Study on the neuroimmune regulatory mechanism of electroacupuncture at Zusanli acupoint for postoperative intestinal paralysis after gastrointestinal surgery

Abstract

BACKGROUND

Postoperative intestinal paralysis is common in gastrointestinal surgery, and the study of electroacupuncture mechanisms is of great significance.

AIM

To explore the neuroimmune regulatory mechanism of electroacupuncture at the Zusanli acupoint (ST36) in postoperative intestinal paralysis following gastrointestinal surgery.

METHODS

A total of 156 patients admitted to the Affiliated Hospital of Jiangnan University between January 2022 and October 2024 for postoperative intestinal paralysis following gastrointestinal surgery were randomly divided into two groups: A control group and an electroacupuncture group, with 75 patients in each. The control group received conventional Western medical treatment, while the electroacupuncture group received electroacupuncture in addition to this, at the bilateral Zusanli acupoints. Both groups received treatment for 7 days. Clinical efficacy, gastrointestinal function recovery, and gastrointestinal hormone [motilin (MTL), gastrin (GAS)], neurotransmitter [vasoactive intestinal peptide (VIP), nitric oxide (NO)], and inflammatory cytokine [tumor necrosis factor-α (TNF-α), serum interleukin-6 (IL-6), interleukin-1β (IL-1β)] levels were compared between the two groups before and seven days after treatment. Adverse reactions were also recorded.

RESULTS

The electroacupuncture group demonstrated a higher overall treatment effectiveness rate and faster recovery of bowel sounds, as well as faster first defecation and first flatus than the control group (P < 0.05). After seven days of treatment, MTL and GAS levels were significantly higher and VIP, NO, TNF-α, IL-6 and IL-1β levels were significantly lower in the electroacupuncture group than in the control group (P < 0.05). No adverse reactions were observed in either group during treatment.

CONCLUSION

Electroacupuncture at the Zusanli acupoint can enhance clinical efficacy, promote the recovery of gastrointestinal function, and regulate the neuroimmune microenvironment in patients with intestinal paralysis after gastrointestinal surgery. This mechanism may involve excitation of the vagus nerve and activation of the cholinergic anti-inflammatory pathway through electroacupuncture stimulation of the Zusanli acupoint.

Key Words: Gastrointestinal surgery; Postoperative intestinal paralysis; Electroacupuncture; Zusanli; Neuroimmune regulatory mechanism; Clinic

Core Tip: This study revealed that electroacupuncture at the Zusanli acupoint can enhance the clinical efficacy of postoperative intestinal paralysis after gastrointestinal surgery, promote the recovery of gastrointestinal function, and regulate the neuroimmune microenvironment. This mechanism may involve vagus nerve excitation and activation of the cholinergic anti-inflammatory pathway.

INTRODUCTION

Postoperative intestinal paralysis, a common complication of abdominal surgery associated with gastrointestinal dysmotility, not only causes patient discomfort and reduces the quality of life but also prolongs hospital stays. However, the pathophysiology of postoperative intestinal paralysis is complex. Surgical trauma-induced sterile intestinal inflammation is considered the main pathological mechanism[1]. This process can be divided into an early neurogenic phase, characterized by oversuppression of reflexes, and a later inflammatory phase, characterized by enhanced local intestinal inflammation lasting several days. Collectively, these phases increase the difficulty of diagnosis and treatment and require clinical attention[2]. Currently, Western medicine primarily treats postoperative intestinal paralysis using prokinetic drugs, early enteral nutrition, and sham feeding. Although these approaches can promote the recovery of gastrointestinal function and shorten hospitalization, their effectiveness is limited in some patients[3].

