Introduction

Obesity is a complex multifactorial metabolic disorder characterized by excessive fat accumulation that poses substantial health risks and has become a major global public health challenge.1,2 The prevalence of obesity continues to rise worldwide, with projections indicating that more than 1.25 billion adults may be affected by 2030.3 Obesity not only increases the risk of chronic diseases, including diabetes and hypertension, but also adversely affects physical and psychological well-being.4 Currently, lifestyle and behavioral interventions remain the cornerstone of weight management.5,6 However, many patients cannot achieve adequate weight loss through these measures alone, leading clinicians to consider pharmacotherapy or surgery.7 Bariatric surgery, while effective for severe obesity, carries risks of nutritional deficiencies and loss of lean mass.8,9 Current pharmacotherapies, primarily glucagon-like peptide-1 (GLP-1) receptor agonists, show efficacy but require injections, have poor long-term adherence, and carry gastrointestinal and other side effects.10–15 Therefore, elucidating obesity pathogenesis and developing safe, effective, and well-tolerated agents remain major priorities.

In recent years, the gut microbiota (GM) has emerged as a key regulator of host energy metabolism, lipid homeostasis, and inflammatory responses.16–20 Dysregulation of the GM not only contributes to the development of obesity but also influences the host’s metabolic response to interventions. However, most current microecological interventions target only a single pathological process, making it difficult to simultaneously regulate complex mechanisms such as inflammation, appetite control, and energy homeostasis. In addition, interindividual variability in the GM limits the efficacy of standardized interventions.21 Notably, Traditional Chinese Medicine (TCM) has attracted considerable attention due to its characteristics of multi-target and holistic regulation, which are consistent with the multi-level regulation of host metabolism by the gut microbiota.22 Increasing studies have demonstrated that various Chinese herbs, natural active ingredients, and classical formulas improve obesity and related metabolic diseases while concurrently altering the composition and metabolites of the GM.23–25 More importantly, accumulating evidence suggests that GM may also influence the metabolic fate and therapeutic activity of herbal compounds. Due to the complexity of many TCM herbs, biotransformation by microbial enzymes in the gastrointestinal tract may alter their absorption, bioavailability, and biological activity.26 Therefore, variability in GM among individuals may contribute to differences in therapeutic responses to TCM.

However, current studies largely interpret these findings within the framework of modern microbial ecology and regard TCM as an exogenous factor of the GM. Meanwhile, most evidence remains fragmented and correlational, with limited integration between TCM theoretical interpretation and contemporary microbiome science. In addition, for non-pharmacological therapies, the mechanisms do not involve direct action on the intestinal lumen but rather influence host physiological states through neural and immune regulation, thereby indirectly altering the GM. Therefore, these gaps underscore the need for a more systematic framework linking TCM theory, gut microbial regulation, and obesity pathophysiology.

TCM has a long history in managing conditions resembling modern obesity, which were classically identified as disorders such as spleen deficiency with dampness.27 In TCM theory, the spleen is regarded as a functional system responsible for nutrient transformation and transportation and governs the limbs and muscles. The functions closely align with intestinal digestion, metabolic regulation, immune homeostasis, and muscle metabolism, all of which are now recognized to be significantly influenced by the GM.28–30 In recent years, some scholars have proposed that the metabolic and immunoregulatory functions of the GM may represent a microecological manifestation of the spleen’s transportation and transformation function.31 Meanwhile, TCM emphasizes that emotional dysregulation may impair the function of the spleen, while modern studies have confirmed the key role of the gut-brain axis in appetite control, stress responses, and metabolic regulation. These findings suggest that obesity may involve an integrative spleen-GM-brain regulatory network, providing a mechanistic basis for interpreting TCM interventions through the lens of microbiome science.

This review not only outlines the roles of the GM in obesity pathogenesis, but also systematically summarizes the evidence of different types of TCM interventions in regulating the GM. More importantly, this review aims to analyze the relationship between the spleen and the GM as well as the regulatory pattern of the spleen-gut-brain axis from the perspective of TCM theory. Meanwhile, we further propose an integrative research approach centered on the interactions among host neural regulation, immune status, and intestinal microecology. This framework aims to provide new theoretical insights and research directions for future exploration of the microecological mechanisms underlying TCM regulation of metabolic diseases.

Relationship Between the Gut Microbiota and Obesity

The GM, a complex ecosystem residing in the gastrointestinal tract, plays a pivotal role in host energy balance and metabolic homeostasis.32 Accumulating evidence underscores a bidirectional interplay between obesity and microbial dysbiosis in metabolic processes, with dysbiosis actively contributing to the onset and progression of obesity. Conversely, alterations in the GM and gastrointestinal environment, such as enhanced energy harvest and increased intestinal permeability, often disrupt this delicate symbiotic relationship, leading to a state of microbial imbalance. Therefore, we systematically summarize characteristic microbial alterations in obesity and the functional role of the microbiota in obesity pathogenesis (Figure 1), along with underlying mechanisms, thereby establishing foundational knowledge for developing microbiota-targeted therapeutic strategies.

