Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review

Abstract

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain–gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

Methods

We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)–based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain–gut axis–modulating interventions in ME/CFS or Long COVID was conducted.

Results

The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome–modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Conclusion

Brain–gut axis–based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.

Supplementary information

The online version contains supplementary material available at 10.1186/s12967-026-07807-w.

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by persistent, medically unexplained fatigue that is not alleviated by rest. Core features include post-exertional malaise (PEM) and unrefreshing sleep, resulting in substantial functional impairment [1]. These symptoms substantially overlap with those observed in post-acute coronavirus disease-19 (COVID-19) syndrome (Long COVID) [2]. Although the etiology of ME/CFS remains unclear, post-viral sequelae are considered a major contributing factor [3]. Before the COVID-19 pandemic, its global prevalence was estimated at 1–2% [4]. Following the emergence of SARS-CoV-2, the incidence of newly diagnosed ME/CFS reportedly increased approximately 15-fold, with infected individuals exhibiting nearly a five-fold higher hazard of developing ME/CFS than non-infected populations [5].

ME/CFS is broadly conceptualized as a complex neuro–immune–endocrine disorder with incompletely defined pathophysiology, and effective treatments remain limited [6]. Although no validated biomarkers exist, evidence suggests central nervous system (CNS) neuroinflammation and altered cytokine profiles, particularly elevated interleukin (IL)-1β, IL-6, and IL-10 [7]. Mechanistic studies also implicate disrupted central neurotransmission, including serotonergic hyperactivity, mitochondrial energy deficits, and hypothalamic–pituitary–adrenal (HPA) axis dysregulation [8–10]. Moreover, brain–gut axis dysregulation is increasingly recognized, characterized by microbial and metabolic alterations such as reduced butyrate biosynthesis, increased intestinal permeability, and bacterial translocation [11, 12].

A substantial proportion of individuals with ME/CFS or Long COVID report gastrointestinal (GI) symptoms, including dyspepsia and postprandial exacerbation of systemic symptoms [13]. GI dysfunction is framesized to contribute to fatigue through impaired gut–brain communication, dysbiosis, and chronic low-grade inflammation [14]. Postprandial worsening of fatigue may reflect cytokine-mediated modulation of energy balance, and in ME/CFS, PEM has been proposed to result from inflammation associated with increased gut permeability and bacterial translocation [15, 16]. Notably, approximately 78% of ME/CFS patients with GI symptoms report that these symptoms worsen following physical or cognitive exertion [17]. In this context, brain–gut interaction–based interventions including neuromodulatory approaches, synbiotics, and lifestyle strategies, may reduce symptom duration or severity.

Vagus nerve stimulation is a promising therapeutic intervention due to its capacity to attenuate endotoxin-induced systemic inflammation and enhance intestinal epithelial barrier integrity [18]. Despite the increasing recognition of brain–gut axis involvement in ME/CFS, robust evidence for neuromodulatory interventions in this population remains scarce [19]. This represents a significant research gap, particularly as vagus nerve stimulation has demonstrated efficacy in conditions with overlapping pathophysiology such as fibromyalgia and Gulf War Illness, which share core clinical features including persistent fatigue, cognitive impairment, and PEM [20–22].

Based on the hypotheses that (1) improving GI function mitigates fatigue by restoring epithelial integrity, and (2) electroacupuncture (EA)-based vagal reflex stimulation can effectively modulate the brain–gut axis, we first present a clinical case successfully managed with EA-driven vagal stimulation. This case serves as a clinical anchor to explore these mechanisms in practice. To further contextualize these findings and identify broader clinical trends, we provide a systematic review of randomized controlled trials (RCTs) evaluating brain–gut axis–based therapies. Through this integration, we aim to define research priorities and establish preliminary evidence for the therapeutic potential of these interventions within the complex pathophysiology of ME/CFS and Long COVID.

Case presentation

This case report and literature review were prepared in accordance with the CAse-BAsed REview sTandards (CABARET) guidelines [23]. The study involved a retrospective analysis of electronic medical records, and written informed consent for the publication of this report was obtained from the patient.

