4.1 General information
In this study, we compiled an extensive corpus comprising 751 documents spanning the period from 2004 to 2024. The discerned pattern indicates a consistent upward trend in the quantity of documents investigating the interaction between TCM regulating gut microbiota and diabetes, signifying a progressive increase from 2004 to 2022. Surprisingly, the number of publications starts to decrease in 2023 compared to 2022. There are four possible reasons for this result: 1) Complexity of Research: The composition of gut microbiota is highly complex and influenced by individual differences, diet, environment, and other factors (Leshem et al., 2020; Kurilshikov et al., 2021). Establishing a clear cause-and-effect relationship in such a multifaceted context is challenging, and many findings are difficult to replicate or verify. 2) Technical Limitations: Although high-throughput sequencing technology has advanced the study of gut microbiota, analyzing and interpreting the data remains a significant challenge (Gao et al., 2021; Wensel et al., 2022). Current technological methods may not fully capture the dynamic changes and complex interactions within the intestinal flora. 3) Reproducibility of Results: Many early studies reported associations between gut microbiota and various diseases, but subsequent research often found that these results lacked reproducibility, raising concerns about the reliability of the initial studies (Islam et al., 2022). 4) Difficulties in Clinical Application: Despite the theoretical potential of intestinal flora research, translating these findings into practical clinical applications is challenging. Developing treatments based on gut microbiota faces numerous technical and regulatory obstacles. Overcoming these difficulties will help to increase researchers’ interest in the field.
In the domain of research on TCM regulating gut microbiota in the treatment of diabetes, China has emerged as a leading nation, producing the highest volume of scholarly publications. This trend reflects the deep-rooted historical significance of TCM in China, which attracts considerable attention from Chinese researchers. The extensive collection of 751 documents was disseminated across 288 journals, with significant contributions from reputable publications such as Frontiers in Pharmacology, Journal of Ethnopharmacology, and Food and Function. Notably, the Journal of Ethnopharmacology distinguished itself as a major focal point, featuring a substantial number of published articles and receiving a considerable volume of citations. This prominence underscores the Journal of Ethnopharmacology as a crucial publication in the field of TCM regulating gut microbiota in the treatment of diabetes, affirming its role as a primary channel for disseminating research findings in this area.
4.2 Hotspots and development trends
Through a comprehensive analysis encompassing literature clustering, keyword frequency analysis, keyword clustering, and theme evolution, we have identified the potential research hotspots in the treatment of diabetes through the modulation of gut microbiota by TCM. The findings indicate that the research frontiers and hotspots in this field are primarily concentrated in three areas. Firstly, the active constituents of TCM, such as flavonoids and polyphenols, which treat diabetes by modulating the gut microbiota. Secondly, the mechanisms by which TCM modulates the gut to treat diabetes, including anti-inflammatory and antioxidant effects. Thirdly, the targeting of specific bacterial populations within the gut microbiota by TCM to treat diabetes.
4.2.1 The active constituents of TCM treat diabetes by modulating the gut microbiota
Through our analysis, we found that active constituents of TCM such as flavonoids and polyphenols play significant roles in regulating gut microbiota to treat diabetes. Flavonoid compounds are widely present in many TCM materials, demonstrating various bioactivities in preclinical studies (Almeida et al., 2022; Song et al., 2020; Bharti et al., 2021). The flavonoids can promote the growth of beneficial bacteria like Bifidobacterium and Lactobacillus (Xiong et al., 2023). These bacteria improve gut barrier function and enhance insulin sensitivity by producing short-chain fatty acids (SCFAs) such as acetate and butyrate (González Hernández et al., 2019). Consequently, they help regulate blood glucose levels. Notably, flavonoids can inhibit harmful bacteria associated with metabolic disorders, such as certain Gram-negative bacteria (Górniak et al., 2019). This inhibition reduces gut inflammation and insulin resistance (Han et al., 2022). These findings offer new insights for the prevention and treatment of diabetes.
Polyphenolic compounds, such as catechins in green tea and proanthocyanidins in grape seeds, also exhibit significant effects in modulating gut microbiota (Wu et al., 2021; Du et al., 2021). Through their potent antioxidant and anti-inflammatory properties, polyphenols reduce oxidative stress and inflammatory responses in the gut, protecting gut barrier function (Truong and Jeong, 2022; Sheng et al., 2020). Specifically, polyphenols can enhance the activity of antioxidant enzymes (e.g., superoxide dismutase and glutathione peroxidase) to scavenge free radicals, reducing oxidative damage to gut cells (Rudrapal et al., 2022). Furthermore, polyphenols can modulate the composition of gut microbiota, increasing the proportion of beneficial bacteria and improving the gut microenvironment, thereby exerting positive effects on diabetes (Li et al., 2018).