Figure 1 Gut microbiota dysbiosis and its role in obesity pathogenesis. The figure illustrates how alterations in gut microbial composition and function disrupt host metabolic homeostasis. Key pathways include: (1) dysbiosis-driven shifts in microbial metabolites such as short-chain fatty acids (SCFAs), bile acids, and trimethylamine N-oxide (TMAO), which influence energy harvest, lipid metabolism, and insulin sensitivity; (2) impaired intestinal barrier integrity leading to increased permeability and metabolic endotoxemia; (3) activation of the gut–brain axis, which modulates appetite, energy expenditure, and neuroendocrine signaling. Collectively, these mechanisms form a vicious cycle that promotes adipose accumulation, systemic inflammation, and metabolic dysfunction characteristic of obesity.

Gut Microbiota Dysbiosis

Under physiological conditions, the GM and the host are in a dynamic balance of mutual benefit and symbiosis.33 However, the balance is disrupted in obesity, which manifests as reduced diversity, disordered community structure, and abnormal proportions of key microbial communities. Metagenomic analyses reveal that the gut microbial ecosystem is primarily composed of six phyla: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia, among which Bacteroidetes and Firmicutes dominate.34–36 Early studies suggested that an increased ratio of Firmicutes to Bacteroidetes (F/B) in obese individuals represented a key feature of GM dysbiosis.37 However, accumulating evidence in recent years has indicated that the association between this ratio and obesity is inconsistent and may be significantly influenced by factors such as diet, host genetic background, and geographic variation.38–40 These findings have suggested that the F/B ratio is unlikely to serve as a reliable biomarker of obesity. Current research has shifted focus from examining single changes in GM proportions to evaluating overall ecosystem properties of the microbiota, with α-diversity serving as a core metric that exhibits more consistent characteristics in obese individuals. Several studies have identified a notable trend of reduced α-diversity in GM across obese pediatric and adult cohorts.41,42 Meanwhile, one research explicitly confirmed a significant negative correlation between the Shannon index and body mass index (BMI).43 Reduced diversity implies diminished capacity for the GM to respond to environmental disturbances and decreased metabolic resilience.

Beyond diversity, changes in specific functional microbiota are crucial for the relationship between dysbiosis and obesity. Research demonstrated that obese individuals exhibit characteristic reductions in protective commensal bacteria such as Akkermansia muciniphila, Faecalibacterium prausnitzii, and Enterococcus.44 The decline of these bacterial groups is associated with decreased short-chain fatty acids (SCFAs) production, compromised intestinal barrier integrity, and elevated systemic inflammation, changes that may collectively undermine the microbiota ecosystem’s capacity to maintain host metabolic health. In contrast, certain potentially harmful bacteria, such as Bacteroides vulgatus, Ileibacterium, and Escherichia coli, exhibit increased abundance in obese individuals and correlate positively with adverse metabolic markers.44,45 Notably, species diversity within the Clostridia phylum, a key group containing numerous SCFAs producers, has also been found to be negatively correlated with human obesity,46 indicating that loss of function at higher taxonomic levels represents a significant feature of obesity-associated dysbiosis. In summary, accumulating evidence implicates the GM in the occurrence and development of obesity, although causal relationships remain to be firmly established.

Energy and Lipid Modulation Mediated by Microbial Metabolites

In recent years, the metabolites of the GM and their functional mechanisms have been gradually revealed, which not only serve as substrates for metabolic reactions within the body but also extensively participate in regulating host energy balance and lipid metabolism as signaling molecules. Among them, SCFAs, as the most extensively studied class of microbial metabolites, have been reported to exhibit distinct dual physiological effects. Research has revealed distinct molecular pathways through which individual SCFAs may modulate host metabolism. For example, butyrate has been shown to activate colonic GPR43 receptors to stimulate GLP-1 secretion, thereby potentially suppressing appetite, and propionic acid inhibits hepatic FIAF expression to reduce lipid storage, while acetic acid may enhance hepatic lipid synthesis by upregulating acetyl-CoA carboxylase activity.47–49 Similarly, a Mendelian randomization study by Sanna et al50 revealed that increased abundance of butyrate-producing bacteria correlates with improved insulin sensitivity, while fecal propionate concentration shows a positive association with BMI. These findings suggest that SCFA regulation of metabolism depends on both the type and concentration of the compound. Notably, the physiological effects of SCFAs also further depend on their distribution and absorption within the host. Previous studies reported conflicting data on SCFA levels in obese individuals, with some reports indicating elevated fecal SCFAs while others observed reduced levels.51–53 However, Müller et al54 observed that circulating SCFA levels positively correlated with improved insulin sensitivity and lipid metabolism, whereas fecal SCFA levels showed no significant association with these metabolic indicators. The results indicate that systemic metabolic benefits are primarily mediated by SCFAs absorbed into the host circulation rather than by the fraction retained in the intestinal lumen and excreted in feces. It should be noted that these mechanistic insights are derived primarily from animal and in vitro studies, and their translational relevance to humans requires further investigation.