Patient characteristics

A 33-year-old man (height: 174.4 cm; weight: 67.5 kg) was admitted to Jaseng Hospital of Korean Medicine on July 24, 2025, with progressively worsening symptoms that had persisted since a PCR-confirmed SARS-CoV-2 infection in June 2024. The initial infection was of moderate severity and treated with antipyretics and home isolation for one week without hospitalization. At admission, his chief complaints included persistent fatigue and flu-like symptoms including headache, chills, and myalgia, that consistently worsened after meals and lasted more than 9 hours per day. These symptoms resulted in marked functional impairment, including bedbound life and leave from work.

He had taken coenzyme Q10 for two months starting in March 2025 without symptom improvement and had received no additional therapies. He reported no prior chronic illnesses, surgeries, hospitalizations, or tobacco/alcohol use. His occupation involved predominantly sedentary activity, although he had engaged in vigorous recreational exercise, including weekly tennis, before symptom onset. No significant comorbidities or family history were noted.

Diagnosis

A diagnosis of ME/CFS was established using the 2015 Institute of Medicine (IOM) criteria [1]. The patient fulfilled the three core diagnostic features: medically unexplained fatigue persisting for more than six months, PEM, and unrefreshing sleep. He also reported cognitive impairment, characterized by difficulty maintaining concentration for more than 10 minutes. Orthostatic intolerance was not observed. His flu-like symptoms developed following the 2024 SARS-CoV-2 infection and had persisted thereafter.

Routine laboratory testing including complete blood count, metabolic panel (glucose and lipid profiles), liver and renal function tests, inflammatory markers, and urinalysis, revealed no abnormalities. Chest radiography and electrocardiography were unremarkable. Vital signs, general physical examination, and neurological assessment demonstrated no pathological findings, including no lymphadenopathy, pharyngeal erythema, or tenderness.

Treatment

Vagal reflex stimulation via EA of the deep peroneal nerve was administered for 12 weeks as a brain–gut interaction–based therapy. Stimulation was performed according to previously published protocols [24]. Sterile acupuncture needles (40-mm length, 0.25-mm diameter; DongBang Co., Seoul, Korea) were inserted bilaterally at ST36. Electrical stimulation was applied at a tolerable intensity (up to 3.0 mA) at 2 Hz for 20 minutes. Correct placement was confirmed by eliciting a sensory response in the anterior ankle region or second toe. EA was administered once daily for three consecutive weeks during hospitalization. After discharge, EA was continued on an outpatient basis with a tapering schedule: three times weekly for three weeks, twice weekly for three weeks, and once weekly for three weeks, after which treatment was completed.

Symptom course

Fatigue severity was evaluated using the 20-item Multidimensional Fatigue Inventory (MFI; total score 20–100, higher scores indicating greater fatigue) [25], which assesses five domains: general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue. Consistent with ME/CFS research standards, diagnostic thresholds of ≥ 13 for general fatigue and ≥10 for reduced activity were applied [26, 27]. Fatigue scores were obtained at baseline and at 4, 8, and 12 weeks after treatment initiation. Regarding flu-like symptoms, the patient was instructed to self-report the daily duration (in minutes) of symptoms, specifically including headache, chills, and myalgia. The duration was recorded whenever at least two of these three symptoms occurred concurrently. Weekly mean durations were then calculated based on these daily records to assess symptomatic changes over time.

As shown in Fig. 1A, the total MFI score steadily declined throughout the 12-week treatment period, decreasing from 71 to 31 (a reduction of more than 50%). General fatigue and reduced activity demonstrated the greatest absolute reductions (each −9 points), whereas the largest proportional improvements occurred in mental fatigue (63.6%, 11 to 4) and reduced motivation (61.5%, 13 to 5). The general fatigue subscale first fell below the diagnostic cut-off ( < 13) at week 8, whereas reduced activity reached the threshold ( < 10) at week 12.

Fig. 1.

