Effects of acupuncture on functional gastrointestinal disorders: special effects, coeffects, synergistic effects in terms of single or compatible acupoints

Abstract

OBJECTIVE:

To investigate how the “special effect”/ “coeffect”/“synergistic effect” can achieve a positive result using an “acupuncture prescription” for functional gastrointestinal disorders (FGIDs) in clinical practice, based on the characteristics of single/compatible acupoints and acupuncture techniques.

METHODS:

According to the search strategy, we searched six electronic bibliographic databases and provided a summary for this overview.

RESULTS:

A large body of evidence has shown that acupuncture has positive effects in the treatment of FGIDs. However, the “prescription” intervention involved different single acupoints, compatible acupoints and acupoints based on expert consensus.

CONCLUSIONS:

The core acupoints, including Tianshu (ST25), Zusanli (ST36), and Shangjuxu (ST37), emphasize the application of special acupoints, meridian points and nerve segments, and the two-way regulatory effect found in this study is often used as the basis of acupoint selection and acupoint prescription for acupuncture treatment of FGIDs.

1. INTRODUCTION

Functional gastrointestinal disorders (FGIDs) are heterogeneous disorders with a variety of clinical manifestations that are primarily defined by symptoms and signs rather than an organic or structural cause.¹ The “Rome IV criteria for FGIDs”, published in 2016, summarized six diseases. However, in clinical practice, functional dyspepsia, irritable bowel syndrome (IBS), functional diarrhoea (FD) and functional constipation (FC) are the most thoroughly studied and the most salient for clinicians.² Using the same survey instruments and statistical analyses, a population sample from 33 countries showed that more than 40% of people in the world have FGIDs.³ In China, the prevalence of functional dyspepsia is estimated to range from 10% to 30%,⁴ that of IBS ranges from 1.4% to 11.5%,⁵ that of FC is approximately 6%,⁶ and that of FD is 1.54%;⁷ these diseases affect quality of life (QOL) and global healthcare costs.³

It is noteworthy that these diseases can change during their clinical course. For example, cases of FD could change to IBS with diarrhoea (IBS-D), and FC could change to IBS with constipation (IBS-C).⁸ At present, pharmacotherapies for FGIDs are mainly used to alleviate physical symptoms; such therapies include prokinetic agents, antidiarrhoeal medicine, antispasmodics, and probiotics.⁹ Regrettably, when using pharmacotherapy to treat major symptoms only, patients can experience alternating symptoms,¹⁰ which can accelerate the patient’s progression from one symptom to another. Although the potentially common pathological mechanisms involved in these diseases have been studied and proposed from various perspectives, their aetiologies are vaguely understood due to the potential of multiple causes. Thus, a significant number of patients who do respond to conventional therapy seek help through nonpharmacological treatments, including acup-uncture.^11,12

In recent years, high-quality randomized controlled trials (RCTs) on acupuncture have not only confirmed its effectiveness for FGIDs,^13,14 but also discussed the influence of various acupoint compatibilities and acupuncture techniques on its clinical efficacy from different perspectives.^15,16 From a Traditional Chinese Medicine (TCM) perspective, acupoint selection is imperative to successful acupuncture treatment.¹⁷ Regrettably, there is no recommended guidelines regarding “acupuncture prescription” for FGIDs. Therefore, the aim of this study is to collect, retrieve, and analyze the literature on clinical studies of acupuncture for functional dyspepsia, IBS, FD and FC. Based on the characteristics of single/compatible acupoints and acupuncture techniques, we investigated how the “special effect”/“coeffect”/“synergistic effect” can achieve a positive result based on identifying clinical diseases that are suitable for acupuncture treatment in clinical practice.

2. METHODS

We searched the following electronic bibliographic databases: Embase, PubMed, Cochrane Library, and three Chinese Medical Databases: China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP) and Wanfang Database (WF) for this review.

3. RESULTS

3.1. Results on literature search and selection

We retrieved 1340 reports according to the search strategy, of which 335 were excluded because of duplication, and 900 were excluded on the basis of title or abstract that was irrelevant to the topic, and 105 were considered eligible, and full-text articles were downloaded. 62 records were excluded and 43 articles were included in this overview. The flow chart of literature studies for FGIDs was illustrated in Figure 1.

Figure 1. Flow diagram of literature search.

