Visual abstract

Introduction

Osteoarthritis (OA) is a prevalent, heterogeneous degenerative joint disease characterized by articular cartilage loss, subchondral bone remodeling, osteophyte formation, and pain [1,2]. Low-grade inflammatory processes may contribute in some phenotypes, but autoimmune features are not universal [1,2]. There are more than 7% of adults worldwide affected by OA [3]. In the United States, the annual per-person health care costs attributable to OA have been estimated at approximately $700 to $15,600 in 2019 [4]. Alterations in T-cell subsets and other immune pathways have been reported in subsets of OA and may contribute to persistent low-grade inflammation and clinical manifestations; however, causality and generalizability remain under investigation [5]. Several reports have been highlighted in a review on the gut–joint axis, in which gut microbes contribute to host homeostasis, immune system development and maturation, and the production of neurotransmitters and other bioactive metabolites, with potential relevance to OA [6]. Within traditional medicine frameworks, acupuncture is posited to support homeostatic regulation and has long been used for musculoskeletal and metabolic conditions [7,8]. Emerging evidence from clinical and preclinical studies suggest that acupuncture may be associated with shifts in gut microbial composition and function however, definitive links to joint structural or functional outcomes in OA have not yet been established [9,10]. Accordingly, this review examined the role of the gut microbiota in OA and reviewed the brain–gut–joint axis mechanisms through which acupuncture might influence immune and neuroendocrine pathways relevant to OA.

Materials and Methods

Evidence linking OA, acupuncture, the gut microbiota, and the immune system was synthesized using PubMed to search for studies from inception through to 25 June 2025. The core strategy of this narrative review was to combine terms for OA, acupuncture (including electroacupuncture and manual acupuncture), and the gut microbiota/microbiome. To capture mechanistic studies beyond OA, acupuncture was also combined with neuroimmune or neuroendocrine terms. The full Boolean strings are provided in Supplementary Table S1. No restrictions were placed on study design. Two reviewers independently screened titles and abstracts, and disagreements were resolved by discussion. Full texts that met the inclusion criteria (peer-reviewed, original research in English, addressing OA and acupuncture with microbiome or immune endpoints, or mechanistic studies of acupuncture involving neuroimmune or neuroendocrine pathways) were assessed. Articles which were not original, an editorial, a protocol without results, not written in English, or did not include an acupuncture intervention were excluded from the study. Given the narrative scope of this review, risk-of-bias was not assessed and meta-analysis was not performed.

Innate and Adaptive Immunity in OA

Joint damage is caused by various factors, including aging, metabolic diseases, and traumatic injury which lead to loss of cartilage with extracellular matrix (ECM) degradation, chondrocyte death, and subchondral bone remodeling during OA. Damage to the cartilage ECM, including proteoglycans and collagen, leads to the activation of damage-associated molecular signals that activate innate immune system components, such as toll-like receptors in immune cells, and release of pro-inflammatory cytokines, and ECM-degrading enzymes such as matrix metallopeptidase (MMP), and protein from a disintegrin and metalloproteinase harboring thrombospondin motifs family [11].