With the development of traditional medicines, the advantages of external traditional Chinese medicine (TCM) therapies for digestive system diseases have become increasingly apparent. TCM attributes postoperative intestinal paralysis to patterns such as “dysfunction of the small and large intestines with dysuria, distention of the abdomen and lianteric diarrhea” and “abdominal pain” often caused by a deficiency of essence and blood and vascular stagnation[4,5]. Electroacupuncture is a common external TCM therapy that activates and adjusts self-function. Zusanli (ST36), a key component of the stomach meridian[6], regulates the spleen and stomach. Recent studies have shown that electroacupuncture at ST36 can stimulate the vagus nerve via the spinal center to restore gastrointestinal motility[7,8]. It can also regulate the neuro-immune-endocrine system, suppressing inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1, reducing inflammation, and promoting repair of the intestinal mucosa. However, the specific neuroimmune mechanisms of electroacupuncture at ST36 for postoperative intestinal paralysis remain unclear and lack sufficient reference data[9,10].

This study aimed to investigate the clinical efficacy, recovery of gastrointestinal function, and neuroimmune regulatory mechanisms of electroacupuncture at ST36 in patients with postoperative intestinal paralysis.

MATERIALS AND METHODS

General information

A total of 156 patients with postoperative intestinal paralysis following gastrointestinal surgery, admitted to the Affiliated Hospital of Jiangnan University between January 2022 and October 2024, were enrolled and randomly assigned to either a control group or an electroacupuncture group, with 75 patients in each. Baseline characteristics showed no significant differences between the two groups (P > 0.05), confirming their comparability. This study was approved by the Medical Ethics Committee of the hospital (Table 1).

Table 1 Comparison of general data between the two groups.

Group	n	Sex		Age (year, mean ± SD)	Abdominal surgical approach		ASA
		Male	Female		Radical resection of colorectal cancer	Radical operation for carcinoma of stomach	II	III
Control	75	42	33	58.61 ± 4.68	48	27	51	24
Electroacupuncture	75	45	30	58.88 ± 4.72	50	25	53	22
χ2/t value		0.246		0.273	0.118		0.125
P value		0.620		0.786	0.731		0.723

ASA: American Society of Anesthesiologists.

Randomization was performed using a computer-generated random number table. Group allocations were concealed in opaque, sequentially numbered envelopes to ensure allocation concealment and reduce the risk of selection bias. Sample size estimation was conducted using PASS 15.0 software. Drawing on previous research, an expected difference in overall efficacy of 80% in the electroacupuncture group vs 60% in the control group was assumed. With a significance level (α) of 0.05 and a power of 0.80, the minimum required sample size was calculated to be 69 per group. To account for an anticipated 10% dropout rate, 75 patients were ultimately enrolled in each group.

Diagnostic criteria

Referencing Surgery (9^th Edition)[11] and literature summaries on postoperative ileus by Vather et al[12], the criteria are as follows: (1) Typical symptoms, such as nausea, vomiting, and generalized abdominal distension, occur within 4 days postoperatively; (2) Slight abdominal rigidity without tenderness or tenderness, percussion reveals mostly absent liver dullness with tympanic resonance; auscultation shows reduced or absent bowel sounds; (3) Inability to tolerate a semi-liquid or solid diet; (4) Abdominal X-ray or computed tomography demonstrates dilation of the stomach, large intestine, or small intestine with air-fluid levels; and (5) Exclusion of other types of intestinal obstruction.

Inclusion and exclusion criteria

Inclusion criteria: (1) Postoperative symptoms conforming to the above traditional Chinese and Western medical diagnostic criteria; (2) Successful completion of abdominal surgery without severe cardiopulmonary dysfunction; (3) No contraindications to electroacupuncture treatment; and (4) Agreement to participate in the study and signed informed consent from all patients.

Exclusion criteria: We excluded patients who (1) were complicated with severe infection or intestinal adhesion; (2) were complicated with severe immune or endocrine system diseases; (3) had closed anus or external stoma; (4) received acupuncture-related treatment within 1 month before enrollment; and (5) had cognitive dysfunction or severe mental disorders with poor compliance.

