Acupuncture regulating the gut-brain axis for postoperative ileus: Neuroimmune mechanisms and clinical translation prospects

Abstract

Postoperative ileus remains a significant challenge in surgical recovery. Increasing evidence highlights the gut-brain axis as a promising target for managing gastrointestinal motility disorders. Acupuncture, particularly at Zusanli (ST36), has shown considerable potential to regulate gut function, although its mechanisms warrant further investigation. This editorial discusses a clinical study demonstrating that electroacupuncture at Zusanli (ST36) accelerates gastrointestinal recovery in patients with postoperative ileus by activating the vagus nerve-cholinergic anti-inflammatory pathway, suppressing pro-inflammatory cytokines, and rebalancing gastrointestinal hormones. We further summarize how acupuncture modulates the gut-brain axis through neural, immune, endocrine, microbial, and central pathways, supporting integration with modern neuroimmunology. These findings support incorporating acupuncture into enhanced recovery after surgery protocols. Future studies should prioritize mechanistic investigations using multi-omics technologies, large-scale clinical trials to enable standardization, and exploration of acupuncture-microbiota-gut-brain interactions to broaden clinical applications in gastrointestinal disorders.

Key Words: Clinical translation; Neuroimmunity; Postoperative ileus; Gut-brain axis; Acupuncture

Core Tip: Based on emerging evidence for electroacupuncture at Zusanli (ST36) in treating postoperative ileus via the vagus nerve-mediated anti-inflammatory pathway, this article systematically details the mechanisms by which acupuncture regulates gastrointestinal motility through neural, immune, endocrine, and microbial pathways. It provides a strong rationale for integrating acupuncture, an effective non-pharmacological therapy, into enhanced recovery after surgery protocols. Future research focusing on multi-omics technologies, large-scale clinical trials, and microbiota-gut-brain interactions will be crucial for advancing the clinical application of acupuncture in gastrointestinal motility disorders.

INTRODUCTION

Postoperative ileus (POI) is a common complication after abdominal surgery, primarily characterized by gastrointestinal motility disorders. Clinical manifestations include abdominal distension, nausea, vomiting, and delayed passage of stool or flatus[1]. POI significantly prolongs hospital stays, increases health care costs, and adversely affects the quality of postoperative recovery and patients’ overall well-being[2]. Conventional western medical management of POI relies mainly on prokinetic agents, gastrointestinal decompression, and nutritional support. Although these approaches have some efficacy, their effectiveness is inconsistent, side effects are notable, and interindividual variability is considerable - particularly among elderly patients, those with multiple comorbidities, or those who have undergone extensive surgical trauma - in whom traditional pharmacological strategies often fall short[3].

Against this backdrop, the medical community is gradually shifting from the application of exogenous drugs toward activating the body’s own regulatory functions. Among these, the “gut-brain axis” - a complex bidirectional communication system between the brain and intestine - has emerged as an ideal target for treating gastrointestinal disorders. It regulates gastrointestinal function through multiple pathways, including neural, immune, endocrine, microbial, and central mechanisms[4]. Within this strategic framework, the randomized controlled trial published by Xu and Li[5] (who used the term ‘postoperative intestinal paralysis’) in the World Journal of Gastrointestinal Surgery is of considerable importance. The study demonstrated that electroacupuncture at the Zusanli acupoint (ST36) accelerates recovery of gastrointestinal function in patients with POI and, supported by robust experimental data, elucidated a core mechanism involving the vagus nerve-cholinergic anti-inflammatory pathway (CAP). This work bridges traditional acupuncture therapy with modern neuroimmunological theory, providing clinical evidence for the use of acupuncture in treating POI[5].

However, regulation of the gut-brain axis constitutes a complex integrated network. Building on the research by Xu and Li[5], this article further elaborates on the mechanisms through which acupuncture exerts effects via neural, immune, endocrine, microbial, and central pathways (Figure 1), and explores the hierarchical relationships and collaborative order among these pathways. It aims to highlight the advantages of the multidimensional and holistic regulatory role of acupuncture and to discuss its implications for transforming the clinical treatment paradigm for POI, as well as future directions for clinical translation.