Hypertrophic chondrocytes are located at the transition zone between cartilage and ossified bone (e.g., the growth plate and articular cartilage) and play a key role in endochondral ossification. As a normal differentiation process, chondrocytes endochondral ossification is involved in bone formation. In contrast, stress, such as inflammation, and pressure within the joint, abnormally promotes the differentiation of hypertrophic chondrocytes [12]. This occurs through increased expression of MMP13 and runt-related transcription factor 2, which eventually induce subchondral bone remodeling, such as growth of osteophytes, and appearance of subchondral sclerosis [12]. In addition, angiogenesis in OA promotes communication between bone and cartilage. This is mediated by proangiogenic factors, such as transforming growth factor β (TGFβ) and vascular endothelial growth factor, and is accompanied by ingrowth of sensory and sympathetic nerve fibers into noncalcified articular cartilage, osteophytes, and the inner meniscus. Infiltration of immune cells is promoted, the death of chondrocytes occurs, and this results in structural damage to the joint and joint pain [13]. Furthermore, damage to the meniscus, ligaments, and joint capsule can reduce joint stability and exacerbate wear. In subsets of OA, excessive activation of innate immune pathways (in the setting of joint inflammation and tissue injury) may initiate a feed-forward cycle. This may worsen the damage, and facilitate increased antigen presentation to T cells, which may contribute to adaptive immune system engagement and potential shifts in the CD4+ T-helper (Th)1/Th2 balance. CD4+ regulatory T (Treg) cells express forkhead box P3, secrete transforming growth factor β 1, and produce interleukin (IL)-10 which suppresses the proliferation of Th cells and the production of pro-inflammatory cytokines, thereby suppressing autoimmune diseases such as rheumatoid arthritis. In addition, an imbalance in Th17/Treg cells, which contribute to maintaining the immune system balance, can promote rheumatoid arthritis, and OA development and progression [5]. Thus, disruption of the adaptive immune system may ultimately lead to the loss of ECM components, such as Type II collagen and aggrecan, through a long-term inflammatory response.

Role of Gut Microbiota in OA

Previously, joints were thought to be relatively unaffected by gut microbes as they are sterile and have relatively poorly developed blood vessels. However, an increasing number of studies have reported dysbiosis in patients with OA, highlighting the importance of the role of gut microbiota in OA [5, 6]. In a large clinical study, conducted by Yu et al [14], on patients with OA of the knee and hip it was reported that the bacteria belonging to the order Desulfovibrionales, family Methanobacteriaceae, and genus Ruminiclostridium5 showed the highest causal relationship with the risk of knee OA [14]. Similarly, in a study by Wang et al [15] based on the findings of 16S rDNA gene sequencing of stool samples, it was reported that the 81 bacteria, at the genus level, differed significantly between healthy volunteers and patients with OA. In a study by Loeser et al [16] no significant difference in α- and β-diversity or genus level composition was reported between healthy volunteers and obese patients with OA. However, lipopolysaccharide (LPS) levels in blood serum were higher in patients with OA than in healthy volunteers. The authors suggested that this reduced gut barrier function may compromise gut permeability. A relationship between gut microbiota and OA has also been reported in preclinical studies [17–21]. High-fat diet (HFD)-induced obesity has been replicated in animal models to study low-grade gut and systemic inflammation [22]. Rats fed an HFD for 28 weeks exhibited gut dysbiosis and increased serum LPS levels, as well as damaged chondrocytes in the joints [17]. Notably, the aggravation of OA in mice that received fecal microbiota transplantation from patients with OA provided evidence that gut microbiota plays a key role in OA development and progression [18]. Moreover, gut microbial dysbiosis and joint function improved following probiotic and prebiotic intake in patients with OA, and the HFD-induced OA rat model [19–21].

Direct experimental evidence linking acupuncture-induced neural modulation to joint-specific outcomes via gut microbiota is limited, but the integration of these systems provides a plausible mechanistic framework.