Methods

Control group: Received conventional Western medical treatment as per the literature[13,14], including: (1) Close monitoring of vital signs, fasting (nothing by mouth); (2) Correction of electrolyte imbalance and acid-base balance according to the surgical fluid replacement principles; (3) Intake of protein and energy-rich nutritional supplements; (4) Placement of a routine gastrointestinal decompression tube to relieve abdominal distension and reduce intra-abdominal pressure; and (5) Encouraging early postoperative ambulation and gradual aerobic and resistance training based on individual conditions. The treatment was continued for 7 days.

Electroacupuncture group: Bilateral Zusanli (ST36) electroacupuncture was administered. The bilateral Zusanli was located according to Names and Locations of Acupoints (GB/T 123456-2006). The patient was placed in the supine position, and the bilateral Zusanli areas were fully exposed. Local acupoints and operator disinfection were strictly performed. Disposable sterile acupuncture needles (Manufacturer: Wuxi Jiajian Medical Devices Co., Ltd., Model: 0.30 mm × 40 mm) were inserted vertically at a 90° angle to a depth of 1-1.2 cun. Twisting manipulation (even the reinforcing-reducing method) was applied until deqi (needle sensation) was achieved. A CMNS6-1 electronic acupuncture therapeutic apparatus (Wuxi Jiajian Medical Devices Co., Ltd.) was connected to the needle handles. The current intensity was adjusted according to the patient’s tolerance using a continuous wave frequency. The needles were retained for 30 min once daily for 7 days.

Observation indicators

Gastrointestinal function recovery: Indicators included the time to bowel sound recovery, first flatus, and first defecation, which were recorded for each patient.

Laboratory parameters: Assessments included gastrointestinal hormones [motilin (MTL) and gastrin (GAS)], neurotransmitters [vasoactive intestinal peptide (VIP) and nitric oxide (NO)], and inflammatory cytokines [TNF-α, interleukin-6 (IL-6), and interleukin-1β (IL-1β)]. Fasting venous blood samples (5 mL) were collected before treatment and on day 7. Samples were allowed to stand at room temperature for 30 minutes, followed by centrifugation at 3000 rpm (centrifugal radius 15 cm) for 10 minutes. The supernatant was then isolated for analysis. Levels of MTL, GAS, VIP, NO, IL-6, and IL-1β were measured using enzyme-linked immunosorbent assay kits and an AU5800 automated biochemical analyzer (Beckman Coulter, United States). All reagents were provided by Wuhan Saiyu Biology (China). To ensure accuracy and objectivity, all laboratory testing was independently conducted by two clinical laboratory physicians with over 10 years of professional experience.

Safety assessment: All adverse events occurring during the treatment period were monitored and documented.

Efficacy evaluation criteria

The following criteria are based on the Rome IV Criteria (2016)[15].

Cure: Disappearance of clinical symptoms (abdominal distension, nausea, and vomiting), normal anal flatus and defecation, and imaging showing resolution of intestinal dilation and air-fluid levels.

Marked effect: Significant relief of clinical symptoms, normal anal flatus, and defecation, and imaging showed an obvious reduction in intestinal dilation and air-fluid levels, tolerating a semi-liquid diet.

Effective: Moderate relief of clinical symptoms, normal anal flatus but incomplete defecation, and imaging showed a partial reduction in intestinal dilation and air-fluid levels.

Ineffective: Failure to meet the above criteria or worsening of symptoms and signs.

The total effective rate was calculated as (cure + marked effect + effective) cases/total cases × 100%.

Statistical analysis

Data analysis was performed using SPSS software version 26.0. Categorical variables were presented as counts and percentages [n (%)], and comparisons between groups were conducted using the χ² test. Continuous variables with normal distribution were expressed as mean ± SD. Between-group comparisons utilized independent samples t-tests, while paired samples t-tests were applied for within-group comparisons before and after treatment. A two-sided P value of less than 0.05 was considered statistically significant.

RESULTS

Comparison of clinical efficacy

The total efficacy rate in the electroacupuncture group was significantly higher than that in the control group. This was found to be statistically significant (P < 0.05; Table 2).

Table 2 Comparison of clinical efficacy between the two groups, n (%).