Beyond SCFAs, other metabolites also participate in regulating energy and lipid metabolism through distinct mechanisms. Studies indicate that elevated trimethylamine N-oxide (TMAO) levels under high-fat dietary conditions are associated with adverse metabolic outcomes, while decreased levels correlate positively with improved insulin resistance.55 Furthermore, GM converts primary bile acids into secondary bile acids through their bile salt hydrolase (BSH) activity.56 In preclinical models, these secondary bile acids have been shown to act as signaling molecules capable of activating farnesoid X receptor (FXR) and takeda G protein-coupled receptor 5 (TGR5), with downstream effects including GLP-1 secretion and enhancing thermogenic signaling that may influence energy expenditure.57–59 Whether these mechanisms operate to the same extent in humans requires further clinical investigation. Moreover, recent research has discovered that 4-hydroxyphenylacetic acid (4HPAA) has been shown to prevent high-fat diet-induced obesity in male mice by acting on the intestinal mucosa, modulating local innate immune responses, and controlling lipid intake.60 Collectively, these findings highlight that the physiological relevance of GM metabolites on lipid metabolism depends not only on their types and concentrations but is also closely linked to host absorption, distribution, and dietary status.

Neuroendocrine Regulation of the Gut-Brain Axis

The gut-brain axis is a bidirectional regulatory network connecting the gut to the central nervous system (CNS), whose signaling efficiency influences energy metabolism and plays a pivotal role in obesity.61 Emerging evidence indicates that the GM may participate in this regulatory process through direct neural sensing and indirect chemical signaling.62 In the direct pathway, a landmark animal study revealed that enteric glial cells located in the deep colonic mucosa can directly detect bacterial flagellin via Toll-like receptor 5 (TLR5), which subsequently triggers rapid vagal afferent signaling to the brainstem within seconds, transmitting neural impulses that inhibit feeding behavior.63 Although this finding is compelling, it currently derives from animal models, and its conservation in humans awaits confirmation. Additionally, preclinical evidence suggests that the GM can modulate the synthesis and turnover of neurotransmitters associated with central appetite regulation, such as gamma-aminobutyric acid (GABA) and serotonin.64

In contrast, the indirect pathway predominates, with GM metabolites being implicated as important signaling mediators. For instance, SCFAs, particularly butyrate, have been reported to activate G-protein-coupled receptors 41 and 43 (GPR41 and GPR43) on intestinal L cells, which may contribute to the release of GLP-1 and peptide YY (PYY) and potentially influence appetite regulation through vagal signaling.47,65,66 Similar regulatory patterns have also been proposed for secondary BAs.67 Meanwhile, studies suggest that specific gut bacteria can secrete hormone-like substances. Yoon et al68 found that Akkermansia muciniphila produces P9 protein, which has been associated with enhanced GLP-1 secretion and thermogenesis responses. Likewise, Bacteroides acidifaciens has been reported to be associated with pathways related to fatty acid oxidation and preservation of GLP-1 bioavailability.69 Notably, gut-brain axis regulation appears to operate bidirectionally, as experimental studies in mice suggest that activation of hypothalamic POMC neurons or central leptin administration may induce rapid remodeling of GM composition.70 Therefore, exploring the bidirectional communication mechanisms of the gut-brain axis may advance our understanding of obesity pathogenesis and could establish a conceptual framework for developing novel metabolic interventions targeting microbiota-brain interactions.

Relationship Between the Spleen and the Gut Microbiota in TCM Theory The TCM Concept of the Spleen and Its Functional Correspondence with the GM

In TCM, the spleen is not viewed as a single anatomical organ but as an integrative functional system encompassing digestion and absorption, fluid metabolism, and aspects of immune defense. Accorded the central status of the “foundation of acquired constitution” and the “source of qi and blood generation”, the spleen governs the transformation and transportation of nutrients derived from food and water, regulates the ascent of essential substances and the descent of metabolic waste, and sustains the nourishment of the muscles and limbs. Its functional integrity directly determines the body’s capacity to absorb, utilize, and eliminate metabolic products.71 Accumulating evidence indicates that the GM plays key roles in energy homeostasis, nutrient metabolism, barrier integrity, and immune regulation,72 a functional profile that shows conceptual parallels with the TCM understanding of spleen transportation and transformation. Such similarities may offer a potential modern biological perspective for interpreting classical theory, although direct equivalence should be interpreted cautiously.73

Under pathological conditions, impairment of spleen transportation and transformation refers not merely to diminished digestive function but to an imbalance in the body’s capacity to transform, distribute, and utilize nutrients. At the microecological level, this state may be associated with reduced metabolic resilience of the host microbiota ecosystem. Therefore, clinical manifestations of impaired spleen transportation and transformation, including poor appetite, abdominal distension, loose stools, and fatigue, have been reported to coincide with gut microbial dysbiosis characterized by reduced diversity and altered microbial composition.74,75 Accordingly, these observations suggest a possible correspondence between microbial alterations and TCM pathological patterns rather than establishing a direct causal relationship.