3.2. Functional dyspepsia

Twelve clinical studies showed that acupuncture improved functional dyspepsia symptoms, as summarized in Table 1. However, the interventions in these studies might have differed because of the acupoint location that was used, numbers, accuracy of the location of acupuncture point treatment, electroacupuncture (EA) apparatus, stimulus depth, or possibility of a placebo effect, all of which may influence the efficacy of acupuncture treatment. Xu et al ¹⁸ reported that the combination of Pishu (BL20), Weishu (BL21), Zhongwan (CV12), Tianshu (ST25), Qihai (CV6), Neiguan (PC6), Gongsun (SP4) and Zusanli (ST36) could improve the function of governing gastrointestinal nerves and normalize gastrointestinal function. One Korean study compared the efficacy of classical six-point (Zhongwan (CV12), Hegu (LI4), Taichong (LR3), Zusanli (ST36), Neiguan (PC6), and Gongsun (SP4)) and nondefined-point (NP) acupuncture. Although symptoms were improved by both acupuncture treatments, specific scores for “pressure in upper abdomen” and “cramps in upper abdomen” were significantly lower in the classical acupuncture group compared with the NP group.¹⁹ Zeng et al ²⁰ indicated that acupuncture and sham acupuncture have relatively different clinical efficacies and brain responses, and the remarkable modulation of the homeostatic afferent network, including the insula, anterior cingulate cortex, and hypothalamus, might be the specific mechanism of acupuncture at Liangqiu (ST34), Zusanli (ST36), Fenglong (ST40), and Chongyang (ST42). Similarly, Ma et al ²¹ designed an RCT to determine the effect of the difference between acupoints and nonacupoints and the effect of the difference among various acupoints. The results showed that the benefit of acupuncture relies on acupoint specificity, and the overall response rate was significantly higher in the acupuncture group [Chongyang (ST42), Fenglong (ST40), Zusanli (ST36) and Liangqiu (ST34)] than in the sham acupuncture group. Three studies based on “syndrome differentiation”, using Zusanli (ST36), Neiguan (PC6), Taichong (LR3) and Neiting (ST44) for patients with excess syndrome and Zusanli (ST36), Neiguan (PC6), Gongsun (SP4) and Yinlingquan (SP9) for patients with deficiency syndrome, have also confirmed that the acupoint has specificity.^22,⇓-24 Yang²⁵ indicated that acupuncture at specific points of the stomach meridian can obviously reduce the functional dyspepsia symptom score. Functional dyspepsia symptoms can be improved by using the lower He-sea point and Front-mu point together or separately, while combined use can produce more significant efficacy. Taixi (KI3) was used to invigorate kidney functions, Zulinqi (GB41) was used to restore liver function, Neiguan (PC6) and Shenmen (HT7) were used to nourish the heart to resume balance of the mind, and MA at Zusanli (ST36), Neiguan (PC6), Taixi (KI3), Zulinqi (GB41) and Shenmen (HT7) improved mental status, in addition to dyspeptic symptoms.²⁶ In contrast with previous studies, an investigation conducted by Sun et al. showed that warm acupuncture at Zhongwan (CV12), Tianshu (ST25), and Zusanli (ST36) improved functional dyspepsia symptoms, but the overall effect was equivalent to that of morpholine.²⁷

Table 1.

Characteristics and categorization of the included literatures for functional dyspepsia