Regulation of the Adaptive Immune System by Gut Microbiota

Gut microbiota plays a crucial role in regulating digestion and metabolism, as well as the innate and adaptive immune systems (Figure 1). The host provides nutrients and a living environment for the microorganisms, while the microorganisms influence the development of the immune system. This maintains homeostasis of the body and protects the body from external pathogens. B cells produce various secretory immunoglobulin (Ig)A antibodies in response to commensal gut microbes which play an important role in gut homeostasis. Secretory IgA is generated through both T cell-dependent and -independent pathways. T cell-dependent IgA interacts with gut microbes to support microbial balance and promotes the expansion of forkhead box P3+ Treg cells which maintain homeostatic IgA responses [23]. This helps prevent disruption of gut homeostasis and excessive inflammatory reactivity. In the absence of B cells or IgA, the intestinal epithelium and the gut microbiota undergo compositional changes driven by upregulation of epithelial innate immune defense mechanisms via interferon-inducible response pathways [23]. Treg cells play a critical role in maintaining homeostasis by providing a pool of T cells that protect the entire body from external pathogens. A subset of immune cells, Th17, can differentiate into noninflammatory or inflammatory cytokines depending on specific bacterial stimuli, and are associated with host protection, and inflammatory conditions and diseases. Cytotoxic CD8+ T cells, which are specialized at eliminating intracellular pathogens and cancer cells, are activated by short-chain fatty acids such as butyrate, which are metabolites of gut microbiota [24]. Primary bile acids secreted into the intestine can be converted by the gut microbiota into secondary bile acids, which exert various effects, including regulation of intestinal retinoid-related orphan receptor γ+ Treg cell homeostasis [25]. T follicular helper (Tfh) cells are a subset of CD4+ T cells that assist B cells in antibody formation and play an important role in the immune system. Tfh cells interact with the gut microbiota and help maintain microbial homeostasis. Segmented filamentous bacteria promote Tfh cell differentia-tion by limiting IL-2 availability to CD4+ T cells, thereby enhancing the expression of B-cell lymphoma (Bcl)-6, a key regulator of Tfh cell development. Furthermore, as segmented filamentous bacteria-induced Tfh cells can contribute to autoantibody production, the microbiota-Tfh axis is implicated in autoimmune diseases such as rheumatoid arthritis [26]. A tissue-resident dendritic cell (DC) can directly capture bacteria by extending its dendritic projections beyond the epithelial barrier. Gut microbiota activates the syk kinase-coupled signaling pathway in DCs, inducing the release of IL-17 and IL-22 from CD4+ T cells. In addition, noncanonical NF-κB-inducing kinase is a key regulator of DC function, and DC-specific NF-κB-inducing kinase is associated with intestinal IgA secretion and maintenance of gut microbiota homeostasis [27]. Furthermore, invariant natural killer (NK) cells, although less studied than other immune cells, may contribute to cancer cell elimination by interacting with the gut microbiota [28].

Effects of Acupuncture

1. Immune modulation and gut microbiota in patients with OA

Acupuncture therapies, including electroacupuncture (EA) and manual acupuncture (MA), have been used to treat metabolic and musculoskeletal disorders [7,8]. Randomized clinical trials in knee OA show that EA/MA can improve symptoms and modulate systemic inflammation [29–31]. In an 8-week randomized controlled trial, EA and MA reduced circulating inflammatory mediators (TNF-α, IL-1β, IL-13) alongside improvements in visual analogue scale (VAS) pain scores and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores [29]. Consistent with these findings, an immune-repertoire sequencing study in patients with knee OA reported that EA rebalanced circulating T-cell homeostasis, and lowered serum IL-8 and IL-18, as well as MMP-3 and MMP-13 [30]. Neutrophil transcriptomic perturbations (e.g., C-X-C motif chemokine ligand 2, interferon regulatory factor 8, platelet endothelial aggregation receptor 1) also normalized following treatment [30]. In a multicenter three-arm randomized controlled trial (N = 301) an intensity–response pattern was demonstrated where strong EA (> 2 mA) produced larger and earlier gains, in reduced pain and WOMAC score than weak EA (< 0.5 mA), or sham EA following 2 weeks of treatment [31].

