Traditional Chinese medicines in regulating gut microbiome: Mechanisms and therapeutic applications

Abstract

The gut microbiome plays a critical role in human health, and its imbalance is associated with a range of gastrointestinal and systemic disorders. Traditional Chinese medicines (TCMs), with a holistic and multi-component nature, shows unique potential in modulating microbial composition and function. TCMs, including herbal formulas, herb pairs, single herbs, active compounds and acupuncture, regulates the gut microbiome through multiple mechanisms, such as enriching beneficial bacterial, restoring microbial diversity and modulating microbial metabolism, and has been applicated in several microbiota-related diseases. However, there are also several controversies that hinder progress in the field. Further well-designed clinical and mechanistic studies are needed to validate these effects and integrate TCMs strategies into mainstream microbiome-based therapies for gastrointestinal health.

Key Words: Traditional Chinese medicines; Gut microbiome; Modulating patterns; Microbiota-related diseases; Controversies

Core Tip: The gut microbiome plays a crucial role in regulating physiological homeostasis and the development of diseases. This review explores the recent advancements and ongoing debates regarding the impact of Traditional Chinese Medicines on gut microbial communities, and delineates future research directions for addressing diseases associated with gut microbial dysbiosis.

INTRODUCTION

Gut microbiota comprises the diverse microorganisms inhabiting the gastrointestinal tract and is increasingly recognized as an essential contributor to human health. It plays a crucial role in nutrient utilization, immune regulation, and metabolic stability, and disruptions in its composition and function are closely associated with multiple gastrointestinal and systemic diseases[1,2].

Traditional Chinese medicines (TCMs), rooted in thousands of years of clinical practice, is an important component of modern healthcare[3,4]. Due to its holistic theoretical concept and multi-target therapeutic approach, TCMs has the potential to modulate the structure and function of the gut microbiota[5]. Accumulating evidence suggests that the therapeutic effects of TCMs in conditions such as type 2 diabetes, non-alcoholic fatty liver disease, depression, and chronic obstructive pulmonary disease are at least partially mediated through remodeling of the gut microbial community and its metabolic output[6-9]. The regulation of TCMs on gut microbiome was presented in Figure 1.

Figure 1 The regulation of traditional Chinese medicines on gut microbiome. The Figure was created by Figdraw (www.figdraw.com). TCMs: Traditional Chinese medicines.

Despite the growing body of literature, the field of TCMs and microbiota research faces several critical challenges. In this review, we firstly emphasized the importance of gut microbiota in health and disease, then systematically review the advances and controversies for regulation of TCMs on gut microbiome. Finally, future research directions were outlined to move the field from descriptive correlation toward mechanism-based precision medicine.

GUT MICROBIOTA IN HEALTH AND DISEASE

Gut microbiota consists of trillions of microorganisms (bacteria, viruses, fungi, archaea, and protozoa) that form the largest microbial ecosystem in the human body. Based on origin, the gut microbiota may be categorized as indigenous or exogenous, while classification by host interaction includes commensal, opportunistic pathogenic, and pathogenic microorganisms[10]. In healthy individuals, the gut microbiota is predominantly composed of nonpathogenic species, with > 90% belonging to the phyla Bacteroidetes and Firmicutes[11].

The gut microbiome is increasingly recognized as a major factor in host physiological function. Besides its role in nutrient digestion and absorption, the gut microbiota contributes to the regulation of metabolism, maintenance of immune homeostasis, and preservation of the structural and functional integrity of the intestinal barrier[12].

External factors, including dietary habits, pharmacological interventions, and chronic disease conditions, can alter the diversity, composition, and function of the gut microbiota, leading to dysbiosis[13]. This state is typically characterized by a reduction in beneficial microorganisms and an increase in pathogenic populations, leading to impaired barrier integrity, metabolic disturbances, and intestinal inflammation[14,15]. Furthermore, the influence of gut microbiota extends beyond the digestive system; it affects systemic diseases via pathways like the gut-liver axis, where microbial imbalance contributes to their development and progression[16].