Study	Sample size	Method/acupoint	Stimulation parameter	Conclusion
Xu GX, Liu YB 200518	87	MA at BL20, BL21, CV12, ST25, CV6, PC6, SP4 and ST36	Twirling reinforcing reducing method, retained 30 min, 5 times per week, 6 weeks	Acupuncture had a significant effect on functional dyspepsia.
Park YC et al 200919	68	MA at LI4, LR3, ST36, PC6, SP4 and CV12	Sterile needles were inserted perpendicularly to a depth of 1 or 2.5 cm (1.0 cm at LI4, LR3, PC6, and SP4; 2. 5cm at ST36 and CV12) and then rotated 90° clockwise three times, retained 15 min, 3 times per week, 2 weeks	Both acupunctures at classical points and nondefined points improved the symptoms of patients with functional dyspepsia.
Ma TT et al 201221	712	In group A, EA at ST42, ST40, ST36 and ST34; In group B, EA at ST38, ST35, ST33 and ST32; In group C, EA at BL21 and CV12; In group D, EA at GB40, GB37, GB36 and GB34.	2/100 Hz, 0.5-1.5 mA, continuous five sessions per week, 30 min, 4 weeks	Acupuncture was effective in the treatment of functional dyspepsia, and was superior to non-acupoint puncture. The benefit of acupuncture relies on acupoint specificity.
Zeng F et al 201220	72	EA at ST34, ST36, ST40, and ST42	2/100 Hz, 0.1-1.0 mA, five sessions per week, 30 min, 4 weeks	Although acupuncture and sham acupuncture had relatively different clinical efficacy and brain responses, the more remarkable modulation on the homeostatic afferent network, including the insula, anterior cingulate cortex, and hypothalamus, might be the specific mechanism of acupuncture.
Fan HZ et al 201228	50	EA at ST36 and PC6	25 Hz, 2-10 mA, five sessions per week, 30 min, 4 weeks	EA can significantly improve the short and long-term efficacy of functional dyspepsia.
Sun JR 201227	50	Warm acupuncture at CV12, ST25, ST36	After “Deqi”, warm acupuncture was applied. Once a day, 30 min, 4 weeks	Warm acupuncture was better than Morpholine in improving symptoms of functional dyspepsia, but the overall effect was equivalent.
Li DD et al 201422	71	ST36, PC6, LR3 and ST44 were needled in patient differentiated with excess syndrome; ST36, PC6, SP4 and SP9 were needled for patients with deficiency syndrome	2Hz/100 Hz, 0.1-1 mA, five sessions per week, 30 min, 4 weeks	EA was safe and effective for treating functional dyspepsia, and the effect of acupoint has specificity.
Yang M 201425	80	EA at ST42, ST40, ST36 and ST34	2Hz/100 Hz, 5 mA, five sessions per week, 30 min, 4 weeks	EA at the specific points of the Stomach Meridian can obviously reduce functional dyspepsia symptom score, improve symptoms and enhance the total effective rate.
Geng D et al 201529	60	EA at CV12 and ST36	2Hz/100 Hz, 1-2 mA, five sessions per week, 30 min, 4 weeks	It can improve the functional dyspepsia symptoms by using the lower He-sea point and Front-mu point together or using them separately, while the combining use can produce a more significant efficacy.
Jin Y et al 201526	60	MA at ST36, KI3, GB41, PC6 and HT7	Needle insertion was perpendicular with a depth of about 25 mm for Deqi sense-tions and twirling with a frequ-ency of 60-120 times/min was performed, 20-60 min, 4 weeks	Classic acupuncture with manual manipulation could improve dyspeptic symptoms, mental status, and quality of life in patients with functional dyspepsia and is superior to nonclassic acupoint acupuncture without manipulations.
Zhang XY et al 201623	60	ST36, PC6, LR3 and ST44 were needled in patient differentiated with excess syndrome; ST36, PC6, SP4 and SP9 were needled for patients with deficiency syndrome	2Hz/100 Hz, 0.1-1 mA, five sessions per week, 30 min, 5 weeks	EA was an effective approach in treating functional dyspepsia.
Zheng H et al 201824	200	ST36, PC6, LR3 and ST44 were needled in patient differentiated with excess syndrome; ST36, PC6, SP4 and SP9 were needled for patients with deficiency syndrome	2Hz/100 Hz, 0.1-1 mA, five sessions per week, 30 min, 4 weeks	Acupuncture efficaciously improves dyspeptic symptoms in patients with refractory functional dyspepsia.

Notes: MA: manual acupuncture; EA: electroacupuncture. BL20: Pishu (BL20); BL21: Weishu (BL21); CV6: Qihai (CV6); CV12: Zhongwan (CV12); GB34: Yanglingquan (GB34); GB36: Waiqiu (GB36); GB37: Guangming (GB37); GB40: Qiuxu (GB40); GB41: Zulinqi (GB41); HT7: Shenmen (HT7); KI3: Taixi (KI3); LI4: Hegu (LI4); LR3: Taichong (LR3); PC6: Neiguan (PC6); SP4: Gongsun (SP4); SP9: Yinlingquan (SP9); ST25: Tianshu (ST25); ST32: Futu (ST32); ST33: Yinshi (ST33); ST34: Liangqiu (ST34); ST35: Dubi (ST35); ST36: Zusanli (ST36); ST38: Tiaokou (ST38); ST40: Fenglong (ST40); ST42: Chongyang (ST42); ST44: Neiting (ST44).

3.3. IBS

Six clinical studies indicated that acupuncture improved IBS symptoms, as summarized in Table 2. Shi et al ³⁰ found that acupuncture at Tianshu (ST25), Zusanli (ST36), Pishu (BL20), Weishu (BL21), Shenshu (BL23), Dachangshu (BL25) and Shangjuxu (ST37) was superior to pinaverium bromide in improving diarrhoea, abdominal pain or discomfort symptoms. Based on the “syndrome differentiation” of TCM, adding Neiguan (PC6), Taichong (LR3) and Sishencong (EX-HN1) can also alleviate depression, tension, anxiety, insomnia and other mental and psychological symptoms. Although Mao et al ³¹ and Pei et al ¹⁵ directly demonstrated the clinical value of acupuncture at Baihui (GV20), Yintang (EX-HN3), Taichong (LR3), Zusanli (ST36), Sanyinjiao (SP6), Tianshu (ST25) and Shangjuxu (ST37) for IBS treatment, the results also had limitations because sham acupuncture was not used to eliminate the placebo effect. Interestingly, Sun et al ³² showed that acupuncture at Jiaji (EX-B2) was an effective approach; however, compared with conventional acupuncture, warm acupuncture at Jiaji (EX-B2) more effectively reduced diarrhoea and abdominal pain symptoms and improved patients’ QOL.³³ In contrast with researchers in previous studies, Wang et al ³⁴ also used warm acupuncture, but the acupoints [Zusanli (ST36), Zhongwan (CV12), Sanyinjiao (SP6) and Tianshu (ST25)] were different, which indicated that acupuncture and moxibustion have dual effects when acupoints are selected according to symptoms.