Course of symptoms. (A) score of fatigue severity, assessed using the MFI, at baseline and at 4, 8, and 12 weeks after treatment initiation. (B) weekly mean duration of daily flu-like symptom persistence (minutes), recorded using a self-reported diary. Fluctuations observed at weeks 4 and 8 reflect transient, single-day symptom flares followed by subsequent improvement, rather than treatment interruption. MFI: multidimensional fatigue Inventory

Daily flu-like symptom duration (Fig. 1B) decreased markedly from baseline to week 12 (557.1 ± 51.2 to 17.1 ± 15.8 min). Except for weeks 4 (282.9 ± 126.0 min) and 8 (285.7 ± 140.5 min), each time point reflected improvement relative to the preceding week. The greatest reductions occurred between weeks 1 and 2 (−202.9 min) and weeks 9 and 10 (−117.1 min). No adverse events were observed during the treatment period.

Method

The protocol for this systematic review was prospectively registered on PROSPERO (CRD420251155243).

Search strategy

A systematic literature search was conducted in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [28]. Four electronic databases: PubMed, Cochrane Library, Embase, and Medline, were searched through October 2025. Primary search terms included chronic fatigue syndrome, ME/CFS, SEID, Long COVID, post-viral fatigue syndrome, brain–gut axis, microbiome, gastrointestinal, brain stimulation, vagus nerve, and randomized controlled trial. The search was limited to English-language RCTs. The detailed search strategy is presented in Supplementary Table 1.

Eligibility criteria

Studies were included if they (1) used an RCT design (parallel-group or randomized crossover), (2) enrolled participants diagnosed with ME/CFS or Long COVID, (3) investigated an intervention targeting ME/CFS or Long COVID, (4) employed a treatment modality acting on the brain–gut axis such as medications affecting GI physiology, brain stimulation, nutritional supplements, or nerve stimulation as in the present case, and (5) reported at least one fatigue-related outcome.

Exclusion criteria were: (1) absence of full-text publication, (2) non-RCT design, (3) unclear diagnostic characterization of ME/CFS or Long COVID, (4) interventions lacking direct relevance to the brain–gut axis, and (5) no fatigue-related outcome assessment. Indirect approaches such as exercise programs or other medications were excluded, as their primary therapeutic effects are not mediated through direct brain–gut interaction.

Data extraction and analysis

Data were extracted on participant number, sex ratio, mean age, diagnostic criteria, intervention type, treatment duration, control condition, and outcome measures. Outcome data were recorded according to the statistical analyses reported in the original studies. Intervention efficacy was classified as significant or not significant based on authors’ determinations (p < 0.05 for between-group comparisons).

Because this review was descriptive rather than quantitative, no additional statistical analyses were conducted. Variables such as participant number, age, and treatment duration are presented as mean ± standard deviation (SD) for adult and adolescent populations.

Result

General characteristics of RCTs

Of the 1,001 records initially identified, eight RCTs met the inclusion criteria (Fig. 2). Across these trials, 790 participants (541 female) were enrolled, with a mean sample size of 98.8 ± 141.9 per study (Table 1). The mean age was 44.8 ± 4.3 years. Six RCTs enrolled individuals with Long COVID and two included patients with ME/CFS. Four trials investigated gut microbiome–modulating interventions including symbiotic supplementation [29, 30], fecal microbiota transplantation [31], and an herbal decoction [32]. The remaining four RCTs evaluated nerve stimulation therapies, including transcranial direct current stimulation (tDCS) [33, 34] and transcutaneous electrical nerve stimulation (TENS) [35, 36]. The mean treatment duration was 8.8 ± 6.8 weeks. Fatigue was assessed in all trials (n = 8, 100%). Additional outcomes included quality of life (QoL) (n = 5, 62.5%), body pain and dyspnea (n = 4, 50.0% each), and anxiety, cognitive impairment, and general wellness (n = 3, 37.5% each).

Fig. 2.

Flowchart of the study. COVID: coronavirus disease, ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome, RCT: randomized controlled trial

Table 1.