Figure 1 Schematic diagram illustrating the mechanism by which acupuncture enhances gastrointestinal motility via the gut-brain axis. This figure depicts the multi-pathway mechanism of acupuncture: ① Acupuncture stimulation suppresses the overactivity of the hypothalamic-pituitary-adrenal axis, reducing glucocorticoid levels, thereby disinhibiting gastrointestinal motility; ② Simultaneously, the acupuncture signal is transmitted to the central nervous system via afferent nerves for integration, which enhances vagus nerve activity and promotes the release of acetylcholine (ACh); ③ ACh acts directly on enteroendocrine cells to upregulate the levels of motilin and gastrin, directly promoting gastrointestinal motility; ④ Furthermore, ACh inhibits macrophage function, reducing pro-inflammatory cytokine levels; ⑤ The decrease in pro-inflammatory cytokines attenuates their suppressive effect on inhibitors of gastrointestinal motility, such as vasoactive intestinal peptide and nitric oxide, thereby indirectly promoting motility; ⑥ This anti-inflammatory environment further helps to increase the abundance of beneficial gut bacteria; ⑦ Short-chain fatty acids produced by beneficial bacterial metabolism enhance the function of regulatory T cells, which in turn feedback to inhibit macrophages, forming a positive feedback loop that consolidates the anti-inflammatory effect; and ⑧ Finally, the enhanced gastrointestinal motility also helps to improve the intestinal environment, promoting the colonization and growth of beneficial bacteria, thereby completing a virtuous cycle. Solid arrow indicates activation or promotion; T-bar arrow indicates inhibition. Created with Figdraw (Supplementary material). HPA: Hypothalamic-pituitary-adrenal; Ach: Acetylcholine; EECs: Enteroendocrine cells; Treg: Regulatory T cell; SCFAs: Short-chain fatty acids; MTL: Motilin; GAS: Gastrin; VIP: Vasoactive intestinal peptide; NO: Nitric oxide.

MULTIFACETED MECHANISMS OF ACUPUNCTURE IN REGULATING THE GUT-BRAIN AXIS

Core mechanism supported by this study: Neuroimmune dialogue

This randomized controlled trial elucidates a bidirectional pathway involving “neuroimmune” interactions, which can be divided into two sequential and complementary processes. The first is direct suppression of immune responses by neural activity. The study showed that serum levels of pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β] were significantly reduced in patients after electroacupuncture at ST36, a hallmark of vagus nerve-CAP activation. Electroacupuncture activates afferent nerves, enhancing centrally mediated efferent vagal activity.

Acetylcholine (ACh) released from vagus nerve terminals binds to the α7 nicotinic ACh receptor on macrophages in intestinal tissues, inhibiting activation of the nuclear factor kappa B signaling pathway in these cells. Nuclear factor kappa B functions as the “master switch” of inflammatory responses; its inhibition directly blocks transcriptional synthesis of key pro-inflammatory factors such as TNF-α, thereby alleviating inflammation induced by surgical trauma[6].

The second process involves feedback regulation of neural function by the immune environment. The study also observed a significant decrease in the levels of inhibitory neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the electroacupuncture group. VIP and NO are important non-adrenergic, non-cholinergic inhibitory transmitters in the gut, and their excessive release is a direct cause of gastrointestinal motility disorders in POI. Notably, their expression and release are influenced by the local immune microenvironment. Pro-inflammatory cytokines (e.g., TNF-α) can stimulate enteric neurons and inflammatory cells to produce additional VIP and NO, thereby creating a vicious cycle[7]. Therefore, by suppressing inflammation via the CAP pathway, electroacupuncture indirectly alleviates the inhibitory effects of inflammation on the enteric nervous system, restores the balance between excitatory (e.g., cholinergic) and inhibitory neurotransmitters, and promotes gastrointestinal motility.