Group	Case	Recure	Excellence	Effective	Of no avail	Overall effective
Control	75	9 (12.00)	30 (40.00)	19 (25.33)	17 (22.67)	58 (77.33)
Electroacupuncture	75	20 (26.67)	39 (52.00)	9 (12.00)	7 (9.33)	68 (90.67)
χ2						4.960
P value						0.026

Comparison of gastrointestinal function recovery

The time taken for bowel sounds to return, the time taken for the first flatus, and the time taken for the first defecation were all shorter in the electroacupuncture group than in the control group (P < 0.05; see Table 3).

Table 3 Comparison of gastrointestinal function recovery between the two groups (hour, mean ± SD).

Group	n	Time to recovery of bowel sounds	First exhaust time	First defecation time
Control	75	26.81 ± 3.66	32.63 ± 5.48	38.93 ± 5.07
Electroacupuncture	75	22.88 ± 2.87	28.32 ± 4.41	36.89 ± 4.35
t value		7.318	5.306	2.645
P value		< 0.001	<0.001	0.009

Comparison of gastrointestinal hormone levels

After seven days of treatment, both groups showed increased MTL and GAS levels compared to baseline, with significantly higher levels observed in the electroacupuncture group than in the control group (P < 0.05, see Table 4).

Table 4 Comparison of gastrointestinal hormone levels between the two groups (ng/L, mean ± SD).

Group	n	MTL		GAS
		Before	After 7 days	Before	After 7 days
Control	75	140.72 ± 26.35	201.03 ± 32.481	94.02 ± 12.53	131.71 ± 18.341
Electroacupuncture	75	141.06 ± 26.42	224.69 ± 35.251	93.46 ± 12.58	145.50 ± 20.281
t value		0.079	4.275	0.273	4.368
P value		0.937	< 0.001	0.785	< 0.001

¹P < 0.05 compared with the same group before treatment.

MTL: Motilin; GAS: Gastrin.

Comparison of neurotransmitter levels

After seven days, both groups showed a decrease in VIP and NO levels compared to baseline, with the electroacupuncture group showing significantly lower levels than the control group (P < 0.05, see Table 5).

Table 5 Comparison of two groups of neurotransmitter levels (mean ± SD).

Group	n	VIP (ng/L)		NO (μmol/L)
		Before	After 7 days	Before	After 7 days
Control	75	81.28 ± 8.21	37.76 ± 6.881	90.06 ± 12.92	68.21 ± 8.601
Electroacupuncture	75	81.42 ± 8.20	32.29 ± 5.701	89.65 ± 12.80	62.03 ± 6.121
t value		0.105	5.302	0.195	5.070
P value		0.917	< 0.001	0.845	< 0.001

¹P < 0.05 compared with the same group before treatment.

VIP: Vasoactive intestinal peptide; NO: Nitric oxide.

Comparison of inflammatory cytokine levels

After 7 days, TNF-α, IL-6, and IL-1β levels decreased in both groups compared to baseline and were significantly lower in the electroacupuncture group than in the control group (P < 0.05, Table 6).

Table 6 Comparison of levels of inflammatory immune cytokines in the two groups (mean ± SD).

Group	n	TNF-α (pg/mL)		IL-6 (pg/mL)		IL-1β (pg/mL)
		Before	After 7 days	Before	After 7 days	Before	After 7 days
Control	75	42.95 ± 6.81	18.08 ± 3.151	65.75 ± 12.40	28.27 ± 5.381	108.91 ± 23.45	68.69 ± 11.031
Electroacupuncture	75	42.66 ± 6.67	16.25 ± 2.301	65.33 ± 12.26	24.45 ± 5.091	108.30 ± 23.28	61.77 ± 9.651
t value		0.263	4.063	0.209	4.467	0.160	4.089
P value		0.793	< 0.001	0.835	< 0.001	0.873	< 0.001

¹P < 0.05 compared with the same group before treatment.

TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; IL-1β: Interleukin-1β.

Safety evaluation

No adverse events occurred in either group during treatment.