Study characteristics

Items	Count
N. of RCT	8
N. of participants (female)	790 (541)
Mean N. of participant (± SD)	98.8 ± 141.9
Mean age (± SD)A	44.8 ± 4.3
Condition of participants (N. of RCT, %)	8 (100.0)
ME/CFS	2 (25.0)
1994 CDC criteria	1 (12.5)
2015 IOM criteria	1 (12.5)
Long COVID	6 (75.0)
CDC Guidance	2 (25.0)
Researcher-defined criteria	4 (50.0)
Type of intervention (N. of RCTs, %)	8 (100.0)
Gut microbiome modulation	4 (50.0)
Synbiotic supplement	2 (25.0)
Fecal microbiota transplantation	1 (12.5)
Herbal medicine	1 (12.5)
Nerve stimulation	4 (50.0)
Transcranial direct current stimulation	2 (25.0)
Transcutaneous electrical nerve stimulation	2 (25.0)
Mean treatment period (weeks ± SD)	8.8 ± 6.8
Mean N. of measurements per RCT (± SD)	5.4 ± 2.7
Outcome domain of measurement (N. of RCTs, %)B
Fatigue	8 (100.0)
Quality of life	5 (62.5)
Body pain	4 (50.0)
Dyspnea	4 (50.0)
Anxiety	3 (37.5)
Cognitive impairment	3 (37.5)
General wellness	3 (37.5)

^AThis is the mean of ages presented as median or mean in original articles

^BItems have been applied multiple times in original articles, thus the total percentage is larger than 100%

CDC: Centers for Disease Control and Prevention, COVID: Coronavirus disease, IOM: Institute of Medicine, ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome, RCT: randomized controlled trial, SD: standard deviation

RCTs with gut microbiome modulation

Four RCTs examined gut microbiome–targeted interventions (Table 2). Two symbiotic supplementation trials [29, 30] were conducted in Long COVID, one trial evaluated a herbal decoction [32], and one assessed fecal microbiota transplantation (FMT) in ME/CFS [31]. Among the symbiotic trials, the smaller study (n = 26; 12 weeks) did not demonstrate significant fatigue improvement, whereas the larger study (n = 463; 24 weeks) reported statistically significant anti-fatigue effects. The herbal medicine trial (Sijunzi decoction) also showed significant improvements in fatigue and general wellness. In contrast, the preliminary FMT trial (n = 11) did not yield statistically significant results.

Table 2.

Summary of the RCTs for participants with physical disorders

Intervention, year [reference]	Condition of participants	N. of participants (female, age)	Control (Tx. period)	Clinical finding (statistical significance)		Finding in brain-gut environment
				Significant	Not significant
Gut microbiome modulation
Synbiotic supplementation, 2024 [29]	Long COVID	26 (13, 38.9)	Placebo (12 weeks)	PEM	Ageusia, Anosmia, Body pain, Cognitive impairment, Dyspnea, FatigueA, Headache, Lung pain	Increased choline levels at the thalamus, Increased creatine levels at frontal white and grey matter
Sijunzi decoction, 2024 [32]	ME/CFS	127 (93, 42.0)	Placebo (8 weeks)	FatigueA, General wellness	QoL	Increased Pediococcus acidilactici, correlating with improvements in fatigue and GI symptoms
Synbiotic supplementation, 2023 [30]	Long COVID	463 (303, 49.4)	Placebo (24 weeks)	Body pain, Cognitive impairment, Dyspnea, Fatigue, GI upset, General wellness, PEM, Sleep quality	Hair loss, Lung pain, Mood disturbance	Increased SCFA-producing bacteria, correlating with improvements in fatigue and GI symptoms
Fecal microbiota transplantation, 2023 [31]	ME/CFS	11 (10, 42.3)	Placebo (single session)	-	FatigueA, QoL	-
Nerve stimulation
Transdermal auricular VNS, 2025 [35]	Long COVID	35 (35, 43.4)	Low intense of VNS (12 weeks)	-	Cortisol, Dyspnea, Fatigue, HRV, QoL, Sleep quality	-
TENS, 2024 [36]	Long COVID	25 (19, 47.0)	Sham TENS (4 weeks)	Body painA	Fatigue, Gait function	-
tDCS, 2024 [33]	Long COVID	33 (23, 42.2)	Sham tDCS (4 weeks)	-	Anxiety, FatigueA, General wellness, Overall COVID symptom, QoL	-
tDCS + Exercise program, 2023 [34]	Long COVID	70 (45, 53.0)	Sham tDCS + Exercise program (5 weeks)B	Anxiety, FatigueA, QoL	Body pain	-

