and its metabolism can directly or indirectly affect the biotransformation of TCM and reconcile the oral bioavailability conundrum of TCM (Chen et al., 2016; Xu et al., 2017; Zhang et al., 2020). This biotransformation may help explain the large interindividual variability in responses to TCM, as the composition of GM varies among individuals. Bioavailability is closely related to the blood concentration of TCM, which can directly reflect the efficacy and toxicity of most drugs and is regarded as an important factor in the evaluation of efficacy and safety.

A study (Kim et al., 2008) showed the GM may activate the pharmacological effects of TCM, and is a biocatalytic converter that converts herbal components into bioactive compounds. GM can induce comprehensive metabolism of herbal components and enhance the bioactivity of TCM such as ginsenosides (Wang et al., 2011). TCM is mainly taken orally. After the components of TCM are absorbed into the blood through the gastrointestinal tract, they are mainly metabolized in the liver, and finally generate a variety of metabolites. However, studies have shown that the bioavailability of most compounds in TCM is very low (Zheng et al., 2020). For example, the bioavailability of ginsenosides is typically around 0.1%–0.5% by oral administration (Liu et al., 2009) and the oral bioavailability of berberine is less than 1% (Chen et al., 2011). Flavonoids are key bioactive substances in herbal medicines with pharmacological potential, but their bioavailability is also low (Dey, 2019). Recent studies have shown that TCM ingredients inevitably come into contact with microorganisms in the gastrointestinal tract during oral administration, especially saponins with larger molecular weight, which are usually poorly absorbed in the intestinal tract, have low bioavailability and a relatively long retention time in the intestinal tract. Longer, more susceptible to the influence of GM. Under the action of GM, the components of TCM will undergo a series of structural changes, and the resulting transformation products may have better bioavailability or stronger biological activity than the original components (Kim et al., 2008; Feng et al., 2015; Dey, 2019). Furthermore, the potential of TCM as a therapeutic agent may not only depend on its bioavailability, but its medicinal value may also stem from its positive effects on GM-mediated gastrointestinal health (Lopresti, 2018).