DISCUSSION

Postoperative ileus after gastrointestinal surgery is a clinical syndrome caused by gastrointestinal motility disorders because of iatrogenic trauma, peritoneal inflammation, neurohumoral stress responses, and other factors. Prolonged progression increases the risk of complications, such as intestinal obstruction, which severely affects recovery[16,17]. Current Western treatments, guided by enhanced recovery after surgery principles, include intestinal decompression, nutritional support, and activity interventions; however, their overall efficacy remains suboptimal[18].

In TCM, postoperative ileus falls under the categories of “intestinal obstruction” and “abdominal pain.” Its pathogenesis involves deficiency of essential blood and collateral stasis. Surgical trauma and anesthesia damage the abdominal meridians, leading to qi stagnation and blood stasis, and disrupting the ascending-descending function of the stomach and intestines. Acupuncture therapy tonifies the body, activates the meridians, and harmonizes qi and blood. Recent studies have shown that acupuncture regulates the local neuroendocrine–immune microenvironment at acupoints and activates the skin-brain axis for systemic neuroendocrine–immune modulation[19-21]. Electroacupuncture, which combines needle stimulation with electrical currents, offers sustained stimulation with high intensity, promotes gastrointestinal motility, and reduces oxidative stress in gastrointestinal diseases[22,23].

In this study, we selected Zusanli (ST36), a key acupoint in gastrointestinal regulation. As stated in Miraculous Pivot: Basic Shu Points, Zusanli is associated with six hollow organs, and its stimulation strengthens the spleen and stomach, resolves dampness, and regulates qi-blood. The results showed that electroacupuncture at Zusanli improved clinical efficacy, shortened gastrointestinal recovery time, and increased MTL/GAS levels, indicating enhanced gastrointestinal motility. Previous studies have reported that electroacupuncture at Zusanli regulates excitatory/inhibitory neurotransmitters in the gastric antrum, restores enteric nervous system control over gastric motility, and protects intestinal mucosal immunity[24,25].

Gastrointestinal motility is regulated by the spinal and supraspinal centers. Surgical trauma and anesthesia activate adrenergic reflexes and hypothalamic neurons, increasing the levels of inhibitory neurotransmitters (NO and VIP) and worsening motility disorders[26-28]. Inflammation, a core pathogenic factor, involves pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) from M1 macrophage polarization, inhibiting smooth muscle function[29-31]. Our study found that electroacupuncture reduced VIP/NO and inflammatory cytokines, suggesting modulation of neuroimmune pathways. Mechanistically, electrostimulation of Zusanli activates the central nuclei (e.g., lateral hypothalamic area, fastigial nucleus) and vagus nerve, influencing neurotransmitter release and inhibiting NF-κB-mediated inflammation via the cholinergic anti-inflammatory pathway[32-34]. These findings align with those that electroacupuncture at Zusanli attenuates postoperative inflammation through vagus nerve-mediated cholinergic pathways[35].

In conclusion, electroacupuncture at Zusanli improved postoperative ileus by enhancing clinical efficacy, accelerating gastrointestinal recovery, and regulating the neuroimmune microenvironment, possibly via vagus nerve excitation and cholinergic anti-inflammatory activation. The limitations include the small sample size and lack of long-term follow-up. Future large-scale trials with extended follow-up are needed to validate the neuroimmune mechanisms and inform clinical acupuncture practice.

CONCLUSION

Recent studies have shown that electroacupuncture may inhibit the activation of the NF-κB signalling pathway, which is a key regulator of inflammatory responses. This reduces the expression of pro-inflammatory cytokines such as TNF-α and IL-1β. Electroacupuncture has also been reported to modulate macrophage polarization, promoting the shift from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. This shift contributes to the resolution of inflammation and tissue repair. Interestingly, electroacupuncture appears to achieve these effects via the vagus nerve–splenic nerve axis, which has been demonstrated to suppress splenic TNF-α release through vagal activation. Incorporating these findings will help to elucidate the molecular mechanisms through which electroacupuncture exerts its neuroimmune regulatory effects.