Furthermore, in addition to the vagus nerve pathway described above, the spinal-sympathetic axis is a crucial component of the gut-brain axis for neural regulation[8]. Surgical trauma and stress can activate the sympathetic nervous system, and its overexcitation releases substantial norepinephrine. This directly inhibits gastrointestinal motility by acting on β-adrenoceptors on intestinal smooth muscle[9]. In addition, these neurotransmitters act on adrenergic receptors on mucosal immune cells (e.g., macrophages), promoting the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6) while potentially suppressing the production of anti-inflammatory factors, thereby disrupting immune homeostasis and exacerbating local and even systemic inflammatory responses[10]. Studies suggest that acupuncture can modulate activity in the spinal dorsal horn and central sympathetic nuclei (such as the nucleus tractus solitarius and ventrolateral medulla), thereby inhibiting excessive sympathetic outflow[11]. This action not only removes direct inhibition of gastrointestinal smooth muscle but also creates a favorable neuroimmune environment for recovery of motility by mitigating neurogenic inflammation[11]. These findings indicate that acupuncture may achieve more comprehensive regulation of gastrointestinal function by coordinately modulating the facilitatory effect of the “vagal-parasympathetic” pathway and the inhibitory effect of the “spinal-sympathetic” pathway, thereby restoring bidirectional balance within the autonomic nervous system.

In summary, this study demonstrates that electroacupuncture at ST36 drives an efficient “neuro-immune” positive feedback loop in the treatment of POI: Activation of a neural pathway (vagus nerve) suppresses immune responses (reducing pro-inflammatory cytokines) and relieves immune-mediated inhibition of neural function (reducing VIP/NO), ultimately restoring gastrointestinal motility[5]. This process exemplifies bidirectional crosstalk between the nervous and immune systems and serves as a paradigm of the bidirectional regulatory effects of acupuncture. It also provides a mechanistic model for understanding acupuncture in the treatment of other inflammation-related gastrointestinal diseases. Nevertheless, the regulatory network of the gut-brain axis extends beyond this framework, connecting to broader pathways downstream of and peripheral to the neuroimmune effects.

Indispensable extension: The endocrine regulatory pathway

Although the study by Xu and Li[5] primarily anchors its mechanism in neuroimmune dialogue, one notable finding in their data cannot be overlooked: Electroacupuncture at ST36 significantly increased levels of motilin (MTL) and gastrin (GAS), two key hormones that promote gastrointestinal motility. This observation suggests that endocrine regulation - functioning as a relatively slow but sustained “slow-tuning” system within the gut-brain axis - is also an indispensable component of the comprehensive effects of acupuncture. The endocrine pathway does not operate in isolation but is interwoven with neural and immune mechanisms into a tightly coupled network.

First, modulation of gastrointestinal hormones by acupuncture is likely a direct downstream result of neural effects. The vagus nerve, as a critical pathway connecting the brain and gastrointestinal tract, extensively innervates the gastric antrum and duodenum and directly governs enteroendocrine cells (EECs)[12,13]. When electroacupuncture activates efferent vagal fibers, released neurotransmitters such as ACh can act on receptors on EECs, stimulating secretion of hormones such as MTL and GAS[14]. Thus, direct vagal innervation of EECs establishes a bridge from ‘instantaneous neural activation’ to ‘gradual endocrine response’, enabling tight temporal coordination between fast neural signals and slower hormonal regulation. MTL can trigger the “migrating motor complex” to clear intestinal contents[15], whereas GAS promotes gastric acid secretion and antral motility[16]. Therefore, the observed increase in hormone levels in this study is likely a direct result of vagal signals activated by electroacupuncture acting on EECs, providing a strong chemical impetus for the recovery of gastrointestinal motility.