MECHANISM AND APPLICATION OF TCMS IN MODULATING GUT MICROBIOME

Many intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer, are closely linked to disturbances in intestinal microbial homeostasis and may respond to TCMs-based interventions[17]. Inflammatory bowel disease is a chronic, relapsing inflammatory condition of the gastrointestinal tract that remains challenging to manage and represents a significant global health burden[18,19]. In colitis models, Wang et al[20] showed that the traditional Chinese herbal formulation Gegen Qinlian decoction significantly altered intestinal microbial diversity and composition, particularly by increasing populations of short-chain fatty acid-producing gut microbiota. These changes were associated with attenuation of intestinal inflammation through increased regulatory T-cell activity and suppression of pro-inflammatory Th17 cell differentiation. Similarly, Huanglian decoction has been reported to promote the growth of beneficial gut microbiota, mucosal repair, and reduce the expression of pro-inflammatory cytokines, showing protective effects in models of stress-induced gastric ulceration[21]. Moreover, maggot-derived extracts have been shown to suppress colorectal carcinogenesis by re-establishing intestinal microbial homeostasis, limiting inflammatory responses, and strengthening intestinal barrier integrity[22]. Zhou et al[23] reported that an integrative treatment strategy combining TCMs with Western medical approaches restored the gut microbiome and improved clinical outcomes after intestinal stoma closure, extending the application of microbiota-modulating therapies to retrospective clinical studies.

Liver-gut axis is an important regulatory pathway through which TCMs can affect intestinal microbiota and contribute to the prevention and treatment of liver diseases[24,25]. Various medicinal herbs and their bioactive compounds, including berberine, ginsenosides, and curcumin, have shown therapeutic benefits in nonalcoholic fatty liver disease by regulating gut microbiota composition and metabolic activity[26-28]. Moreover, the traditional formulation Yinchenhao decoction, along with its active component rhein, showed significant efficacy in mouse models of intrahepatic cholestasis of pregnancy[29]. These effects were associated with modifications in gut microbiota diversity and structure, characterized by a reduction in g-Fimenecus and an enrichment of g-Intestinimonas.

The gut-brain axis is a bidirectional communication system linking the gut with the central nervous system[30,31]. The gut microbiota, which is crucial to maintaining the physiological function of this axis, is regulated by TCMs[32]. Studies indicate that the TCMs formula BuYang HuanWu Tang restored intestinal microbial balance in children with autism spectrum disorders[33], Similarly, Jiaotai pill reduced pro-inflammatory bacterial populations and ameliorated sleep abnormalities in experimental models of insomnia[34], Dengzhan Shengmai also improved cognitive performance and learning ability in aging-related cognitive impairment models by reshaping gut microbiota composition and suppressing inflammatory mediators[35].

The gut-heart axis is a complex, bidirectional network linking intestinal homeostasis with cardiovascular function[36,37]. Changes in the gut microbiota have increasingly been recognized as key contributors to the progression and clinical outcomes of myocardial infarction and heart failure[38,39]. Cui et al[40] reported that the traditional Chinese formulation Jiashen prescription significantly improved cardiac function in a rat model of heart failure by correcting gut microbiota dysbiosis. This intervention increased microbial diversity, enriched beneficial bacterial populations, and reduced pathogenic taxa, highlighting a potential microbiota-targeted therapeutic strategy for heart failure.

Gut-lung axis aligns with TCMs theory, which defines a close functional association between the lung and large intestine (“fei yu da chang xiang biao li”)[41,42]. Recent studies have shown that several respiratory disorders are associated with alterations in intestinal microbiota composition[43,44]. Studies have shown that Maxing Shigan Decoction attenuated inflammatory cell infiltration in influenza A virus-induced pneumonia by increasing the abundance of Actinobacteriota and Desulfobacterota while reducing Planctomycetota within the gut microbiota[45]. Similarly, Cangma Huadu granules alleviated severe lung injury caused by lethal influenza A infection by inhibiting apoptosis and modulating gut microbial diversity and composition[46]. The regulation of distal organ by TCMs formula through the gut-X axis was summarized in Table 1.

Table 1 Regulation of distal organs by traditional Chinese medicine formulas through the gut-X axis.