^AThis is primary outcome measurement

COVID: Coronavirus disease, GI: gastrointestinal, HRV: Heart rate variability, ME/CFS: Myalgic encephalomyelitis/chronic fatigue syndrome, PEM: Post-exertional malaise, QoL: Quality of life, SCFA: short-chain fatty acids, tDCS: Transcranial direct current stimulation, TENS: Transcutaneous electrical nerve stimulation, Tx.: Treatment, VNS: Vagus nerve stimulation

Three studies evaluated objective markers of brain or gut function, all using microbiome-modulating interventions (Table 2). Two symbiotic studies in Long COVID identified increases in thalamic choline and frontal white/grey matter creatine [29], and enrichment of short-chain fatty acid (SCFA)–producing bacteria correlating with improvements in fatigue and GI symptoms [30]. The herbal decoction study similarly reported increased abundance of Pediococcus acidilactici, which was associated with reductions in fatigue and GI symptoms [32].

RCTs with nerve stimulation

Four RCTs evaluated nerve stimulation in Long COVID. Interventions included auricular vagus nerve stimulation (VNS) via TENS, peripheral lower-limb TENS, and two tDCS protocols (Table 2). Peripheral TENS significantly reduced body pain, but failed to improved fatigue compared with sham stimulation [36]. A combined tDCS and exercise program improved anxiety, fatigue, and QoL [34]. In contrast, standalone auricular VNS [35] and tDCS [33] interventions did not demonstrate statistically significant benefits over control conditions.

Discussion

GI manifestations and postprandial symptom exacerbation in ME/CFS are closely associated with autonomic nervous system dysfunction and intestinal dysbiosis [37]. The vagus nerve, a major component of the parasympathetic nervous system, regulates GI motility, secretion, inflammatory responses, and intestinal permeability, thereby maintaining mucosal homeostasis [38, 39]. Conversely, the gut microbiome influences CNS function through neurotransmitter-related metabolic pathways, including modulation of tryptophan availability (a serotonin precursor) and production of SCFAs, which can cross the blood–brain barrier and modulate neuroinflammation [40]. Given that viral infections can induce persistent disturbances in the brain–gut axis and microbial environment, therapeutic strategies targeting these pathways are critical for elucidating ME/CFS pathophysiology and developing novel treatments [41].

EA-based deep peroneal nerve stimulation in this case aimed to activate the dorsal motor nucleus of the vagus (DMV) via nociceptor-mediated pathways to alleviate postprandial symptom exacerbation [24]. EA-mediated vagal stimulation has been reported to enhance GI motility through vagal reflexes, exert intestinal anti-inflammatory effects, and modulate gut-microbiota composition [42, 43]. Vagal stimulation may also ameliorate intestinal barrier dysfunction [44]. In this case, unlike other subscales that showed gradual and consistent improvement, physical fatigue demonstrated a delayed therapeutic response (Fig. 1A). Notably, substantial recovery emerged following episodes of reversely aggravated systemic symptoms at weeks 4 and 8 (Fig. 1B). This response pattern likely reflects the brain–gut axis framework and its sequential neurophysiological processes, including the effects of gut-derived metabolites on the CNS, anti-inflammatory actions, and subsequent restoration of barrier function [45].

Regarding neurotransmitter-related metabolic processes in the intestinal environment, modulation of gut-microbial composition has been widely examined in psychiatric disorders including major depressive disorder, schizophrenia, and bipolar disorder [46]. However, in the RCTs using gut-microbiome modulation included in this review, synbiotic interventions did not meaningfully improve mood disturbance and yielded inconsistent findings for fatigue and cognitive impairment (Table 2). Given that serotonergic hyperactivity has been proposed as a pathophysiological feature of ME/CFS, therapeutic strategies may differ from those for major depressive disorder, where increasing serotonin-precursor availability is typically beneficial [9, 47].