In addition to governing transportation and transformation, the spleen also plays a crucial role in “governing the muscles and limbs”. This theory indicates that the spleen continuously nourishes muscle tissue by transporting and transforming the essence of food and water to generate qi and blood, thereby maintaining the structural and functional integrity of the muscles. Therefore, the function of the spleen not only determines digestive and absorptive capacity but also directly influences muscle metabolism and limb strength. This function is also closely associated with the GM and is particularly evident in the pathological characteristics of obese patients. Obese individuals frequently develop concomitant sarcopenia, referred to as sarcopenic obesity, a condition in which GM dysbiosis has been increasingly implicated.75,76 For example, dysbiosis-associated reductions in butyrate may impair skeletal muscle anabolism, as preclinical evidence suggests that butyrate can promote muscle protein synthesis and suppress proteolytic degradation pathways.77,78 Meanwhile, chronic low-grade inflammation driven by dysbiosis has been proposed to accelerate muscle atrophy by activating the ubiquitin-proteasome degradation pathway of muscle proteins.79,80 In addition, gut microbial dysregulation of branched-chain amino acid (BCAA) metabolism has been associated with compromised substrate availability for muscle protein synthesis.81–83 From the perspective of TCM, the principle that the spleen governs muscles reflects its role in continuously supplying muscular tissue with the essential qi and blood generated through transportation and transformation, whereas a deficiency of spleen qi results in inadequate nourishment of muscles and consequent weakness or atrophy. The dysbiosis-associated alterations in inflammation, SCFAs, and amino acid metabolism may be interpreted as a microecological parallel to the pathological state described as “muscle malnutrition due to spleen deficiency” in TCM, though this conceptual framework remains to be systematically validated by empirical research. Consequently, ameliorating obesity by strengthening the spleen is not simply aimed at enhancing gastrointestinal motility but rather at restoring the host’s overall metabolic regulatory capacity. Subsequently, approaches such as resolving turbidity to activate the spleen or regulating qi and awakening the spleen are applied to restore the spleen’s transportation and transformation function and provide a stable metabolic environment for microbiota reconstitution.

The Spleen Storing Intention: Theoretical Foundation of the Gut-Brain Axis in TCM

In TCM, intent refers to the capacity for thought, memory, and the regulation of behavior, which are closely related to modern concepts of cognitive function. The core implication of the classical principle “spleen storing intent” (Pi cang yi) is that the function of the spleen, governing transportation and transformation, not only determines the source of nutriment to nourish the brain but also directly influences the material basis of mental and conscious activities by regulating the absorption and distribution of food essence. As recorded in the classical texts of TCM, “The spleen stores nutritive qi (ying), and the nutritive qi houses intent”, revealing an inherent physiological connection between digestive function and the regulation of cognition and emotion. From the perspective of modern neuroendocrinology, the hypothalamus stands as the key region integrating peripheral nutrient signals to regulate appetite, energy expenditure, and emotional responses, with its function being highly dependent on metabolic signals received from the gut. Therefore, the theory of spleen storing intent may provide a conceptual framework that partially overlaps with modern understandings of gut-brain communication, although such correspondence remains primarily interpretive rather than experimentally validated.

The gut-brain axis is a bidirectional communication system that closely links intestinal function and microbial ecology with the regulation of emotion and feeding by the CNS.84 Research indicates that the GM conveys peripheral metabolic status to appetite centers such as the hypothalamus through multiple pathways, including the vagus nerve, immune mediators, gut-derived hormones, and metabolites, thereby regulating feeding behavior and energy balance.70 The intestinal microecosystem on which the spleen’s transportation and transformation depend serves as a major peripheral signal source modulating central nervous function.68,69,85 Meanwhile, the CNS may exert regulatory influences on the GM. Experimental evidence in mice suggests that activation of hypothalamic POMC neurons and central leptin administration can be associated with rapid remodeling of microbial composition.70 These findings may support a bidirectional interaction between the spleen and the intent, although direct extrapolation to TCM theory requires caution.

Under the pathological condition of obesity, “impaired spleen transportation and transformation” and “failure to store intent” often reinforce each other in a vicious cycle. Under the pathological condition of obesity, “impaired spleen transportation and transformation” and “failure to store intent” often reinforce each other in a vicious cycle. On one hand, high-fat diet-induced dysbiosis and intestinal barrier dysfunction activate peripheral and central inflammatory responses via the lipopolysaccharide (LPS)-mediated signaling involving Toll-like receptor 4 (TLR4) pathway, directly affecting the function of hypothalamic nuclei that regulate appetite.86 On the other hand, chronic stress-induced sustained activation of the hypothalamic-pituitary-adrenal axis suppresses intestinal motility and changes the microbial colonization niche through sympathetic output, which further aggravates dysbiosis.87 Clinically, this cycle manifests in obese patients as the occurrence of attenuated satiety signaling to the brain with poor control of eating impulses, reflecting dual abnormalities in gut-brain signal sensing and central reward regulation.

Based on the interpretation of the gut-brain axis from the perspective of the theory that the spleen stores intent, there is a unique advantage of TCM in obesity intervention by exerting synergistic effects through both mental regulation and pharmacological intervention. For mental regulation, TCM emphasizes that “excessive rumination impairs the spleen”, highlighting the influence of emotional states on spleen function, and advocates regulating CNS activity through approaches such as regulating qi and awakening the spleen, thereby optimizing the intestinal microbial microecology from top to bottom. As for pharmacological intervention, therapeutic strategies such as supplementing qi and strengthening the spleen or resolving turbidity to activate the spleen can regulate the composition and metabolites of the GM, improve intestinal barrier integrity, and promote the secretion of gut-derived hormones, thereby transmitting satiety signals to the brain. This bidirectional regulatory mode integrating mental and pharmacological approaches enables TCM to act simultaneously on both the central and peripheral components of the gut-brain axis, ultimately improving abnormal appetite and intestinal dysfunction and fully reflecting the holistic therapeutic concept of “integration of body and mind” in TCM.