Table 2.

Characteristics and categorization of the included literatures for IBS

Study	Sample size	Method/acupoint	Stimulation parameter	Conclusion
Wang W 200834	110	Warm acupuncture at ST36, CV12, SP6 and ST25	After “Deqi”, warm acupuncture was applied. Once every other day, 10 times as 1 course, 2 courses	Warm acupuncture can effectively improve the clinical symptoms of IBS-D.
Shi XH et al 201030	70	EA at ST25, ST36, BL20, BL21, BL23, BL25 and ST37	Small equal manipulations involving twirling, lifting, and thrusting were implemented to elicit Deqi. EA therapeutic apparatus, once every other day, 15min, 4week	EA was safe and effective in the treatment of IBS-D, which had the value of further research and promotion.
Sun YZ, Song J 201532	60	EA at Jiaji (EX-B2)	After “Deqi”, lifting, inserting and twisting manipulation for 2 min. 60 Hz, five sessions per week, 30 min, 3 weeks	Acupuncture at Jiaji (EX-B2) was an effective approach in treating IBS.
Zhang Z 201633	60	Warm acupuncture at Jiaji (EX-B2)	After “Deqi”, warm acupuncture was applied. Six sessions per week, 30 min, 6 weeks	Compared with conventional acupuncture, warm acupuncture at Jiaji (EX-B2) can effectively improve the symptoms of diarrhea and abdominal pain, and improve the quality of life of patients, which was worthy of clinical application.
Mao WJ 201931	80	MA at GV20, EX-HN3, LR3, ST36, SP6, ST25 and ST37	Small equal manipulations involving twirling, lifting, and thrusting were implemented to elicit Deqi, 30 min, 3 times a week for 6 weeks	MA was effective in IBS-D, which can alleviate the clinical symptoms of patients, improve the quality of life, and have a long-term effect.
Pei L et al 202015	531	MA at GV20, EX-HN3, LR3, ST36, SP6, ST25 and ST37	Small equal manipulations involving twirling, lifting, and thrusting were implemented every 10 min to elicit Deqi, once every other day, 30 min, 3 times a week for 6 weeks	Acupuncture may be more effective than PEG 4000 or pinaverium bromide for the treatment of IBS, with effects lasting up to 12 weeks.

Notes: MA: manual acupuncture; EA: electroacupuncture. IBS: irritable bowel syndrome; IBS-D: irritable bowel syndrome with diarrhoea; PEG: polyethylene glycol. BL20: Pishu (BL20); BL21: Weishu (BL21); BL23: Shenshu (BL23); BL25: Dachangshu (BL25); CV12: Zhongwan (CV12); EX-B2: Jiaji (EX-B2); EX-HN3: Yintang (EX-HN3); GV20: Baihui (GV20); LR3: Taichong (LR3); SP6: Sanyinjiao (SP6); ST25: Tianshu (ST25); ST36: Zusanli (ST36); ST37: Shangjuxu (ST37).

3.4. FD

As summarized in Table 3, Wang et al ³⁵ aimed to observe the clinical efficacy of EA at Tianshu (ST25), Shuifen (CV9), Qihai (CV6), Zusanli (ST36) and additional nerve points (i.e., Zhixie: at the red and white border vertically downward from the lateral ankle tip.) for chronic FD treatment and investigate its mechanism. From a neuroanatomy perspective, the EA stimulation signal is mainly transmitted from the dominant acupoints to the central nervous system, and its regulatory information is transmitted from different levels of the brain-gut axis to gastrointestinal effector cells, thereby achieving therapeutic effects. For further research, Zhong et al ³⁶ focused on the Quchi (LI11) and Shangjuxu (ST37) points to investigate the two-way adjustment mechanism of acupuncture in treating FGIDs (constipation and diarrhoea). The results showed that EA at the Quchi (LI11) and Shangjuxu (ST37) acupoints was effective in bidirectionally regulating FGIDs, with persistent effect. Based on the same therapeutic effect in different disease states, Quchi (LI11) and Shangjuxu (ST37) were shown to achieve synergy and efficiency. Moreover, according to the theory of Shu-mu point combination, Zhao et al ³⁷ investigated the effects of stimulating Tianshu (ST25) and Dachangshu (BL25). Compared with loperamide hydrochloride capsules, the effects of acupuncture at Tianshu (ST25) and Dachangshu (BL25) were persistent and safe, with small individual differences. In brief, stimulation of the two acupoints might affect the function of sympathetic and parasympathetic nerves, thus demonstrating a two-way regulatory (treatment) role of the points.