Second, an improved immune microenvironment creates favorable conditions for normal hormone secretion. Persistent inflammation can directly inhibit EEC function, leading to dysregulated secretion of gastrointestinal hormones. For instance, cytokines such as TNF-α can interfere with hormone synthesis and release[17]. This study found that electroacupuncture effectively reduced levels of pro-inflammatory cytokines (TNF-α, IL-6), suggesting that by suppressing inflammation via the CAP pathway, acupuncture indirectly relieves suppression of EECs and restores their function. This enables EECs to respond appropriately to neural signals or other physiological stimuli, secreting adequate levels of MTL and GAS. This pattern reflects close dialogue between the immune and endocrine systems.

In summary, regulation of gastrointestinal hormones by acupuncture is not merely an isolated ‘slow process’; it functions as a rapid-response mechanism that begins synchronously with neural activation and acts in synergy with immune improvement. Direct innervation by the vagus nerve provides the initial impetus for rapid onset, whereas the subsequently improved immune microenvironment ensures sustainability and stability of this endocrine response. Together, these processes constitute a synergistic dialogue within the neuroimmune-endocrine network.

Furthermore, acupuncture may regulate higher-level endocrine axes, such as the hypothalamic-pituitary-adrenal (HPA) axis. Surgery, as a potent physiological and psychological stressor, activates the HPA axis and leads to massive release of glucocorticoids (e.g., cortisol)[18]. Glucocorticoids inhibit gastrointestinal motility and are significant endocrine factors in the development of POI. Extensive research indicates that acupuncture is an effective tool for stress modulation, potentially reducing excessive HPA axis excitability by regulating activity in key brain regions such as the paraventricular nucleus, thereby lowering circulating stress hormones and alleviating their inhibitory effects on gastrointestinal motility[19]. Although this study did not measure related indicators, this mechanism is a plausible component for explaining the holistic regulatory effects achieved by acupuncture.

In summary, the endocrine pathway plays a pivotal role in linking mechanisms in acupuncture treatment for POI. It functions both as an effector of neural signals (vagus nerve-mediated stimulation of hormone release) and as a beneficiary and responder to the immune microenvironment (reduced inflammation supporting normalized hormone secretion), while also potentially being influenced by central stress modulation. The MTL and GAS data in this study provide a window into this mechanism, suggesting that electroacupuncture at ST36 collaboratively reshapes a neuroimmune-endocrine microenvironment conducive to recovery of gastrointestinal function through multisystem cooperation. However, mechanistic exploration must extend further upstream, as trillions of gut microbes and their metabolites are emerging as additional regulators in this field.

Frontiers and prospects: The microbiota-gut-brain axis and central integration pathways

Potential role of the microbial pathway: Gut microbiota and their metabolites serve as biochemical messengers that connect the gut and the brain, playing a significant role in functional and inflammatory gastrointestinal disorders[20]. A body of evidence indicates that acupuncture can effectively reshape the composition of the gut microbiota[21]. Notably, in rat models of chronic atrophic gastritis and severe acute pancreatitis, electroacupuncture at ST36 has demonstrated a repeatable and specific regulatory pattern on the gut microbiota: It significantly promoted the proliferation of beneficial bacteria such as Lactobacillus, Bifidobacterium, Christensenellaceae, and Romboutsia, while effectively inhibiting the overgrowth of opportunistic pathogens including Desulfovibrio and Helicobacter[22,23]. More importantly, this specific optimization of the microbiota structure directly drives the synthesis of their functional metabolites - short-chain fatty acids (SCFAs) - with significant increases in butyrate levels observed in both independent animal models[22,23]. Based on this experimental evidence, we propose a reasonable scientific hypothesis: Although the study by Xu and Li[5] did not directly assess microbial metrics, the mechanism by which electroacupuncture at ST36 treats POI may be partially achieved through the above-mentioned pathway of “modulating specific microbiota - increasing SCFAs (particularly butyrate)”.