In practice, TCM often improves both appetite dysregulation and emotional fluctuations, whose benefits may partly arise from coordinated modulation of gut-brain communication rather than from mere improvement in local digestive function. Collectively, the relevant effects may extend beyond remodeling the GM composition and systemic integration through neural, endocrine, and immune approaches can help reestablish coordination between the spleen as a gut and metabolic functional system and intent as a center and cognition. Accordingly, interpreting the gut-brain axis through the perspective of “the spleen storing intent” not only provides a theoretical basis for TCM approaches to regulating appetite, emotion, and metabolic behavior but also opens new research avenues to investigate the mechanisms of therapies such as strengthening the spleen, activating the spleen, and awakening the spleen. The functional correspondence between the TCM spleen and the GM, together with their integrated regulation of the gut-brain axis in obesity, is schematically illustrated in Figure 2.

Figure 2 The TCM spleen-GM-brain axis in obesity. This figure depicts a conceptual framework in which the TCM spleen serves as the theoretical core, with its three classical principles demonstrating functional correspondence with contemporary biological systems involved in gut microbial ecology, skeletal muscle metabolism, and the gut-brain axis. The spleen’s function of transportation and transformation parallels the role of the GM in maintaining energy homeostasis, nutrient metabolism, intestinal barrier integrity, and immune balance, indicating that dysbiosis in obesity may reflect impaired spleen function. In accordance with the theory that the spleen governs muscles and limbs, GM dysbiosis in obesity contributes to the disruption of skeletal muscle homeostasis through reductions in butyrate and BCAA availability and the promotion of chronic low-grade inflammation, collectively manifesting as sarcopenic obesity. Furthermore, the theory of the spleen storing intention is consistent with the gut-brain axis. The GM interacts with hypothalamic appetite centers via the vagus nerve, gut-derived hormones, immune mediators, and microbial metabolites. Conversely, the central nervous system (CNS) modulates GM composition through activation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system activity. Within this integrated framework, herbal and mental therapies are proposed as complementary TCM interventions targeting peripheral and central pathways, respectively, in line with the TCM principle of mind–body integration.

Mechanisms of TCM in Modulating Gut Microbiota in Obesity

Based on TCM theory, obesity is often associated with spleen deficiency and phlegm dampness accumulation, in which dysregulation of the GM may play an important role.88 In recent years, TCM has attracted increasing attention as a potential therapeutic approach for obesity management, particularly through approaches such as supplementing qi and strengthening the spleen, resolving turbidity to activate the spleen, and regulating qi and awakening the spleen. Accumulating evidence suggests that TCM may improve obesity-related metabolic disorders partly through modulation of gut microbial composition and metabolic activity (Table 1 and 2, for detailed information, seeSupplementary Tables 1 and 2).89,90 Nevertheless, most available evidence remains preclinical and largely correlational, making it difficult to establish direct causal links between specific microbial changes and therapeutic outcomes. Meanwhile, the interaction between TCM and the GM may extend beyond a unidirectional regulatory process. In addition to reshaping microbial composition and function, the GM may participate in the biotransformation of herbal compounds and influence their bioavailability and biological activity.91 Such microbial transformations can convert inactive precursor molecules into bioactive metabolites with enhanced absorption or novel pharmacological activities.92 Conversely, the same metabolic processes may also generate less active or even toxic compounds.93,94 Variability in microbial ecology may further contribute to differences in therapeutic responses to TCM interventions. Therefore, the mechanisms through which TCM regulates obesity should be interpreted within the context of reciprocal interactions between herbal medicines and the GM. The major pathways by which TCM may alleviate obesity through GM-related regulation are summarized in Figure 3.

Table 1 Anti-Obesity Effects of Single Chinese Herbs and Active Ingredients via GM Modulation. For the Complete Dataset of All Herbs, See Supplementary Table 1

Table 2 Multi-Targeted Mechanisms of TCM Formulas in Alleviating Obesity Through GM Regulation. For the Complete List of All Formulas and Detailed Data, See Supplementary Table 2

Figure 3 Mechanisms of TCM in alleviating obesity via GM modulation. TCM interventions, including single herbs, active compounds, and formulated decoctions, act upon the gut microbial community to restore ecological balance. This remodeling increases microbial α-diversity and promotes the abundance of beneficial genera. The modulated microbiota produces metabolites such as short-chain fatty acids and secondary bile acids, which engage host receptors (GPR41/43, TGR5, FXR). Subsequent activation of signaling cascades enhances mitochondrial biogenesis and energy expenditure via the PGC-1α/UCP-1 axis, stimulates fatty acid oxidation through PPAR-α, and suppresses pro-inflammatory pathways mediated by TLR4. Concurrent strengthening of the intestinal mucus layer and modulation of gut–brain communication further contribute to improved metabolic homeostasis and reduced adipose tissue accumulation.