In addition to these clinical and immunological findings, preclinical evidence and human trials have directly evaluated gut microbiome changes (Table 1 [32–34]). In a randomized clinical trial of EA treatment of knee OA which included healthy (n = 30), diseased (n = 30), and sham control (n = 30) groups, participants received 24 sessions of EA over 8 weeks, and provided stool samples at baseline and post-treatment for 16S ribosomal ribonucleic acid sequencing. Compared with sham-acupuncture, EA produced larger reductions in WOMAC total scores and NRS pain scores [32]. Alpha diversity was largely unchanged, whereas β-diversity in the EA group shifted toward a healthy profile. EA also reversed knee OA-associated taxa, with increased numbers in Bacteroides, Agathobacter, and the Eubacteriumhallii_group, and a decrease in Streptococcus. Among the clinical responders, increases in the number of Bacteroides and Faecalibacterium, and a reduction in Streptococcus were more pronounced. Taxonomic shifts correlated with clinical outcomes; higher relative abundances of Bacteroides and Agathobacter negatively correlated with NRS scores, WOMAC total scores, and WOMAC subscale scores (pain, stiffness, function), whereas Streptococcus showed positive correlations with these outcomes [32]. In addition, in a randomized clinical trial study of knee OA using a combined regimen, it was reported that EA and Tuina improved WOMAC scores for reduced pain, stiffness, and improved function, whilst modulating gut microbiota [33]. Beta-diversity analyses showed distinct pre- versus post-treatment community patterns in the EA+Tuina group, and both groups (EA and EA+Tuina) exhibited significant shifts in microbial abundance with notable variations in Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes, findings consistent with an improvement in dysbiosis [33]. However, the intervention combined 2 modalities without investing a group who received Tuina alone, therefore attribution beyond the additive effects of EA should be interpreted cautiously.

2. Microbiota–immune interactions in experimental OA models

In experimental models of OA, EA at ST36 and GB34 attenuated local joint pathology while modulating inflammatory processes (Table 1 [32–34]). In HFD-induced OA, EA reduced cartilage degradation and down-regulated matrix-degrading enzymes and pro-inflammatory mediators, consistent with improved histological and molecular indices of joint homeostasis [34]. Furthermore, EA increased the Bacteroidetes/Firmicutes ratio, and was associated with lower relative abundances of Akkermansia, Butyricimonas, and Clostridium, alongside a higher relative abundance of Lactococcus [34]. Notably, the HFD elevated LPS concentrations in blood serum and articular synovial fluid. EA was associated with lower LPS levels and reduced activation of TLR4/NF-κB signaling in cartilage, findings consistent with attenuation of dysbiosis-related endotoxemia and a potential improvement in gut barrier function [34].

Effects of Acupuncture (Non-OA Mechanistic)

1. Neuro–immune pathways (vagal and sympathetic mechanisms)

In human knee OA randomized, sham-controlled trial of transcutaneous vagus nerve stimulation (with an auricular electrode) reported improvements in the level of pain and function (e.g., VAS, Knee Injury and Osteoarthritis Outcome Score, PainDETECT Questionnaire, Douleur neuropathique 4) versus the sham control group suggesting that engaging vagal pathways may influence symptoms [35]. Clinical studies have also described autonomic dysregulation in knee OA (reduced high-frequency heart-rate variability at rest and blunted autonomic–nociceptive stress responses) and sympathetic signaling in OA-related inflammatory processes have been implicated [36,37]. Against this backdrop, EA/MA are thought to engage autonomic neuro–immune circuits (Figure 2). Lower-intensity stimulation preferentially recruits vagal cholinergic signaling, whereas higher intensities engage sympathetic pathways [38,39]. Causal manipulations are consistent with this framework. Vagotomy abolishes EA/MA-induced effects, indicating reliance on vagal pathways [38,40–42], whereas splenectomy and adrenalectomy at higher stimulation intensities attenuates these effects, implicating β-adrenergic sympathetic pathways [39,43].