Table 3.

Characteristics and categorization of the included literatures for FD

Study	Sample size	Method/acupoint	Stimulation parameter	Conclusion
Wang ZD et al 201035	80	EA at ST25, CV9, CV6, ST36 and extra nerve point, i.e. Zhixie	After “Deqi”, twisting, EA therapeutic apparatus, once every other day, 30 min, 4 week	Treatment with EA in patients suffering from chronic functional diarrhoea can significantly improve curative effect.
Zhong F et al 201836	132	EA at LI11 and ST37	20 Hz, five sessions per week (week 1-2); 3 times a week (week 3-4); 30 min, 4 week	EA at LI11 and ST37 acupoints was effective on regulating bidirectionally functional bowel disorders, and the effect was certainly persistent.
Zhao PP et al 202037	118	EA at ST25, BL25	20 Hz, six sessions per week (week 1-2); 3 times a week (week 3-4); 30 min, 4 week	Treatment of loperamide hydrochloride capsules and needling on ST25 and BL25 (with EA) was effective in treating functional diarrhoea and the short-term efficacy was equivalent. However, compared with the medicine group, the effect of acupuncture group was more persistent and safer with smaller individual differences.

Notes: FD: functional diarrhoea; EA: electroacupuncture. BL25: Dachangshu (BL25); CV6: Qihai (CV6); CV9: Shuifen (CV9); LI11: Quchi (LI11); ST25: Tianshu (ST25); ST36: Zusanli (ST36); ST37: Shangjuxu (ST37).

3.5. FC

As summarized in Table 4, Two studies showed that acupuncture increased stool consistency and spontaneous complete bowel movements, particularly in participants with severe symptoms.^38,39 However, the therapeutic effect of a Hwato nerve and muscle stimulator (SXDZ-100) on chronic functional constipation was superior to that of a regular electronic stimulator (SDZ-II).⁴⁰ Cao et al,⁴¹ Wang et al ³⁸ and Zheng et al ⁴² reported that EA had dual functions of electrical stimulation and improving the perception of acupuncture. Density waves can increase metabolism, promote blood circulation and promote the excretion of stool. In addition, the study results showed that the benefit of acupuncture relies on acupoint specificity. Five trials attempted to determine a better therapeutic method for FC when EA was applied at Tianshu (ST25).^{43,⇓,⇓,⇓-47} During deep puncture in the Tianshu (ST25) group, Tianshu (ST25) was punctured deeply into the peritoneum. Conversely, in the other group, Tianshu (ST25) was only punctured shallowly, 5 mm beneath the skin. These results showed that both deep and shallow needling at Tianshu (ST25) can remarkably improve intestinal function; how-ever, deep needling had a more stable effect than shallow needling. Fur-ther research showed that EA involving deep needling combined with Fujie (SP14) had a better and steadier effect on severe FC.⁴⁸ Zheng⁴⁹ conducted an RCT to verify the advantages of EA at Tianshu (ST25) combined with the He-mu [Quchi (LI11)-Da-changshu (BL25)) and Shu-mu (Tianshu (ST 25)-Dachangshu (BL25)] points. Intriguingly, the long-term effect of the combination of acu-points with the He-mu point was better than that of the Shu-mu point. In contrast to previous in-vestigations, four studies focused on different combination points [Qu chi (LI11) and Shang-juxu (ST37)], which may have a two-way regu-latory effect on FG-IDs.^{50,⇓,⇓-53} Acupuncture at Quchi (LI11) and Shang-juxu (ST37) was eff-ective in improving cons-tipation-related QOL, anxiety and depression. Furthermore, the two points also had a good effect on diarrhoea, with results better than those of medication. Similarly, five studies revealed that needling at acupoints Tianshu (ST25), Fujie (SP14), and Shangjuxu (ST37) can improve defecation frequency and constipation symptom scores via parasym-pathetic activation to stimulate the distal colon.^{54,⇓,⇓,⇓-58} Intriguingly, Zhang et al ⁵⁹ showed that, owing to acupoint selection guidance of hand-foot meridians of the same name, EA at the Yangming meridian [Tianshu (ST25), Hegu (LI4), Zusanli (ST36) and Shangjuxu (ST37)] had more advantages in terms of defecation frequency.

Table 4.