Supplementing Qi and Strengthening the Spleen: Restoring Intestinal Ecology

In TCM theory, the core pathological factor of obesity is frequently attributed to “spleen deficiency”, a state characterized by impaired transportation and transformation that disrupts the distribution of essential nutrients derived from food and water. From the perspective of modern microecology, this state of impaired transformation reflects not only reduced digestive and absorptive function of the host but also a decline in the overall metabolic capacity and resilience of the intestinal microecosystem. Accordingly, the fundamental goal of supplementing qi and strengthening the spleen is to enhance host function and systematically correct GM dysbiosis and functional impairment induced by spleen deficiency, rather than directly antagonizing specific pathological targets. Preclinical studies have shown that representative qi-supplementing and spleen-strengthening herbs may exert anti-obesity effects, primarily suggested to occur through enhancing GM diversity, strengthening intestinal barrier integrity, and promoting the synthesis of beneficial microbial metabolites.120,121

The α-diversity of the GM serves as a critical indicator of its ecological stability and functional redundancy, whose reduction commonly observed in obesity is thought to indicate a diminished capacity of the microecosystem to resist perturbations. Studies have reported that Astragalus membranaceus polysaccharide significantly increases both the Shannon and Simpson indices of the GM in obese animal models, an effect that promotes the proliferation of commensal bacteria such as Lactobacillus and Bifidobacterium while simultaneously reducing the relative abundance of potentially pathogenic taxa, including Escherichia and Shigella.97 Of note, Astragalus polysaccharide is a high-molecular-weight compound that resists degradation by human digestive enzymes.122 Its beneficial effects are believed to largely depend on fermentation by GM into bioactive fragments that can be utilized.123 This microbial transformation may be essential for the prebiotic activity of many qi-supplementing polysaccharides. The broad and non-selective modulation of microbial structure is consistent with the therapeutic strategy of the qi-supplementing approach, which aims to comprehensively improve the internal environment. For the formulas, Shenling Baizhu powder has also been shown to increase the abundance of Bifidobacterium and Anaerotruncus and to improve overall community structure.115 Therefore, increasing microbial diversity constitutes the foundation for rebuilding a healthy intestinal ecosystem through the method of supplementing qi and strengthening the spleen.

Beyond directly regulating the abundance of GM, qi-supplementing and spleen-strengthening herbs have demonstrated considerable promise in ameliorating obesity by increasing the beneficial metabolites of the GM. Among all metabolites, SCFAs represent the most extensively targeted regulatory molecules,43 such as Citri Reticulatae Pericarpium and Poria cocos polysaccharides.23,103 Concurrently, certain TCM extracts, such as Ganoderma lucidum polysaccharides and resistant starch from Euryale ferox seeds,96 can be metabolized by GM to produce SCFAs, thereby acquiring additional regulatory functions.100 These findings suggest that the GM is not merely a passive recipient of TCM interventions, as its metabolic activity may influence the bioavailability and functional properties of specific herbal components. Accordingly, the metabolic status of the host GM may serve as an intrinsic determinant of the therapeutic efficacy of qi-supplementing and spleen-strengthening therapies. Recent research has found that resveratrol, a grape-derived compound with qi-supplementing properties, may undergo microbial metabolism to increase levels of 4-HPA, which may contribute to anti-obesity effects through activation of the SIRT1 signaling pathway.124 This mechanism further illustrates that the metabolic transformation activity of the GM may be essential for converting these compounds from their prototype forms into bioactive forms. However, current studies are limited to laboratory animal models and require further clinical validation.

The intestinal barrier serves as both a physical and functional defense that prevents the translocation of gut-derived endotoxins, such as lipopolysaccharide (LPS), thereby restraining chronic low-grade inflammation. SCFAs, particularly butyrate, serve as primary energy substrates for colonic epithelial cells and directly induce the upregulation of tight junction proteins such as occludin and ZO-1, which provides a precise molecular explanation for the “enhanced intestinal barrier function” reported with formulas like Shenling Baizhu powder.125 Also, water extract of Ganoderma lucidum alleviates obesity-related metabolic inflammation by enriching SCFA-producing bacteria, including Roseburia and immunomodulatory Clostridium clusters.99 Collectively, the TCM concept that the spleen governs the muscles receives a modern interpretation, as qi-supplementing and spleen-strengthening herbs enhance the integrity of the intestinal epithelium as a muscular tissue, thereby reinforcing the barrier. And this effect may be regarded as a specific microcosmic manifestation of classical theory.

In summary, the microbiological mechanisms underlying the anti-obesity effects of the method of supplementing qi and strengthening the spleen can be characterized as three interconnected biological processes that play a foundational role in establishing and regulating the internal environment within comprehensive obesity interventions. However, for obese individuals with prominent pathological factors corresponding to dampness or phlegm-stasis, foundational regulation alone is insufficient to rapidly reverse pronounced metabolic disturbances. Therefore, supplementing qi and strengthening the spleen is frequently combined with or followed by approaches aimed at eliminating pathogenic factors.

Resolving Turbidity to Activate the Spleen: Correct Imbalanced Inflammation

Based on “spleen deficiency”, obesity is often accompanied by an excess pattern of “internal retention of dampness and turbidity”, manifested as abnormal accumulation of metabolic products and a state of chronic low-grade inflammation. From a pathophysiological perspective, this “dampness-turbidity” can be correlated with the translocation of endotoxins into the blood induced by GM dysbiosis, disturbances in BA metabolism, and elevated levels of proinflammatory cytokines. Accordingly, the therapeutic focus of the method of resolving turbidity to activate the spleen lies in directly intervening in and eliminating these pathological factors, aiming to rapidly alleviate the metabolic burden and break the vicious cycle of inflammation.