The autonomic nervous system, comprising the sympathetic nervous system and parasympathetic nervous system, regulates vital physiological functions. Specific regions of the hypothalamus and the brainstem modulate its activity. The vagus nerve plays a crucial role in bidirectional communication between the brain and the gut, transmitting both motor and sensory signals. This neural pathway is regulated by the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) of the medulla oblongata. Tracer studies from ST36 and the stomach implicate the lateral hypothalamus, paraventricular nucleus, NTS, DMV, and raphe nuclei in the autonomic regulation of the gastrointestinal tract [44], and somatosensory inputs from ST36 ascend to these centers [45]. In a mouse model of acute pancreatitis, EA at ST36 activated α7-nicotinic acetylcholine receptor-dependent anti-inflammatory signaling in the pancreas via vagal acetylcholine release; cervical vagotomy abolished this effect, indicating dependence on vagal efferents [40]. Low-intensity stimulation further recruits a Prokr2-positive sensory–vagal efferent–adrenal circuit that culminates in adrenal catecholamine release, a configuration commonly referred to as the vagal-adrenal axis [38]. Consistent with central involvement, EA stimulation at ST36 or ST37 increases electrophysiological firing within the NTS and the DMV, and enhances gastric activity [46]. In the LPS-induced endotoxemia mouse model, MA at ST36 has also been shown to activate vagal and splenic nerves arising from the dorsal vagal complex, and suppress production of pro-inflammatory cytokines such as TNF-α [42]. In a burn/scald-induced gut ischemia model in the rat, cervical vagotomy abolished ST36 EA-induced improvements in gastrointestinal motility and mucosal blood flow, underscoring the requirement for vagal signaling [41]. In a murine breast-tumor model, EA at ST36 lowered circulating TNF-α, IL-1β, and IL-6, increased IL-10, and enhanced the proportion and cytolytic activity of CD8+ T cells and NK cells; these effects were eliminated by vagotomy, consistent with vagal dependence [47].

The sympathetic pathways are engaged in a stimulation parameter-dependent manner. In acute inflammation models, EA at ST36 engages frequency-dependent sympathetic mechanisms: (1) at low-frequency stimulation of < 2 Hz, the sympathetic postganglionic neurons are activated with catecholamine release, reducing leukocyte migration in a zymosan air-pouch model and attenuating carrageenan-induced paw swelling and inflammation; (2) at a frequency of 1 Hz, the sympathetic postganglionic neurons are stimulated; and (3) stimulation at 120 Hz requires involvement of the sympatho-adrenal medullary axis, and the anti-inflammatory effects are abolished by propranolol (β-adrenergic receptor antagonist), but not by RU-486 (glucocorticoid receptor antagonist), consistent with β-adrenergic rather than glucocorticoid mediation [39,48]. In support of these findings, in an LPS-induced endotoxemia rat model, high-intensity EA at ST25 preferentially engaged the sympatho-adrenal medullary pathway, and was associated with increased circulating norepinephrine, reduction in IL-6 and IL-1β, with a rise in IL-10, and improved survival, with an intensity optimum around 3 mA [49]. Furthermore, using an LPS–induced systemic inflammation model, Liu et al [38] mapped somatotopy- and intensity-dependent autonomic circuits engaged by EA. Low-intensity hindlimb stimulation (post-ST36, 0.5 mA) drove a vagal–adrenal anti-inflammatory pathway that required NPY+ adrenal chromaffin cells, and this effect was abolished by subdiaphragmatic vagotomy. This paradigm reduced TNF-α (serum/spleen) and improved survival. In contrast, high-intensity abdominal stimulation (ST25, 3 mA) recruited spinal sympathetic pathways that activated NPY+ splenic noradrenergic neurons and modulated inflammation via adrenergic-receptor, showing disease-state–dependent effects. Intersectional genetic ablation of NPY+ sympathetic neurons or adrenal chromaffin cells disrupted the corresponding EA effects, establishing pathway dependence [43].

Taken together, these findings indicate that acupuncture may modulate gastrointestinal and systemic inflammatory tone via coordinated vagal and sympathetic mechanisms (Tables 1 [32–34] and 2 [38–43,46–49]). Through improvements in gastrointestinal motility, mucosal perfusion, and immune signaling, vagal engagement may contribute to the regulation of gut microbiota diversity and composition following acupuncture.