TCMs formula	Diseases	Axis	Ref.
Yinchenhao decoction	Intrahepatic cholestasis of pregnancy	Liver-gut axis	[29]
Buyang Huanwu Tang	Autism spectrum disorders	Gut-brain axis	[33]
Jiaotai pill	Insomnia	Gut-brain axis	[34]
Dengzhan Shengmai	Aging-related cognitive impairment	Gut-brain axis	[35]
Jiashen prescription	Heart failure	Gut-heart axis	[40]
Maxing Shigan decoction	Influenza A virus-induced pneumonia	Gut-lung axis	[45]
Cangma Huadu granules	Lung injury caused by H1N1 infection	Gut-lung axis	[46]

TCMs: Traditional Chinese medicines; H1N1: Lethal influenza A.

Besides, oral medications, acupuncture, and moxibustion are important modern modalities within TCMs due to broad clinical applicability and minimal adverse effects[47,48]. Acupuncture at specific acupoints also suppresses tumor growth and regulates gut bacterial abundance in osteosarcoma-bearing mouse models[49]. Similarly, moxibustion treatment promoted the repair of gastric mucosal injury in acute gastric ulcer models by increasing the abundance and diversity of beneficial gut microbiota[50].

CURRENT CONTROVERSIES: FROM DESCRIPTIVE CORRELATION TO CAUSAL VALIDATION

Despite the rapid increase in publications reporting associations between TCMs interventions and gut microbiota alterations, significant controversies persist that hinder advancement in mechanistic understanding and clinical application. The primary controversy revolves around whether the microbiota changes observed following TCMs administration constitute a causal mechanism or are simply an epiphenomenon[51]. Although numerous studies have reported associations between TCMs treatment and changes in specific bacterial taxa, few have employed the experimental rigor necessary to establish causality[52,53]. We suggest that future research should aim to validate causality through the use of fecal microbiota transplantation or germ-free models.

A second area of contention involves the identification of the active components responsible for the modulation of the microbiota. TCMs formulas generally consist of multiple herbs, each containing numerous bioactive compounds, which represents a significant challenge for mechanistic deconvolution[54,55]. While complex formulas may exert broad, ecosystem-level effects on the microbial community, purified compounds might target specific bacterial enzymes or metabolic pathways[56]. We propose that future research should explicitly differentiate between mechanisms attributable to individual compounds and those resulting from formulation-level synergy.

The third area of contention pertains to the hypothesized relationship between acupuncture and the gut microbiota. Although a number of recent studies have indicated that acupuncture and moxibustion can modify microbial composition in animal models, the mechanistic pathway connecting needle stimulation to microbial alterations remains speculative[57-59]. We contend that the field of acupuncture-microbiota research necessitates a fundamental reevaluation. Instead of focusing on descriptive studies, we propose the pursuit of systematic mechanistic investigations aimed at elucidating the neural pathways, effector mechanisms, and microbial mediators involved[60].

CONCLUSION

The gut microbiome is a key regulator of human health, and disturbances in its homeostasis are closely related to multiple diseases. TCMs shows potential for regulating gut microbial structure, diversity, and functionality. Studies support its use across gastrointestinal, hepatic, pulmonary, neurological, and cardiovascular conditions. Nevertheless, several controversies hinder progress in this field, including the distinction between causality and correlation, the identification of active components, and the relationship between acupuncture and gut microbiota.

To facilitate the translation of gut microbiota-targeted TCMs interventions into clinical practice, future research directions must be considered. Firstly, it is essential to establish causality rather than rely on correlative findings by employing rigorous experimental models, such as fecal microbiota transplantation or germ-free models. Secondly, active components should be elucidated using complementary strategies, including high-throughput screening of purified compounds or herbal fractions against defined microbial consortia or specific bacterial enzymes. Finally, standardizing acupuncture parameters and utilizing modern tools are necessary to develop a mechanistic understanding of acupuncture-microbiota interactions. Ultimately, the objective of mechanistic research is to enhance patient outcomes. It is noteworthy that most of these investigations are based on preclinical models. Therefore, well-designed clinical studies are needed to confirm these results and to promote the translation of gut microbiota-targeted TCMs interventions into clinical practice.