Diabetic foot ulcers (DFU) are one of the common and severe complications in diabetic patients, characterized by high incidence and morbidity rates. DFU not only severely reduces patients’ quality of life but also increases the medical economic burden. Statistical data show that approximately 15%–25% of diabetic patients worldwide will experience foot ulcer problems, and these patients have a significantly increased risk of amputation (Jifar et al., 2021). The gut-skin axis refers to the bidirectional communication network linking intestinal microbiota, immune responses, and skin homeostasis. Dysregulation of this axis—characterized by gut microbial imbalance, increased intestinal permeability, systemic inflammation, and impaired skin barrier function—contributes to DFU pathogenesis by exacerbating tissue damage and delaying wound healing (Mahmud et al., 2022). Recent studies have identified the gut-skin axis as a critical factor in the occurrence and progression of DFU. Dysregulation of the gut microbiota, enhanced inflammatory responses, and diminished skin barrier function are all closely associated with the progression of foot ulcers (Ye et al., 2022; Liu et al., 2022). Special traditional Chinese medicine preparations (STCMP) and acupuncture, as conventional therapeutic approaches, have demonstrated potential in modulating gut microbiota, alleviating inflammation, and promoting skin healing, thereby providing new insights and strategies for DFU intervention (Dai et al., 2022; Liang et al., 2024). In this article, special traditional Chinese medicine preparations include single botanical drugs and their extracts, metabolites, and formulas composed of multiple botanical drugs. Specific dosage forms include decoctions, pills, powders, and ointments.

In the treatment of DFU, the application of TCM has gained increasing attention. Studies have demonstrated that botanical drugs such as Astragalus membranaceus Bunge (Milkvetch root, Fabaceae; official drug name: Huangqi) and Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. et Mey. (Chinese foxglove root, Orobanchaceae; official drug name: Dihuang) can promote blood circulation, improve microcirculation, and enhance immune function, effectively alleviating clinical symptoms in DFU patients (Fan S. et al., 2021; Zhang Z. et al., 2019). In the treatment of DFU, traditional Chinese medicine (TCM) has built a bridge between traditional pharmacology and modern pharmacology. In a multicenter, randomized, positive controlled clinical trial, Sun et al. found that Shengji Ointment combined with bromelain could significantly promote the formation of tendon granulation in diabetes foot ulcers. The treatment group not only had a higher coverage of granulation tissue than the control group, but also significantly better wound healing rate, granulation formation time, Maryland foot function score, necrotic tendon tissue debridement time, and granulation tissue score than the control group (Sun X. et al., 2024). For neuropathy, acupuncture can improve local blood flow and nerve function by stimulating specific points, thus improving the neuropathic pain of diabetes patients, which also shows that acupuncture is effective as an auxiliary treatment for diabetes feet (Heidari et al., 2023; Lee et al., 2020). On the other hand, acupuncture may also influence the pathological process of DFU by modulating the composition of gut microbiota and improving metabolic status. Existing research has shown that acupuncture significantly improves microcirculation in diabetic patients, providing a theoretical basis for its application in DFU treatment (Valentini et al., 2024).

This review aims to investigate the mechanisms of action of STCMP and acupuncture in modulating the gut-skin axis and its application strategies in the intervention of diabetic foot ulcers. By analyzing relevant literature, we hope to provide new perspectives for the comprehensive treatment of DFU, integrating the advantages of modern medicine and TCM to promote patient recovery and quality of life improvement (Bragg et al., 2024; Huang et al., 2025).