2. Neuroendocrine system (hypothalamic–pituitary–adrenal axis)

In a single, blind, sham-controlled, randomized trial of EA treatment of knee OA, it was reported that improvements in WOMAC and VAS scores were accompanied by increased plasma β-endorphin and reduced cortisol, and these findings were consistent with involvement of the hypothalamic-pituitary-adrenal (HPA) axis alongside symptomatic benefit [50]. Within this clinical context, preclinical studies indicate that EA can modulate neuroendocrine–immune signaling along the HPA axis, providing mechanistic support for a plausible link between HPA modulation and symptom change (Figure 2; Table 3 [51,52]). In the complete Freund’s adjuvant-induced inflammatory pain rat model, the anti-inflammatory actions of EA at GB30 were diminished in adrenalectomized animals, implicating adrenal/HPA involvement in downstream immune effects [51]. In a functional-dyspepsia rat model, characterized by stress-related low-grade inflammation and mucosal barrier impairment, EA stimulation at RN12 and ST36 improved the stress state, reduced mast cell activation, and inflammatory injury, and was associated with modulation of brain-gut CRF signaling, consistent with HPA axis engagement [52]. More broadly, work on the brain-gut microbiota axis links HPA activity to microbial and immune cues, providing contextual support for a neuroendocrine system through which acupuncture could influence systemic inflammatory tone [53].

Discussion

The findings in this review support plausible involvement of the brain-gut-joint axis, by which acupuncture may modulate microbiota-linked immune dysregulation in OA. However, evidence for the neuro-immune and neuroendocrine pathways of acupuncture are derived largely from non-OA mechanistic models, with supportive data from a study in healthy volunteers; thus, current evidence should be regarded as indirect with respect to OA.

This review is narrative rather than following the Preferred Reporting Items for Systematic reviews and Meta-Analyses, consequently, we did not perform a formal risk-of-bias assessment or a meta-analytic synthesis. The evidence base linking acupuncture to the gut microbiota and joint outcomes in OA remains limited. Only 2 human studies assessed microbiome endpoints, and neither established a longitudinal, causal chain from acupuncture to microbiome change to joint structure or function. Several mechanistic findings are derived from non-OA models (for example, endotoxemia, pancreatitis, tumor models) and should be regarded as indirect when extrapolated to OA. Clinical trials vary in acupoint prescriptions, stimulation parameters (current, frequency, duration), dosing schedules, and control conditions (including a combination regimen), which complicates effect attribution and comparative interpretation. Potential confounding in microbiome studies, including dietary intake, medications (such as non-steroidal anti-inflammatory drugs, proton pump inhibitors, antibiotics, and probiotics), regional and cultural factors, bowel habits, and sample handling, was incompletely controlled and/or reported in several studies. OA itself is heterogeneous; inflammatory phenotypes (for example, obesity-associated disease with elevated LPS burden) are not universal, so generalization across OA subtypes should be made with caution. Small sample sizes, short follow-up, and possible publication bias further limits inference, including the durability of benefit.

Implications and future work ought to prioritize OA phenotypes most likely to benefit from microbiota-immune modulation, such as obesity-related OA with evidence of endotoxemia or metabolic inflammation, and participants need to be stratified by baseline inflammatory status and relevant comorbidities. Multicenter, randomized, sham-controlled trials with prespecified protocols and registration, adherence to Consolidated Standards of Reporting Trials with Standards for Reporting Interventions in Clinical Trials of Acupuncture for acupuncture reporting, and the use of an established microbiome framework such as Strengthening the Organization and Reporting of Microbiome Studies is recommended. Interventions can be standardized around a core prescription (for example, ST36 with or without GB34 with clearly defined adjuncts) and stimulation parameters need to be reported completely (current, frequency, pulse width, session length, number and spacing of sessions); intensity-stratified dosing informed by prior RCTs (strong versus weak EA) is reasonable with safety monitoring.