Notably, two RCTs using synbiotic supplementation demonstrated significant improvement in PEM, which is widely recognized as a core hallmark feature of ME/CFS [1]. Although PEM pathophysiology remains unclear, neuroinflammation within limbic structures, including the thalamus, is consistently observed [48]. These studies reported increased thalamic choline levels and increased abundance of SCFA-producing bacteria, both suggesting potential CNS anti-inflammatory effects [49–51]. Interestingly, PEM severity is reportedly higher in ME/CFS cases following GI infections, supporting a role for gut-derived neuroinflammation in its etiology [52]. An RCT using herbal medicine similarly demonstrated significant anti-fatigue effects accompanied by increased Pediococcus acidilactici, a strain with known anti-neuroinflammatory properties, correlating with improvements in fatigue and GI symptoms [32, 53].

Among RCTs employing nerve stimulation interventions, two used TENS, and neither demonstrated significant improvements in fatigue (Table 2). One trial applied auricular TENS targeting the vagus nerve, similar to the present case, a technique widely used in psychiatric, cardiac, and neurological disorders but with limited evidence for effects on fatigue or neuroinflammation [54]. Another study targeted a site capable of activating the peroneal nerve, anatomically analogous to the target in this case [36]. These approaches may differentially influence vagal activity due to differences in the nature and depth of neural activation, as DMV neurons exhibit heterogeneous outputs depending on the specific afferent pathways engaged [55, 56]. For interventions targeting lower-limb peripheral nerves, current evidence suggests that stimulation must reach deeper nociceptors, rather than relying solely on transcutaneous stimulation, to effectively evoke a vagal reflex [24]. These observations underscore that vagus nerve stimulation for ME/CFS may rely on the activation of highly specific neural circuits. Because therapeutic efficacy appears to vary significantly based on the stimulation site and the approach used (e.g., invasive vs. transcutaneous), identifying disease-specific therapeutic circuits is a crucial priority for future research.

The other 2 RCTs applied tDCS, and only the combination of tDCS with an exercise program resulted in significant reduction in fatigue compared with exercise alone (Table 2). tDCS can modulate gut-microbiota composition and is increasingly applied in GI and neurological disorders [57, 58]. It has also been shown to attenuate neuroinflammation within brain [59]. From a brain–gut axis perspective, the synergistic effect of combined tDCS and exercise may relate to modulation of intestinal permeability, acute exercise transiently increases permeability, whereas sustained exercise improves barrier integrity [60]. In this context, the hypothesis that ME/CFS symptoms, PEM especially, are driven by endotoxin exposure secondary to microbial translocation further supports this mechanism [61]. Although a large RCT in 2011 demonstrated the efficacy of exercise therapy and led the CDC to recommend exercise, substantial criticism emerged due to severe PEM, resulting in withdrawal of the recommendation in 2017 [62].

Regarding the assessment of treatment efficacy, the included RCTs utilized various fatigue scales, including the MFI in three studies [29, 31, 34], consistent with the instrument used in the present case, alongside five other distinct measures. Although these instruments vary in structure, they are all patient-reported outcomes that capture the subjective severity of fatigue. The use of different primary endpoints across trials limits direct quantitative comparison and requires caution in synthesis.

Taken together, although the included RCTs are characterized by small sample sizes and substantial methodological heterogeneity, leading to inconsistent results across different intervention types, they collectively provide a valuable overview for generating new therapeutic hypotheses. While some trials demonstrated significant clinical improvements, others yielded null results, particularly in certain neuromodulatory applications, highlighting the complexity of targeting the brain-gut axis. This review suggests that brain–gut axis–directed interventions, whether through synbiotics or nerve stimulation, may exert therapeutic effects in ME/CFS by modulating neuroinflammation. This process likely involves favorable alterations in the gut environment and the enhancement of intestinal barrier integrity, which together prevent endotoxin translocation and subsequent systemic exacerbations. While the inherent inconsistencies and disparate methodologies of current trials necessitate caution in clinical application, these findings point toward a convergent mechanism of action that warrants rigorous validation in larger, standardized studies.