It should be noted that there are some shortcomings in the research field regarding the treatment of diabetes through the regulation of gut microbiota by the active ingredients of TCM. (1) Insufficient depth of mechanism studies: Although studies have shown that flavonoids and polyphenols can play an anti-diabetic role by regulating intestinal flora, most of this research has been conducted on animal models or in vitro experiments. The specific molecular mechanisms, particularly those in the human body, still need further exploration. (2) Composition complexity: TCM often contain a variety of active ingredients, which may have synergistic or antagonistic effects. Most existing studies focus on the role of single components, with few addressing the interactions among complex components. This gap limits our understanding of the overall efficacy of TCM. To bridge this gap, network pharmacology combined with multi-omics technologies can be employed to construct component-target-pathway network models, providing a more comprehensive understanding of the multi-component, multi-target action mechanisms. Through this approach, key nodes of specific components within the network can be identified, revealing their potential synergistic or antagonistic effects, and predicting the interactions among multiple constituents (Gu et al., 2024; Bi et al., 2024). Additionally, machine learning and artificial intelligence-assisted analyses offer promising tools for exploring potential synergistic patterns and mechanisms from high-dimensional data. In particular, deep learning can help analyze complex datasets and uncover novel interaction patterns among components, providing fresh perspectives on the study of composition complexity (Li et al., 2022). (3) Dose and safety: The effective dose and safety of TCM active ingredients have not been fully defined. In particular, the long-term effects of TCM active ingredients on gut microbiota and overall metabolic health require further verification through clinical studies.
4.2.2 Mechanism of TCM regulating gut microbiota treatment of diabetes
Through the analysis of the literature in this field, we found that anti-inflammatory and antioxidant effects are the most frequently mentioned mechanisms by which TCM regulates gut microbiota in the treatment of diabetes. It is well-established that intestinal inflammation and oxidative stress play key roles in the onset and development of diabetes and its complications (Malik et al., 2020). However, many molecular mechanisms related to the gut microbiome and diabetes have been extensively studied. For example, Sirtuin 1 protects high-fat diet-fed mice from metabolic disorders by modulating Firmicutes and Bacteroidetes (De Vadder et al., 2014). Mice lacking sirtuin 1 develop adipose tissue hypertrophy, fatty liver, and insulin resistance. Zinc transporter 8 (ZnT8) in pancreatic B-cells is involved in diabetes development. ZnT8 deficiency leads to fat accumulation and glucose intolerance by altering gut microbiota, increasing T2DM and obesity risk (Wan et al., 2017; Mao et al., 2019). Fexaramine, an FXR agonist, improves insulin sensitivity and glucose metabolism by activating the TGR5/GLP-1 pathway and increasing Acetatifactor and Bacteroides (Pathak et al., 2018). In addition, the intestinal barrier plays a key role, and its dysfunction leads to chronic inflammation (Scheithauer et al., 2020). Hyperglycemia increases intestinal permeability by affecting junction integrity (Thaiss et al., 2018). GLUT2 deficiency maintains barrier integrity, suggesting it as a target for reducing inflammation (Xu et al., 2020). Gut microbiota also affects intestinal permeability via GLP-2 secretion. Faecalibacterium prausnitzii’s MAM repairs the intestinal barrier, and A. muciniphila improves metabolic health by restoring mucus thickness and enhancing tight junction protein expression (Zhang et al., 2020).
In fact, we have not summarized all the molecular mechanisms related to the gut microbiome and diabetes treatment. But it can be seen that the molecular mechanisms associated with the gut microbiota are definitely not limited to antioxidants and anti-inflammatory. They also include improving insulin resistance (Chen et al., 2021), regulating intestinal barrier function (Chen et al., 2017), influencing the production of SCFAs (Zhao et al., 2020), modulating host immune responses (Zhou et al., 2023), regulating energy metabolism (Xia et al., 2021), inhibiting the proliferation of harmful bacteria, and promoting the colonization of beneficial microbiota (Yang et al., 2021), among various other mechanisms. Therefore, in studies on the mechanism of TCM in regulating gut microbiota treatment of diabetes, researchers should strive to explore a wide range of molecular mechanisms. Overemphasis on anti-inflammatory or antioxidant mechanisms may limit the development of this research field.