The WOMAC scores (for pain and function) need to be used to measure the primary outcomes, with repeated measures at baseline, during treatment, end of treatment, and follow-up, and follow-up of at least 3 to 6 months needs to be planned to assess durability of treatment and outcome. Secondary endpoints that link mechanism to symptoms, including systemic cytokines (e.g., IL-6, TNF-α), cartilage turnover markers (e.g., MMP-3 and MMP-13), immune phenotypes (e.g., Treg/Th17 balance and NK activity), autonomic readouts (e.g., heart rate variability), and HPA axis markers (e.g., cortisol or corticosterone proxies) need to be prespecified. The microbiome and barrier biology needs to be addressed with harmonized sampling and preregistered pipelines, using 16S ribosomal ribonucleic acid and/or shotgun metagenomics as appropriate, together with short-chain fatty acid quantification, bile acid and tryptophan/indole metabolites, and markers of barrier function or endotoxemia (LPS or lipopolysaccharide-binding protein, zonulin, intestinal fatty acid-binding protein). Where feasible, stool samples need to undergo targeted mucosal assessments.

Preclinical studies are needed to pair EA or MA with gnotobiotic transfer from treated donors, antibiotic depletion and restoration, and multi-omics (metagenome, metabolome, and transcriptome) are needed to test whether microbiota shifts are necessary and sufficient for joint protection. Human studies can incorporate mediation analyses to evaluate whether microbiome or metabolite changes account for clinical improvements. When isolating acupuncture effects on the microbiome pathway, monotherapy arms are necessary. Once effects are defined, pragmatic combinations, such as diet or weight-loss programs, can be evaluated in phenotypes with prominent dysbiosis or endotoxemia using factorial designs to assess additivity. Trial blinding, treatment fidelity and adherence metrics, and transparent sharing of data, code, and checklists will improve interpretability and reproducibility.

Conclusion

Acupuncture can potentially be positioned as a complementary option for OA symptom management. However, definitive evidence for disease-modifying effects remains to be established. Moving forward requires rigorously designed, preregistered clinical trials with standardized protocols, validated endpoints, harmonized microbiome and inflammatory measures, and careful control of confounders. In parallel, mechanistic investigations should delineate causal pathways within the brain-gut-joint axis, integrating autonomic, neuroendocrine, and immune interfaces with the microbiome, and define predictive biomarkers and phenotypic strata that identify likely responders and mechanisms of benefit.

Supplementary Materials

Article information

Author Contributions

Conceptualization: JHJ. Investigation: JHJ, SHH, and YS. Visualization: JHJ and JYO. Writing original draft: JHJ. Writing - review and editing: JHJ and HJP.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Author Use of AI Tools Statement

The authors used AI-based tools (e.g., ChatGPT, Grammarly) only to improve grammar and language clarity during manuscript preparation. All content, interpretation, and conclusions are the sole responsibility of the authors.

Funding

This research was supported by grants from the National Research Foundation of Korea funded by the Korean government (grant no.: RS-2024-00409969, 2021R1A2C2006818, and 2022M3A9B6017813).

Ethical Statement

No ethical approval was needed.

Figure 1

Relationship between the gut microbiota and the immune system in osteoarthritis. Gut microbiota regulates immune cells and cytokines, influencing Th1, Th17, Treg, Tfh, and CD8+ T cell activity via metabolites, Bcl-6, SCFA, and LPS–TLR4 signaling. Dysbiosis disrupts cartilage metabolism, driving inflammation, autoimmunity, and OA progression.

LPS = lipopolysaccharide; OA = osteoarthritis; RANKL = receptor activator of nuclear factor κB ligand; SCFA = short-chain fatty acid; SFB = segmented filamentous bacteria; Tfh cell = T follicular helper cells; TLR4 = toll-like receptor 4.

Figure 2

The role of the brain-gut-joint axis in acupuncture for treating OA. Acupuncture modulates brain–gut–joint neuroimmune pathways via HPA, vagal, and sympathetic axes. By regulating catecholamines, stress hormones, and immune cells, it reduces dysbiosis, endotoxins, and inflammation, restoring immune balance and protecting cartilage in osteoarthritis.

ACTH = adrenocorticotropic hormone; CAs = catecholamines; CRH = corticotropin-releasing hormone; EA = electroacupuncture; HPA = hypothalamic-pituitary-adrenal; LPS = lipopolysaccharide; MA = manual acupuncture; NK = natural killer; OA = osteoarthritis.

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