Within this pathway, butyrate plays a central role, primarily manifested in three aspects. In immune modulation, butyrate, as a histone deacetylase inhibitor, may enhance regulatory T cell function through epigenetic mechanisms, thereby suppressing excessive inflammatory responses[24]. This mechanism aligns well with the anti-inflammatory effects observed in the present study. In neural regulation, SCFAs can stimulate EECs to secrete neuroactive substances such as serotonin, which directly act on the enteric nervous system and may participate in the recovery of gastrointestinal motility via vagal afferent pathways[24]. In barrier reinforcement, butyrate, as a key energy source for colonic epithelial cells, has been proven to enhance intestinal barrier integrity, which is directly associated with the observed upregulation of tight junction proteins (occludin, zonula occludens-1) in animal experiments[23].

Therefore, we propose an integrated hypothesis: The mechanism by which electroacupuncture at ST36 treats POI may partly stem from its ability to specifically increase the abundance of beneficial bacteria (such as Lactobacillus and Christensenellaceae) in the gut, suppress harmful bacteria (such as Desulfovibrio), and promote the production of SCFAs including butyrate, thereby synergistically exerting anti-inflammatory, prokinetic, and barrier-repairing effects. Certainly, the specific role of this pathway, preliminarily validated in animal models, in human POI and its exact relationship with core pathways such as the vagus nerve still require final confirmation. Future studies that specifically measure dynamic changes in gut microbiota structure and SCFA levels in POI patients before and after electroacupuncture at ST36 will robustly test this hypothesis and further refine the mechanistic map of gut-brain axis regulation by acupuncture.

Central integration mechanisms: All peripheral signals, including neural, immune, endocrine, and microbial, are ultimately integrated at a higher level in the central nervous system. The brain, as the central command center in gut-brain axis communication, plays a core regulatory role[17]. Functional magnetic resonance imaging studies provide direct evidence for this mechanism, demonstrating that electroacupuncture at ST36 significantly modulates activity in multiple key brain regions[14].

The insula, a critical hub for receiving and processing visceral sensory information, is closely linked to visceral hypersensitivity when dysregulated[25]. In close concert, the anterior cingulate cortex integrates emotion, cognition, and pain, serving as a key region that contributes to anxiety and discomfort associated with gastrointestinal symptoms[26].

It is noteworthy that the insula and anterior cingulate cortex do not operate in isolation; together they form the core of the “salience network”. The primary function of this network is to identify and filter important stimuli from both internal and external sources. In POI, when surgical trauma induces intestinal inflammation and motility disorders, aberrant signals ascend to the central nervous system via pathways such as the vagus nerve and the spinal-sympathetic axis. The salience network evaluates the significance of these signals and translates them into neural activity that captures attention and generates perceived discomfort[27]. Simultaneously, the “default mode network”, when hyperactive under pathological conditions, promotes morbid over-attention and rumination on postoperative gut sensations (such as bloating and peristaltic sensations), thereby amplifying subjective discomfort and exacerbating anxiety[28]. Research indicates that acupuncture can synergistically regulate functional connectivity across multiple brain networks. The intervention not only optimizes the ability of the salience network to filter aberrant gut signals and allocate attention but also suppresses hyperactivity of the default mode network, reducing morbid self-focused attention to somatic sensations[29]. This bidirectional, network-level regulation helps simultaneously improve postoperative patients’ perception of pain and emotional state and provides a central explanation for the regulation of gastrointestinal motility and the alleviation of visceral hypersensitivity. The regulatory effects of these higher-order brain networks are ultimately executed through the hypothalamus - the key hub of the autonomic nervous and neuroendocrine systems. As the principal control center for the autonomic nervous system and the HPA axis, the hypothalamus translates neural signals generated by acupuncture in the central nervous system into specific physiological instructions that modulate stress responses and restore autonomic balance[14].

In summary, the therapeutic effects of acupuncture on gastrointestinal function arise not only from direct actions at the peripheral organ level but also from modulation of the excitability of the above brain regions and their associated functional networks (such as the salience and default mode networks). This central integration, mediated through key hubs such as the hypothalamus, effectively restores functional homeostasis of the entire gut-brain axis in a top-down manner. Therefore, acupuncture can simultaneously exert multi-target, holistic regulatory effects on gastrointestinal motility, inflammatory responses, pain perception, and emotional state.