Previous research has confirmed that LPS acts via the Toll-like receptor 4 (TLR4) signaling pathway to diminish tight junction protein expression in the intestinal epithelium, resulting in heightened intestinal permeability.126,127 Gegen Qinlian Decoction, a representative formula for clearing damp-heat, contains baicalin and berberine (BBR), both recognized antagonists of the TLR4 signaling pathway, potentially contributing to anti-inflammatory effects.128,129 Kong et al105 demonstrated that BBR, a benzodioxoloquinolizine alkaloid derived from Coptidis Rhizoma and related medicinal plants, ameliorates endoplasmic reticulum stress-induced goblet cell apoptosis, upregulates Akkermansia muciniphila (A. muciniphila) abundance, and stabilizes tight junctions to enhance epithelial barrier integrity, which is similar to the protective effect of cordycepin on obesity.106 Importantly, BBR is poorly absorbed from the small intestine because of its low lipophilicity and efflux by P-glycoprotein. Its bioavailability is dramatically enhanced by gut microbial reduction to dihydroberberine, which exhibits greater lipophilicity and can be absorbed more efficiently.130 Therefore, the pharmacological microbial activity of the core bioactive components in Gegen Qinlian Decoction may depend on microbial metabolic transformation, highlighting the importance of GM-drug interactions. A. muciniphila has been identified as a mucin-degrading bacterium and a commensal resident of the mucus layer.131 Meanwhile, correlation analysis conducted by Chen et al106 revealed a negative association between the abundance of A. muciniphila and serum LPS levels, suggesting that cordycepin may further contribute to the reduction of endotoxin production and its translocation into the circulatory system through microbial modulation. For the formulas, Bofutsushosan and Huanglian Wendan Decoction have both been demonstrated to induce a significant bloom of A. muciniphila, changes that are associated with attenuated weight gain, improved body composition, and favorable lipid profiles.113,114 However, the role of A. muciniphila remains controversial, as treatment with Shenling Baizhu powder was found to decrease its abundance in HFD-fed rats, highlighting the need for further clarification.115 Furthermore, Ding et al98 demonstrated that honokiol differentially modulated GM in a sex-specific manner, with a marked increase in beneficial taxa such as Akkermansia observed specifically in obese male mice, which was similar to the results of Zheng et al95 These findings highlight the influence of sexual dimorphism on the efficacy of GM-targeting TCM herbs, but further research is necessary to validate these observations.

Notably, the reduction of specific harmful metabolites serves as a common anti-obesity strategy for these types of herbs. For example, it was found that the ginger extract constituent citral effectively inhibits the production of TMAO, which is closely associated with metabolic dysfunction and obesity.102 Lee et al104 showed that the water-dispersible turmeric extract alleviates obesity by reducing the levels of indole-3-propionic acid and branched-chain amino acids.

Furthermore, another critical pathway through which TCM ameliorates obesity involves the modulation of cholesterol and bile acid metabolism. Platycodonis Radix polysaccharides have been reported to influence bile acid metabolism partly through microbial transformation of primary BAs into secondary forms, which may contribute to suppression of intestinal FXR signaling and reduced lipid absorption.101 Simiao Wan attenuates hyperlipidemia by reducing gut bacterial bile salt hydrolase (BSH) activity, which increases conjugated bile acids that antagonize intestinal FXR signaling and promote hepatic cholesterol conversion to bile acids.111 Lingguizhugan Decoction modulates the F/B ratio and upregulates genes involved in bile acid metabolism, including CYP7A1 and TGR5, facilitating cholesterol catabolism and energy dissipation.112 As Zhang et al109 found, Erchen Decoction enriches beneficial bacteria like Akkermansia and Butyricicoccus, with associated elevated levels of the SCFAs butyrate, which promotes PPARα-mediated fatty acid β-oxidation, which is similar to the results of Sangguayin decoction.110 Taken together, the therapeutic effects of resolving turbidity to activate the spleen may also involve microbial transformation of herbal components, which may influence their biological activity and therapeutic consistency across individuals.

Regulating Qi and Awakening the Spleen: Stabilize the Gut-Brain Axis

During the progression of obesity, emotional distress and psychological stress act not only as common triggers but also as persistent concomitant states throughout the disease course.132–134 In TCM theory, the pathogenesis is characterized as “stagnation of qi with impaired spleen” or “excessive contemplation and fatigue depleting spleen intent”, with the core mechanism being that dysregulation of qi movement obstructs the transportation and transformation of the middle energizer. Therefore, the method of regulating qi and awakening the spleen is not to directly modulate the GM composition but rather to restore the normal ascending and descending order of qi movement to modulate central neuroendocrine control of metabolic homeostasis. From the perspective of modern physiology, the pathological basis corresponding to qi stagnation is closely associated with intestinal motility disorders, abnormal secretion of gut-derived hormones, and disrupted signal transduction along the gut-brain axis, which provides an important entry point for investigating the modern mechanisms of the method of regulating qi and awakening the spleen.