Characteristics and categorization of the included literatures for FC

Study	Sample size	Method/acupoint	Stimulation parameter	Conclusion
Wang CW et al 201043	95	EA at ST25	ST25 was punctured deeply to the peritoneum. Once a day, 2/15 Hz, 30 min, 4 weeks	The deep puncture at ST25 with electric stimulation presents similar efficacy on FC as shallow puncture at ST25, but it acted more quickly than shallow puncture at ST25, both of them were more advantageous than medication and the long-term efficacy was better.
Wang CW et al 201044	95	EA at ST25	2/15 Hz, 1-12 mA, 5 times per week, 30 min, 4 weeks	Deep needling EA of ST25 had a positive effect in improving FC, being faster in the onset of action and stable efficacy in comparison with shallow needling.
Geng T, Lin RZ 201145	75	EA at ST25	5/10 Hz, 5 times per week, 30 min, 4 weeks	Deep needling at ST25 for FC had a positive effect, which can reduce the use rate of laxatives, and had a certain mid-term curative effect.
Cao J 201241	41	EA mainly at ST25, ST36, LI4, ST37, SJ6 and KI6	5 times per week, 30 min, 4 weeks	EA had the dual functions of electrical stimulation and strengthening the sense of acupuncture. The density wave can increase metabolism and promote blood circulation, and promote the excretion of stool.
Xu J et al 201240	64	MA at SJ6, ST25, ST36 and ST37	1/20 Hz, twirling and rotating manipulation wave for 30 min. Once a day, 2 weeks	The therapeutic effect of Hwato neuro and muscle stimulator (SXDZ-100) on chronic functional constipation was superior to that of a regular electronic stimulator (SDZ-II).
Zhang C et al 201359	60	EA at ST25, LI4, ST36 and ST37	Twirling and rotating manipulation wave for 30 s. 5 times per week, 30 min, 4 weeks	EA performed better than prepulsid in the treatment for functional constipation with slow transmission.
Hu JW et al 201454	49	EA at ST25, SP14 and ST37	15 Hz, 0.1-1.0 mA, 5 times per week, 30 min, 8 weeks	EA treatment had better curative effect on severe FD than sham EA, and the long-term effect was also better.
Wang XL et al 201438	51	EA at ST25, SP14, ST37, SJ6 and KI6	15 Hz, 0.1-1.0 mA, 3 times per week, 30 min, 4 weeks	EA and general acupuncture were effective for FC, but the EA treatment can improve clinical scores of constipation and quality of life much better than ordinary acupuncture.
Xiong F et al 201450	92	EA at LI11 and ST37	2/50 Hz, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 2 weeks. 30 min, 4 weeks	EA therapy can increase stool frequency, improve stool consistency, decrease the patient’s anxiety and depression.
Zheng HB et al 201442	69	EA at ST25 and ST37	10 Hz, 5 times per week, 30 min, 4 weeks	EA at ST25 combined with He-mu and Shu-mu points were both effective treatments for chronic FC. The long-term effect of the combination of acupoint with He-mu was better than that of Shu-mu.
Wu J et al 201446	475	EA at ST25	2/15 Hz, 0.1-1 mA, 5 times per week, 30 min, 4 weeks	Deep needling and shallow needling at ST25 can improve intestinal function remarkably and safely. Therapeutic effects of deep needling and shallow needling were not superior to that of lactulose; however, the sustained effects of deep and shallow needling after stopping the acupuncture treatments were superior to the therapeutic effect of lactulose, which might qualify the superiority of deep and shallow needling.
Qi LJ et al 201451	28	EA at LI11 and ST37	20 Hz, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 2 weeks. 30 min, 4 weeks	Acupuncture at LI11 and ST37 had therapeutic effect on FC and diarrhea, which were better than medicine. LI11 and ST37 may have two-way regulatory effect on FBDs.
Liu J et al 201548	70	EA at ST25 and SP14	15 Hz, 0.1-1.0 mA, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 4 weeks. 30 min, 8 weeks	EA deep needling had a better and more steady effect on severe FC.
Da N et al 201555	67	EA at ST25, SP14 and ST37	2/15 Hz, 0.1-1.0 mA, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 6 weeks. 30 min, 8 weeks	It was effective and safe with EA to treat FC.
Xue QM et al 201547	96	EA at ST25	2/15 Hz, 5 times per week, 30 min, 4 weeks	Using EA at ST25 to treat patients with FC was effectively, and deep needling had more stable effect than shallow needling.
Study	Sample size	Method/acupoint	Stimulation parameter	Conclusion
Chen L et al 201656	63	EA at ST25, SP14 and ST37	15 Hz, 0.1-1.0 mA, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 6 weeks. 30 min, 8 weeks	Deep needling at ST25 and SP14 plus EA was an effective method in treating severe FC.
Shen YF et al 201657	70	EA at ST25, SP14 and ST37	15 Hz, 0.1-1.0 mA, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 6 weeks. 30 min, 8 weeks	EA can improve complete spontaneous bowel movements in severe FC, but it’s insignificantly different from sham acupuncture in improving stool form and defecation difficulty.
Liu Z et al 201658	1075	EA at ST25, SP14, and ST37	10/50 Hz, 0.1-1.0 mA, 5 sessions in each of the first 2 weeks, and 3 sessions in each of the remaining 6 weeks. 30 min, 8 weeks	8 weeks of EA increased complete spontaneous bowel movements and was safe for the treatment of chronic severe FC. Additional study was warranted to evaluate a longer-term treatment and follow-up.
Wu X et al 201752	201	EA at LI11 and ST37	10/50 Hz, 16 sessions of acupuncture treatments, 30 min, 4 weeks	EA was effective and safe at both current intensities for FC; therapeutic effects of low current intensity and high current intensity were not superior to mosapride. EA was superior to mosapride in improving patients’ life quality and satisfaction level of treatment; EA had fewer adverse events than mosapride.
Lee HY et al 201839	30	MA at ST25, ST27, BL52 and BL25	After “deqi”, maintaining them for 30 min. 4 weeks	This study demonstrated that a future clinical trial would be feasible with some modifications to the primary outcome measure and comparator. An additionally finding was that 12 acupuncture sessions over 4 weeks had possible effects of increasing stool consistency and spontaneous complete bowel movement, particularly in participants with severe symptoms.
Zheng H et al 201849	684	EA at ST25, BL25, LI11 and ST37	15 Hz, 30 min, 4 weeks	Acupuncture was effective to relieve symptoms of patients with functional constipation. Therapeutic effect of He, Shu-mu, and He-shu-mu acupuncture was at least as effective as mosapride; however, non- specific effects of acupuncture may play a relevant role in this trial. Future studies should focus on the non-specific effect of acupuncture by comparing acupuncture with sham acupuncture.
Xu XH et al 202053	96	EA at LI11 and ST37	2/50 Hz, 0.1-1.0 mA, 30 min, 4 weeks	EA was effective in the improvement of the constipation-related QOL, anxiety and depression, which seems to be better than that by mosapride. However, it seems that the sham acupuncture did not play a crucial role or a supplementary role in treating FC. These findings suggested that EA could be effective in the treatment of FC.