A multi-pathway integrated network of acupuncture in regulating the gut-brain axis

In summary, the mechanism by which acupuncture treats POI is a multi-pathway, hierarchical, and dynamic process. Regulation begins at the local functional tier: On the one hand, acupuncture initiates rapid effects primarily through neural pathways, directly suppressing macrophage-mediated inflammatory responses[7]; on the other hand, it promptly stimulates the release of gastrointestinal hormones from EECs, establishing a foundation for motility recovery[14]. Subsequently, the suppressed inflammatory microenvironment (immune pathway) alleviates its inhibitory effects on enteric neurons and endocrine cells. Meanwhile, the improved intestinal milieu drives remodeling of the microbial community (e.g., promoting proliferation of beneficial bacteria and production of SCFAs)[21]; this remodeling, in turn, feedback to the immune system, forming a positive feedback loop that reinforces the anti-inflammatory effect[24]. Ultimately, the process reaches the central integration tier, where all ascending signals converge in the brain. Through higher-order regulation of key brain networks and autonomic centers, functional homeostasis of the gut-brain axis is reset in a top-down manner[14,29]. Thus, acupuncture acts through a systemic biological process that progresses from rapid to sustained, from local to systemic, and from peripheral to central effects. Viewing these pathways as a dynamic, interwoven, integrated network - rather than as isolated, parallel mechanisms - is essential for fully understanding the scientific basis underlying the therapeutic philosophy of acupuncture, “holistic regulation”.

CLINICAL SIGNIFICANCE AND BROAD PROSPECTS: FROM MECHANISM TO DISEASE TRANSLATION

The study by Xu and Li[5] not only confirms the clinical efficacy of electroacupuncture for POI but also provides robust evidence for the regulation of the “gut-brain axis” by acupuncture, with significant implications for the management of gastrointestinal diseases. In treating POI, conventional pharmacological strategies often adopt a “blocking” or “inhibitory” approach, such as using prokinetic agents to forcibly activate intestinal motility or anti-inflammatory drugs to broadly suppress immune responses. However, these methods are frequently accompanied by side effects and often fail to address the fundamental problem of multisystem dysregulation[30]. In contrast, the mechanism of electroacupuncture elucidated in this study highlights an alternative strategy: Activating the body’s inherent, highly integrated self-repair network to achieve synergistic reconstruction of homeostasis across the nervous, immune, and endocrine systems[6]. This therapy, characterized by mobilizing endogenous resources, shows unique advantages and a favorable safety profile for treating complex syndromes such as POI, which involve multiple intertwined factors.

Furthermore, this study provides strong evidence supporting the incorporation of acupuncture into enhanced recovery after surgery (ERAS) protocols. ERAS aims to reduce surgical stress and accelerate patient recovery through a series of evidence-based interventions[31]. As a nonpharmacological, low-cost intervention with a favorable safety profile, electroacupuncture aligns well with the philosophy and clinical needs of ERAS because of its ability to promote gastrointestinal motility and suppress inflammatory stress[32]. Building on the successful practice reported in this study, an exemplary electroacupuncture protocol that integrates tightly into the ERAS workflow is proposed. Core parameters should follow the original study: Initiate the intervention within 24 hours after surgery; select bilateral Zusanli (ST36) acupoints; apply continuous-wave stimulation; set the current intensity at a level tolerable and comfortable for the patient; and deliver 30-minute sessions once daily. To better align with ERAS goals, the treatment course may be flexible rather than fixed at 7 days. Restoration of normal flatus and defecation can serve as the key indicator for concluding treatment, which is typically achieved within 3 days to 5 days after surgery. It must be noted with caution that the significance of this mechanistic framework extends beyond POI, providing a referential model and testable scientific hypotheses for understanding acupuncture in the treatment of other gut-brain interaction disorders.