This case-based systematic review has limitations. First, lack of follow-up data precluded assessment of treatment durability. In the absence of longitudinal symptom information, no definitive conclusion can be drawn regarding the long-term maintenance of the observed clinical improvements. Furthermore, as the patient was not receiving any concurrent treatments, aside from temporary nutritional supplements, the potential impact of the placebo effect or the Hawthorne effect must be considered. Second, objective measures such as gut-microbiota profiling and brain-activity imaging were not obtained. Although the case was interpreted within a brain–gut framework, confirmation of causal mechanisms requires such data. Third, the number of included RCTs and sample sizes were small, likely reflecting the recency of research applying brain–gut axis–based interventions, as all included RCTs were published after 2023 (Table 2). Fourth, this review included only RCTs employing interventions that directly targeted brain–gut interactions. Consequently, indirect approaches such as other nutritional supplements or exercise programs that may influence the brain–gut axis were excluded. Lastly, our search was limited to English-language articles and databases to ensure standardized diagnostic criteria and enhance generalizability. While this may have omitted relevant regional trials from East Asia where herbal medicine and EA are extensively studied, prioritizing international peer-reviewed literature ensures broader clinical applicability. Future research should incorporate multi-regional databases for a more comprehensive perspective.

Despite these limitations, this study has strengths. It proposes a novel therapeutic option for ME/CFS, an illness with limited effective treatments, and represents the first systematic review to analyze RCTs from a brain–gut axis perspective. For patients with severe symptoms who cannot tolerate other interventions, EA-based vagal stimulation may represent a viable alternative. Further mechanistic studies are needed to clarify how vagal stimulation modulates neuroinflammation and strengthens intestinal barrier integrity to prevent endotoxin-driven exacerbations in ME/CFS, and to inform development of additional interventional strategies.

Conclusion

This case-based systematic review suggests that brain–gut axis–based therapies may exert anti-fatigue effects in ME/CFS and Long COVID through potential modulation of neuroinflammation, restoration of gut microbial balance, and of intestinal barrier integrity. This study also provides early evidence supporting vagal stimulation, particularly EA-based deep peroneal nerve activation, as a promising but preliminary approach for individuals with severe or treatment-resistant symptoms. As research on brain–gut mechanisms in post-viral fatigue states continues to expand, well-designed mechanistic studies and larger clinical trials are needed to clarify therapeutic pathways and to guide the development of targeted interventions aimed at reducing endotoxin translocation, neuroinflammation in ME/CFS.

Electronic supplementary material

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Abbreviation

CABARET

CAse-BAsed REview sTandards

CNS

Central nervous system

COVID-19

Coronavirus disease 2019

DMV

Dorsal motor nucleus of the vagus

EA

Electroacupuncture

FMT

Fecal microbiota transplantation

GI

Gastrointestinal

HPA

Hypothalamic–pituitary–adrenal

IL

Interleukin

IOM

Institute of Medicine

ME/CFS

Myalgic encephalomyelitis/chronic fatigue syndrome

MFI

Multidimensional fatigue inventory

PEM

Post-exertional malaise

PRISMA

Preferred Reporting Items for Systematic reviews and Meta-Analyses

QoL

Quality of life

RCT

Randomized controlled trial

SCFA

Short-chain fatty acid

SD

Standard deviation

tDCS

Transcranial direct current stimulation

TENS

Transcutaneous electrical nerve stimulation

VNS

Vagus nerve stimulation

Author contributions

DY.K: Methodology, Investigation, Data Curation, Writing - Original Draft, Review & Editing, and Visualization. J.Y: Investigation, Data Curation, and Writing - Original Draft. N.K and SI.C: Methodology and Writing - Review & Editing. IH.H: Conceptualization, Writing - Review & Editing, and Supervision.

Funding

None.

Data availability

The data presented in this study are available upon reasonable request from the corresponding author. The data are not publicly available owing to privacy and ethical restrictions.

Declarations

Ethics approval and consent to participate

The case study reported in this case-based literature review was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (IRB) of Jaseng Hospital of Korean Medicine (Approval No. JASENG 2025–11-007; Approval Date: November 20, 2025). Written informed consent for participation and publication of this paper was obtained from the patient.

Consent for publication

All authors provided consent to publish this case report and review article.

Competing interests

The authors declare that they have no competing interests.