Intestinal motility represents a critical physiological condition for maintaining microbial homeostasis, as the rhythmic movements of peristalsis may indirectly shape the GM structure by influencing the local intestinal pH, oxygen partial pressure, and substrate distribution.135 As a commonly used TCM for the treatment of obesity, Xiexin Tang enhances the capacity of GM to produce SCFAs by upregulating key microbial enzymes such as acetate kinase and butyrate kinase, and subsequently activates the PGC-1α/UCP-2 pathway to increase energy expenditure while inhibiting the mTOR pathway to suppress lipogenesis.107 Therefore, microbial metabolism may modify the intestinal availability and biological activity of specific components, thereby potentially influencing downstream signaling involved in energy expenditure and metabolic regulation. Similarly, Gualou-Xiebai-Banxia-Tang counteracts obesity by modulating GM to downregulate hepatic lipogenic proteins like SCD1, thereby directly inhibiting liver fat synthesis.108 The above evidence indicates that qi-regulating formulas may indirectly achieve systemic regulation of microbial structure and metabolic function by restoring intestinal motility and internal environmental stability.

The stabilizing effect of the method of regulating qi and awakening the spleen on the gut-brain axis is mainly manifested in the bidirectional integration of gut-derived hormone secretion and central appetite regulation. For instance, Shenlian Decoction increases the relative abundance of Bacteroides acidifaciens to stimulate GLP-1 secretion, which may contribute to improving insulin sensitivity and glycemic control.117 This effect is consistent with the documented pharmacological actions of Salacia Chinensis, which significantly modulate the gut hormones PYY and ghrelin to suppress appetite.136 These findings suggest that formulas for regulating qi and awakening the spleen may contribute to the transmission of satiety signals from the gut to the brain through modulation of GM and enteric endocrine activity, thereby helping to restore energy intake balance. Given the substantial interindividual variability in GM, its metabolic capacity may further influence the efficacy of these interventions by affecting the generation of bioactive metabolites involved in gut hormone regulation and gut-brain communication. Additionally, Renshen Zhuye decoction improves insulin sensitivity and reduces systemic inflammation by enhancing gut barrier function and modulating GM metabolites.116 For central regulation, Chowiseungcheng Tang has been reported to alleviate obesity partly through modulation of the gut-brain axis, significantly mediated by downregulation in the expression of agouti-related peptide (AgRP) and neuropeptide Y (NPY).118 A similar mechanism is observed with Daesiho-Tang, collectively providing preliminary evidence for the potential of TCM to modulate the gut-brain appetite regulatory circuitry.119 Collectively, the above evidence indicates that the method of regulating qi and awakening the spleen can simultaneously act on both the peripheral and central components of the gut-brain axis. It synergistically restores normal appetite regulation through the dual mechanism involving the optimization of gut-derived hormone secretion and the downregulation of orexigenic neuropeptide expression.

In summary, the strategy of regulating qi and awakening the spleen is aimed at restoring the ascending and descending dynamics of qi, with improvement of intestinal motility serving as a key entry point. Through modulation of the GM, regulation of gut-derived hormone secretion, and reconstruction of central appetite control, the bidirectional signaling coordination of the gut-brain axis is systematically stabilized, ultimately enabling integrated regulation of appetite and energy metabolism. Compared with the method of supplementing qi and strengthening the spleen, which prioritizes the reconstruction of the intestinal ecological foundation, and resolving turbidity to activate the spleen, which directly targets the elimination of harmful metabolites and inflammatory signals, the method of regulating qi and awakening the spleen is specifically focused on correcting qi stagnation and gut-brain signal dysregulation.

Accordingly, mechanistic analyses of these three therapeutic approaches suggest that the interaction between TCM and the GM is likely bidirectional. While TCM interventions may modulate microbial composition and metabolic activity, the GM may also influence the biotransformation and bioavailability of herbal compounds. Consequently, interindividual differences in microbial ecology could partly contribute to variability in therapeutic responses. These three methods, each with its own emphases and operating synergistically, collectively constitute a comprehensive TCM therapeutic strategy for intervening in obesity based on the GM.

Critical Appraisal of Current Evidence

It should be acknowledged at the outset that while numerous studies have reported associations between TCM interventions, GM changes, and metabolic improvements, the evidence base has several inherent limitations that warrant careful interpretation. For instance, although numerous studies have shown that TCM can ameliorate obesity alongside changes in the GM, the existing evidence remains markedly heterogeneous. In some studies, alterations in microbiota composition after intervention did not consistently correspond to improvements in metabolic parameters, and no reliable association was observed between GM remodeling and weight loss.137,138 These findings suggest that, in certain contexts, microbial alterations may reflect concomitant changes rather than serving as core mediating mechanisms. Substantial heterogeneity across studies in animal models, dietary induction protocols, TCM formulas, treatment duration, and microbial sequencing methods has further contributed to inconsistent findings regarding GM alterations.

Although some studies observed alterations in gut microbial composition, neither weight loss nor metabolic improvement reached significant levels, suggesting that the changes do not necessarily translate into consistent clinical benefits.139–141 In addition, interindividual differences in gut microbial ecology may lead to substantial variability in responses to the same TCM intervention, which may partly contribute to the inconsistency observed across studies. A specific manifestation of this interindividual variability is the differential capacity of gut microbes to metabolize herbal components. Individuals with distinct baseline GM may convert the same TCM formula into different sets of bioactive metabolites, leading to divergent therapeutic outcomes. This microbial biotransformation is rarely examined in current studies, representing a critical gap in understanding response heterogeneity.

It should be noted that current evidence regarding the role of TCM in modulating the GM to alleviate obesity is primarily derived from high-fat diet-induced animal models, whereas human studies remain relatively limited. Importantly, the GM of humans and experimental animals differs profoundly in species composition, functional redundancy, and metabolic capacity.142–144