DFU are caused by various risk factors, such as peripheral neuropathy, peripheral vascular disease, foot deformities, arterial insufficiency, metabolic disorders, dysbiosis, inflammation, trauma, and reduced anti-infective capacity (Lao et al., 2019). Following DFU onset, wounds often exhibit prolonged non-healing, and the underlying pathogenesis is illustrated in Figure 1. Existing studies have shown that the development of DFU is closely associated with metabolic disorders, particularly the hyperglycemic state caused by poor glycemic control (Wang KX. et al., 2024). Hyperglycemia induces multiple metabolic abnormalities, including insulin resistance, lipid metabolism disorders, and protein synthesis dysfunction, which can all impair the normal function of microcirculation (Wang KX. et al., 2024; Raja et al., 2023). Research indicates that microcirculatory dysfunction in diabetic patients is a critical factor contributing to DFU. Damage to microvessels leads to ischemia and hypoxia in foot tissues, thereby compromising skin healing capacity and triggering ulcer formation (Liang et al., 2024). Additionally, microcirculatory dysfunction exacerbates inflammatory responses, further worsening tissue damage (Ye et al., 2022). Therefore, improving microcirculatory function and restoring blood supply to the feet represent one of the key strategies in DFU treatment.

Changes in the gut microbiota are also closely associated with the immune function of diabetic patients, as intestinal microbes can influence diabetic complications by regulating immune responses (Yuan et al., 2022). The immune system of diabetic patients is often suppressed, a change that renders them more susceptible to infections and impairs healing after infection (Fan S. et al., 2021). Studies have found that leukocyte function is weakened in diabetic patients, particularly the functions of macrophages and T cells, leading to reduced resistance to infection (Sun S. et al., 2024). Additionally, diabetes induces a state of chronic low-grade inflammation, which further suppresses immune responses and affects the wound healing process (Fu et al., 2022). Therefore, enhancing the immune function of diabetic patients and improving their resistance to infection represent critical strategies in the prevention and treatment of DFU.

Gut microbiota dysregulation can lead to increased metabolic endotoxins, thereby triggering systemic inflammatory responses, which are recognized as one of the key pathological mechanisms of DFU (Zhang K. et al., 2024). Diabetic patients often experience chronic low-grade inflammation, a state that delays wound healing and increases the risk of complications (Huang et al., 2025). Studies indicate that the inflammatory response in DFU is primarily driven by abnormal activation of macrophages and other immune cells, leading to excessive release of inflammatory mediators that impair wound healing (Lao et al., 2019). Additionally, inflammation may induce cell apoptosis and tissue damage, further exacerbating the condition. Therefore, controlling inflammatory responses is regarded as a critical strategy for improving DFU healing, and related clinical studies are continuously exploring effective anti-inflammatory treatment strategies (Wang KX. et al., 2024).

The gut microbiota is composed of diverse microorganisms, including bacteria, fungi, and viruses. Bacteria are the most dominant component of the gut microbiota, with common phyla including Firmicutes, Bacteroidetes, and Actinobacteria. Different microbial species perform various metabolic functions in the intestine, such as fermenting undigested food residues, synthesizing short-chain fatty acids (SCFAs), and producing vitamins (Luo et al., 2024). SCFAs like acetic acid, propionic acid, and butyric acid play critical roles in anti-inflammation, immune regulation, and maintenance of intestinal barrier function (Patel et al., 2022). Additionally, gut microbiota is involved in drug metabolism, influencing the efficacy and toxicity of medications (Wang J. et al., 2024). Therefore, the composition and metabolic functions of the gut microbiota are vital for host health.

The gut microbiota exhibits dynamic characteristics, with its composition and function influenced by multiple factors such as diet, environment, age, and disease state. Studies have shown that the gut microbiota undergoes significant changes throughout an individual’s lifecycle, particularly during infancy and the stage of introducing solid foods, where microbial diversity and composition shift remarkably (Du et al., 2023). Additionally, the stability of the gut microbiota is a critical research area. A healthy gut microbiota typically demonstrates high stability, capable of resisting external disturbances such as antibiotic use or dietary changes. However, dysregulation of the gut microbiota may lead to the development of various diseases, including diabetes, obesity, and intestinal inflammation (Zhang K. et al., 2024; Du et al., 2023; Cai et al., 2024). Therefore, a deep understanding of the dynamic changes and stability of the gut microbiota is of great significance for developing new intervention strategies and therapeutic approaches.