Notes: MA: manual acupuncture; EA: electroacupuncture. FBDs: functional bowel disorders; FC: functional constipation; FD: functional diarrhoea; QOL: quality of life; BL25: Dachangshu (BL25); BL52: Zhishi (BL52); KI6: Zhaohai (KI6); LI4: Hegu (LI4); LI11: Quchi (LI11); SJ6: Zhigou (SJ6); SP14: Fujie (SP14); ST25: Tianshu (ST25); ST36: Zusanli (ST36); ST37: Shangjuxu (ST37).

4. DISCUSSION

In this study, we found that acupuncture was effective in the treatment of FGIDs. All these results were based on the “special effect” of acupoints, the “coeffect” of channel and collateral connections, and the “synergistic effect” of ingenious compatibility. Therefore, acupoints play a vital role in acupuncture research.

4.1. Properties of acupoints

The essential properties of acupoints include not only a “resting state” but also an “activating state”. When the human body is healthy, acupoints are deemed to be in the “resting state”; when the body is unhealthy, they are in the “activating state”, that is, the “sensitization state”.⁶⁰ This change in functional state is called acupoint sensitization. Qi et al ⁶¹ selected patients with functional diarrhoea and FC as research subjects and analysed the distribution of sensitized acupoints and the change in the tenderness threshold. The results showed that Zusanli (ST36), Shangjuxu (ST37), Xiajuxu (ST39) and Yinlingquan (SP9) were in a pain-sensitive state in patients with FC and diarrhoea. However, Quchi (LI11) and Dachangshu (BL25) only decreased the threshold of tenderness in patients with FC. Similarly, a trial by Qi et al.⁶² confirmed this phenomenon again by studying the distribution of sensitized acupoints in patients with FGIDs. It is noteworthy that the sensitization range of Zusanli (ST36), Shangjuxu (ST37) and Xiajuxu (ST39) in patients with FGIDs was expanded, and significant pain sensitivity still appeared 2 inches away from the side. Intriguingly, in a study by Lei et al,⁶³ Evans blue (EB) dye was injected into the tail vein of IBS model rats. Two hours later, the spot distribution range of EB on the body surface was consistent with the location of “Dachangshu (BL25)”. In summary, the phenomenon of acupoint sensitization is widespread. The above acupoints are frequently applied in the clinical treatment of functional dyspepsia, IBS, functional diarrhoea and FC, as shown in Table 5, which suggests that the most frequently applied (sensitized) acupoints are effective stimulation points for acupuncture treatment.

Table 5.