In addition, the gut microbiota, as a critical metabolic regulatory center, exhibits complex and multi-layered dynamic interactions in the treatment of diabetes with TCM formulations and antidiabetic drugs. The metabolism of active components in TCM, such as flavonoids, polyphenols, and saponins, relies heavily on enzymatic reactions mediated by gut microbiota (Zhou et al., 2024). These reactions, including hydrolysis, reduction, and demethylation, can convert parent compounds into metabolites with higher bioactivity, thereby enhancing their pharmacological effects (Pant et al., 2023). However, dysbiosis of the gut microbiota may hinder this metabolic transformation, reducing the efficacy of TCM and potentially generating harmful metabolites (Gong et al., 2020). Notably, antidiabetic drugs like metformin alter the composition of the gut microbiota, directly regulating metabolic pathways and indirectly influencing the bioavailability and pharmacological activity of TCM components (Zhang et al., 2021). For example, metformin increases the abundance of short-chain fatty acid-producing bacteria, which improves insulin sensitivity (Mueller et al., 2021). This microbiota change may synergistically enhance the anti-inflammatory and hypoglycemic effects of certain TCM components. However, such complex synergy can be disrupted by competition within metabolic pathways. Specifically, when TCM components and antidiabetic drugs share hepatic enzymes (e.g., the CYP450 family) or intestinal transport proteins, significant pharmacokinetic and pharmacodynamic changes may arise (Xu et al., 2021b). Importantly, drug interactions mediated by gut microbiota involve multiple potential mechanisms, including metabolic synergy, regulation of signaling pathways, and competitive metabolism (Wan and Zuo, 2022; Li et al., 2019). For instance, gut microbiota may produce indole derivatives or secondary bile acids that modulate the pharmacological activity of TCM components by influencing the activation of critical receptors such as FXR and TGR5 (Lin et al., 2021; Xu et al., 2024). Meanwhile, the bioaccumulation of antidiabetic drugs in the gut microbiota warrants close attention. Studies have shown that commonly used antidiabetic agents, such as gliclazide, can undergo bioaccumulation within the microbiota, potentially influencing drug metabolism and pharmacokinetics (Đanić et al., 2023). This may affect the pharmacological activity, therapeutic outcomes, and adverse reactions of TCM. Additionally, interactions between the gut microbiota’s barrier function or immune system may further modulate the pharmacodynamics and pharmacokinetics of these drugs (Tsunoda et al., 2021). A comprehensive understanding of these mechanisms will help elucidate the potential benefits and risks of combining TCM formulations with antidiabetic drugs, thereby providing a theoretical basis for their clinical application.
4.2.3 TCM regulates specific gut bacteria in treating diabetes
Numerous studies have demonstrated that TCM can improve diabetes by modulating specific bacterial populations within the gut microbiota. Wei et al. showed that ginsenoside Rg5 reduces blood glucose levels in diabetic db/db mice. Subsequent research indicated that ginsenoside Rg5 significantly increased the abundance of Bacteroidetes and Proteobacteria, while decreasing Firmicutes and Verrucomicrobia in the gut of diabetic db/db mice (Wei et al., 2020). Aloin altered the gut bacterial community by increasing Bacteroidota prevalence and reducing the diversity of Firmicutes, Proteobacteria, and Actinobacteriota. Consequently, this intervention mitigated weight loss, lowered fasting blood glucose levels and hemoglobin A1c, enhanced glucose tolerance, and increased fasting serum insulin in T2DM rats (Zhong et al., 2022). Additionally, licorice extract regulates intestinal microbiota balance by increasing Akkermansia, Alloprevotella, and Bacteroides content, while decreasing Lachnospiraceae content, effectively improving diabetes progression (Zhang et al., 2022b).
Despite numerous research achievements in this field, there remain underlying issues that must be addressed. Firstly, whether TCM can accurately and consistently target specific bacterial populations to avoid adverse effects on the overall gut microbiota ecology requires further investigation. Current research primarily focuses on short-term intervention effects, with long-term impacts remaining unclear. Secondly, the gut microbiota is a complex ecosystem where interactions among different microbial groups exist. TCM’s regulation of specific bacterial populations may trigger reactions from other microbial groups, thereby influencing overall therapeutic efficacy. Currently, research on these complex interactions is limited. Furthermore, despite demonstrating potential in regulating gut microbiota in laboratory and animal models, translating TCM into practical clinical therapies faces challenges such as individual differences in drug metabolism and bioavailability.