The microbial profiles of DFU patients differ significantly from those of healthy individuals. Studies have shown that the wound microbiota in DFU patients typically exhibits higher abundance of Gram-negative bacteria such as Klebsiella and Pseudomonas, which are closely associated with wound infection and poor healing (Díaz-Velis et al., 2023). Additionally, the microbiota of DFU patients often features reduced diversity, and this loss of diversity is negatively correlated with the severity of foot ulcers (Li YY. et al., 2024). In one study, the gut microbiota of diabetic patients demonstrated significant changes in specific genera compared to healthy controls, particularly a reduction in beneficial bacteria and an increase in pathogenic bacteria, which may be an important factor contributing to DFU development (Jnana et al., 2020). Collect wound samples from DFU patients, divided into three stages: inflammatory phase, proliferative phase, and remodeling phase. Analysis shows that Peptoniphilus, Lactobacillus, Prevotella, Veillonella, Dialister, Streptococcus, and Ruminococcus were the signature wound microbiota for the inflammatory stage; Anaerococcus, Ralstonia, Actinomyces, and Akkermansia were important species for the proliferation stage; and the crucial genera for the remodeling stage were Enterobacter, Pseudomonas, Sondgrassella, Bifidobacterium, and Faecalibacterium (Li Y. et al., 2024). In another animal experiment, Fufang-zhenzhu-tiaozhi formula treatment increased the content of short chain fatty acids (propionic acid and butyric acid), and inhibited the intestinal flora disorder caused by diabetes, including the growth of Weissella, Enterococcus and Akkermansia (Lan et al., 2023). These microbial characteristics not only influence the progression of diabetes but also affect the wound healing process. Therefore, microbiota-targeted intervention strategies may hold significant clinical implications in DFU management.

Studies have shown that gut microbiota dysregulation can influence the progression of diabetes through multiple mechanisms (Deng et al., 2022; Zaky et al., 2021; Liu et al., 2020). First, changes in the gut microbiota lead to a decline in intestinal barrier function and increased intestinal permeability, thereby triggering systemic inflammatory responses (Sechovcová et al., 2024). For example, the proliferation of certain harmful bacteria causes the release of endotoxins, which in turn initiates systemic inflammation—a process recognized as a key inducer of diabetes and its complications (Li et al., 2023). Second, microbial metabolites such as SCFAs play critical roles in regulating immune responses and inflammation. Reduced levels of SCFAs may exacerbate metabolic disorders and inflammation in diabetic patients (Huang et al., 2025). Additionally, gut microbiota dysregulation is associated with endocrine disorders, affecting insulin secretion and action, thus worsening diabetic conditions (Wang J. et al., 2024; Du et al., 2023).

SCFAs are a crucial component of gut microbiota metabolites. Studies have demonstrated that SCFAs play a key role in regulating immune and inflammatory responses, particularly in the progression of DFU. SCFAs inhibit inflammatory reactions by activating G protein-coupled receptors (such as GPR41 and GPR43), reducing the release of pro-inflammatory cytokines and alleviating diabetes-related chronic inflammation (Sechovcová et al., 2024). In diabetic patients, SCFA levels often decrease, which is closely associated with gut microbiota dysregulation and thereby potentially contributes to the occurrence and development of DFU (Li YY. et al., 2024). Additionally, SCFAs enhance intestinal barrier function, preventing endotoxins (such as lipopolysaccharides) from entering the bloodstream and reducing systemic inflammation—a process of significant importance for DFU prevention and treatment (Huang et al., 2025).