Dysfunction of the gut-brain axis is a common pathophysiological basis for multiple functional and inflammatory gastrointestinal diseases[33]. The multifaceted effects demonstrated in this study directly address core aspects of these disorders. For instance, in irritable bowel syndrome, patients commonly experience visceral hypersensitivity, motility abnormalities, low-grade inflammation, and microbial dysbiosis. Electroacupuncture can simultaneously alleviate symptoms such as abdominal pain, bloating, and bowel habit irregularities through mechanisms that include central analgesia, motility regulation, anti-inflammatory effects, and potential microbiota modulation[34]. In functional dyspepsia, electroacupuncture alleviates symptoms such as early satiety and postprandial fullness by regulating low-grade inflammation, modulating gut-brain axis function, improving microbial imbalance, and correcting abnormal gastric acid secretion[35]. For inflammatory bowel disease, although the primary cause is autoimmune dysfunction, acupuncture can still assist in alleviating functional symptoms such as abdominal pain and diarrhea through anti-inflammatory and neural regulatory effects, thereby improving patients’ quality of life[36]. However, substantial differences exist among POI, irritable bowel syndrome, functional dyspepsia, and inflammatory bowel disease in core etiology, pathophysiological focus, and clinical manifestations. Therefore, directly translating the mechanisms identified in this study to these disorders remains a reasonable inference based on shared pathways (i.e., the gut-brain axis), the applicability and efficacy of which require prompt validation through independent clinical and mechanistic studies specific to each condition.

CONCLUSION

At the mechanistic level, future research should be advanced by integrating multi-omics technologies. The necessity and sufficiency of each pathway in acupuncture effects can be tested individually using gene-edited animal models, chemogenetics, and microbial depletion or colonization experiments, thereby clarifying causal and temporal relationships[37]. Meanwhile, integrating multi-omics approaches such as metagenomics, metabolomics, and proteomics can systematically characterize dynamic changes in host-microbial co-metabolism after acupuncture, further identifying effector molecules and regulatory targets beyond butyrate[38]. This strategy will enable a more comprehensive analysis of the material basis underlying systemic biological effects of acupuncture. For clinical translation, efforts should continue to advance the precision and standardization of acupuncture therapy. Although this study confirms the efficacy of electroacupuncture at ST36, optimal stimulation parameters (waveform, frequency, intensity, treatment course) require further optimization. Moreover, to generate higher-level evidence supporting widespread inclusion of acupuncture in clinical guidelines, large-scale, multicenter, high-quality randomized controlled trials are essential. A core methodological challenge in such trials is the design of a credible ‘sham acupuncture’ control that successfully blinds participants and assessors while adequately excluding nonspecific effects, including placebo responses and tactile stimulation.

Future research should conduct dose-effect studies across disease types to establish personalized stimulation protocols. In addition, developing objective, multidimensional biomarker panels for efficacy prediction (such as neuroactive indicators, cytokine profiles, and microbial signatures) will help identify optimal patient populations and enable precision treatment. The primary advantage of such biomarkers is the ability to complement patient-reported outcomes by providing quantifiable, objective evidence for evaluating the efficacy of acupuncture, thereby strengthening the persuasiveness and reliability of the findings. Regarding interdisciplinary integration and innovative therapies, active exploration of synergistic effects between acupuncture and microbial agents, pharmaceuticals, and novel physical therapies is warranted. For example, studies should assess whether combining electroacupuncture with specific probiotics enhances efficacy through synergistic regulation of the microbiota-immune-neural axis. Such combined strategies may overcome limitations of existing therapies and support the development of treatment paradigms based on the regulation of endogenous networks.

In summary, the study by Xu and Li[5] establishes a foundation for understanding acupuncture in treating POI, whereas future explorations should advance toward more integrated and precise approaches. Through interdisciplinary collaboration and innovative integration, acupuncture - an ancient medical practice - has the potential to evolve into a widely accepted integrative therapeutic approach in modern medicine, applicable to a broader patient population.