In addition to SCFAs, other metabolites such as bile acids and amino acids also play significant roles in the progression of DFU. Bile acids not only play a critical role in fat digestion but also participate in the regulation of inflammatory responses by modulating gut microbiota and influencing metabolic pathways (Dos Santos and Galiè, 2024; Asadi et al., 2022). Studies have found that abnormal bile acid metabolism in diabetic patients is closely associated with the development of DFU, and changes in bile acids may affect the composition of gut microbiota, thereby exacerbating inflammatory reactions (Chen et al., 2024). Furthermore, alterations in amino acid metabolism are also linked to DFU progression. Levels of certain amino acids (such as glutamate and arginine) are significantly elevated in diabetic patients, which is closely correlated with the inflammatory state and tissue damage in DFU (Sutanto et al., 2022). Therefore, regulating the levels of these metabolites may emerge as a new strategy for DFU intervention, alleviating the occurrence and progression of foot ulcers by improving metabolic status (Wang and Wang, 2024).

TCM is a pivotal component of China’s traditional medical heritage, with its theoretical framework grounded in the “Yin-Yang and Five Elements” doctrine, emphasizing the harmonious relationship between the human body and the natural environment. TCM posits that health is a state of balanced Yin and Yang and unobstructed flow of Qi (vital energy) and blood, while diseases arise from the imbalance of Yin and Yang and blockage of Qi and blood circulation. Through syndrome differentiation and personalized treatment, TCM employs STCMP, acupuncture, and other modalities to regulate bodily functions and restore health. In recent years, with the deepening of TCM research, growing evidence indicates that The ability of STCMP (e.g., Jinhuang Powder) and acupuncture can effectively control blood glucose levels and alleviate the incidence of diabetic complications through multi-mechanistic actions, such as modulating gut microbiota, improving metabolism, and enhancing immune function (Chen and Wang, 2021; Feng et al., 2024; Zhang B. et al., 2019).

In a RCT, patients in the acupuncture treatment group can significantly enhance the treatment effect without side effects (Xia et al., 2010). In a randomized controlled trial of DFU, the control group received gentamicin alone, while the treatment group received external application of Jinhuang powder combined with gentamicin. After 6 weeks of treatment, compared with the control group, the average wound healing time of the treatment group was shortened by nearly 7 days, and the effective rate reached 92% (Xiaobin Cui and Zhenli, 2011). In Liu et al.'s study (Liu, 2024), the effective rate and average wound healing time of the combination of Ruyi Jinhuang powder and Western medicine in the treatment of DFU were significantly better than those of the control group, which is consistent with the previous research results of Cui et al. Acupuncture, for instance, requires no complex equipment and can be administered by primary care providers after standardized training, ensuring wide applicability. Similarly, TCM formulas can often be locally prepared using readily available botanical drugs, reducing reliance on complex supply chains.

STCMP and acupuncture belong to one of Chinese medicine treatment methods.Despite the promising potential of STCMP and acupuncture in the treatment of DFU, their clinical application still faces numerous challenges. First, the lack of unified treatment standards and guidelines leaves clinicians without clear directions or evidence-based protocols when applying STCMP and acupuncture (Liu et al., 2023). Second, there is varied patient acceptance of STCMP and acupuncture, as some patients may remain skeptical of traditional therapies, affecting treatment compliance. Additionally, the mastery of professional knowledge and skills regarding STCMP and acupuncture is uneven across clinical settings, with some medical institutions lacking relevant training and resources, which restricts the promotion and application of these treatments (Selçuk et al., 2022). Finally, data on the efficacy and safety of STCMP and acupuncture remain insufficient, causing clinicians to hesitate when selecting treatment protocols due to the lack of robust evidence. Therefore, conducting large-scale, multi-center RCTs is of utmost importance. Such studies would not only validate the efficacy and safety of STCMP but also provide a scientific basis for its integration into modern medical practice.

Existing studies on the use of STCMP and acupuncture in DFU treatment, while providing preliminary evidence, have numerous methodological limitations. First, many studies have small sample sizes, calling into question the reliability of their results. For example, although some literature mentions the effects of acupuncture on diabetic peripheral neuropathy and shows certain efficacy, the insufficient sample size makes it difficult to generalize findings to a broader patient population (Meyer-Hamme et al., 2021); while (Yanan Zhao et al., 2017) demonstrated that SYD activates the Wnt/β-catenin pathway in diabetic ulcer rats, we note that the study lacked a dose-response analysis, which limits conclusions about optimal therapeutic concentrations. Similarly, in the clinical trial by Bacelar de Assis et al. (2021) on auricular acupuncture for diabetic foot, we highlight that the small sample size (n = 44) and short follow-up period (8 weeks) restrict the generalizability of their findings on improved peripheral circulation. Second, many studies lack RCTs designs, failing to effectively exclude potential biases and undermining the credibility of results. Additionally, The lack of standardization in the study of botanical drugs metabolites and dosage control makes it difficult to compare and synthesize the results of different studies. Moreover, the reports on botanical drugs extraction methods are inconsistent (for example, Honeysuckle: water extract and ethanol extract in the study) (Xing et al., 2022). Finally, many studies do not adequately account for patient-specific differences such as age, gender, and diabetes type, all of which may influence the evaluation of treatment outcomes.

To better evaluate the role of TCM and acupuncture in DFU treatment, future research should focus on several key aspects. First, it is recommended to conduct large-scale RCTs to enhance the reliability and generalizability of research findings (Fu et al., 2020). These studies should incorporate multi-center designs to ensure sample diversity and representativeness (Fan et al., 2024). Second, research should emphasize standardization of botanical drugs metabolites and dosage control to facilitate comparison and integration of results across different studies. Additionally, future studies should account for patient-specific differences, exploring how different patient groups respond to TCM and acupuncture to develop personalized treatment protocols (Xing et al., 2022). Although there is evidence to support the upregulation of SCFA in traditional Chinese medicine, quantitative insights are still limited. Finally, by integrating modern biotechnology with TCM theories, investigations into how TCM components influence host metabolism through modulating gut microbiota could provide new strategies for DFU treatment (Zhu et al., 2024). We will continue to conduct in-depth research on the mechanism of gut skin axis crosstalk, and combine multi omics (metagenomics, metabolomics) to elucidate how traditional Chinese medicine regulates microbial metabolites (such as SCFA, bile acids) and downstream pathways (such as Nrf2, PI3K/AKT) in human DFU samples. Meanwhile, researchers must also address the long-term effects of TCM on gut microbiota and its safety profile to ensure the efficacy and safety of clinical applications (Li X. et al., 2024).

As research on the gut-skin axis deepens, an increasing body of evidence indicates that gut microbiota and immune responses play pivotal roles in the initiation and progression of DFU. Therefore, modulating intestinal health and improving skin condition will emerge as critical strategies in the management of DFU.

In the perspectives and findings of different studies, the effectiveness of STCMP and acupuncture is closely linked to their unique mechanisms of action. STCMP (e.g., Jinhuang Powder, Shengjiang Xiexin Decoction) ameliorate gut microbiota dysbiosis by enriching beneficial bacteria (Lactobacillus, Bifidobacterium) and inhibiting pathogens, while acupuncture modulates neuroendocrine and immune responses by stimulating specific acupoints. The combination of these two not only complements each other’s shortcomings but also creates a synergistic effect, thereby enhancing clinical efficacy.

However, in research and clinical applications, we must also exercise caution. Varied study designs, sample selection, and intervention protocols may lead to divergent results. Therefore, future research should place greater emphasis on standardized research methodologies and conduct large-scale RCTs to validate the true efficacy and safety of the combined application of STCMP and acupuncture. In addition, Future studies should focus on identifying specific microbial taxa (e.g., butyrate-producing bacteria like Faecalibacterium prausnitzii) modulated by TCM botanical drugs (e.g., A. membranaceus Bunge). Combining metagenomic sequencing with metabolomics could reveal how botanical drugs metabolites (e.g., astragaloside IV) reshape microbial metabolic pathways (e.g., SCFA synthesis) to enhance skin repair.

In summary, STCMP and acupuncture demonstrates broad prospects in the treatment of DFU. Through further research, we expect to develop more effective treatment strategies based on the modulation of the gut-skin axis, thereby improving patients’ quality of life.