Individual acupoint frequency

Grade	Acupoint	Number
I	Tianshu (ST25)	25
II	Zusanli (ST36)	20
III	Shangjuxu (ST37)	19
IV	Fujie (SP14)	7
V	Neiguan (PC6)	7
VI	Zhongwan (CV12)	6
VII	Quchi (LI11)	6
VIII	Taichong (LR3)	6
IX	Dachangshu (BL25)	4
X	Gongshu (SP4)	4

Notes: if the acupoint is present in no more than three studies, the data is not shown.

4.2. “Coeffect” of acupoints

Do multiple acupoints have common effects? Does a single acupoint have multiple effects? We found that acupoints for the treatment of FGIDs were mainly distributed in the abdomen and limbs (supplementary Figure 1). It is worth noting that these acupoints focus on the stomach channel of foot-Yangming [Tianshu (ST25), Zusanli (ST36), Shangjuxu (ST37)], the spleen channel of foot-Taiyin (Fujie (SP14)), the ren channel [Zhongwan (CV12)] in the abdomen, the large intestine channel of hand-Yangming [Quchi (LI11)] and the pericardial channel of hand-Jueyin [Neiguan (PC6)] in the limbs. From a TCM perspective, the meridians of the above acupoints belong to or are associated with the gastrointestinal tract and have the effect of treating gastrointestinal diseases. Modern medicine has found that the distribution of acupoints is closely related to the innervation of ganglion segments. In other words, if the acupoints of different meridians are located in the same nerve segment, their main functions are basically equal. The lesion sites of FGIDs involve the entire gastrointestinal tract, with a predominance of the stomach, jejunum, and colon. The sympathetic nerves of the stomach are T6-T10, T9-T12 to the jejunum, T11-L2 to the colon, and S2-S4 to the parasympathetic nerves. According to acupoint anatomy, Zhongwan (CV12), Tianshu (ST25), Pishu (BL20) and Weishu (BL21) are all located in the above segments. Contiguous nerve segments within the spinal cord are connected to each other, and close connections also exist between the upper and lower sympathetic stem ganglia.⁶⁴ Therefore, acupoints beyond the range of selected acupoint segments are still effective, such as Shangjuxu (ST37) (distribution of the deep peroneal nerve from L4-S1) and Zusanli (ST36) (distribution of the nervus peroneus communis from L4-S1, the deep tibial nerve from L4-S3, and the median nerve from C5-T1). Although Neiguan (PC6), the common acupoint of FGIDs in supplementary Figure 2, is not among the above segments, Liu et al ⁶⁵ showed that oxytocin (OT), as a neurotransmitter transported from the paraventricular nucleus to the dorsal vagal complex, activates motor neurons of the brainstem vagus nerve, thereby inhibiting gastrointestinal motility. Conversely, compared with the normal group, mice with OT gene knockout showed weakening of this regulatory effect on the stomach by acupuncture at “Zusanli (ST36)” and “Neiguan (PC6)”. Overall, nerve segments are not the sole mechanism of acupuncture effects, and the central nervous system also plays an important role, which needs to be studied deeply in future practical applications.

Interestingly, we found that Tianshu (ST25) and Zusanli (ST36) were commonly used for the treatment of FGIDs, respectively (Figure 2, supplementary Figure 2). Previous studies using data mining methods also found that the top three most frequently used acupoints in the treatment of constipation and diarrhoea were Zusanli (ST36), Tianshu (ST25), and Shangjuxu (ST37). Among them, Tianshu (ST25) (88.15%), Shangjuxu (ST37) (68.89%) and Zusanli (ST36) (60.74%) were associated with constipation, and Tianshu (ST25) (88.54%), Zusanli (ST36) (80.21%) and Shangjuxu (ST37) (45.83%) were associated with diarrhoea.⁶⁶ The same acupoint is associated with different pathological conditions in the human body and can play two opposite and effective therapeutic roles; that is, bidirectional regulation of acupoints exists. Two types of gastric pyloric motility in normal conscious rats were stably recorded by Tatewaki, a Japanese scholar. Acupuncture at “Zusanli (ST36)” for 30 s excited aperiodic gastric movement and converted it into the periodic type; however, this treatment exerted an inhibitory effect on periodic-type gastric movement.⁶⁷ Conversely, these two patterns of gastric motility were stably repeated in both groups one week after acupuncture.⁶⁸ In summary, acupuncture at Zusanli (ST36) induced dual effects on gastric motility in conscious rats. Tianshu (ST25) and Shangjuxu (ST37) also have two-way regulatory effects.⁶⁶

Figure 2. Venn diagram showing acupoints that were differentially administered across the FD, IBS, functional diarrhea and FC relevant studies.

FC: functional constipation; FD: functional dyspepsia; IBS: irritable bowel syndrome. BL20: Pishu (BL20); BL21: Weishu (BL21); BL23: Shenshu (BL23); BL25: Dachangshu (BL25); BL52: Zhishi (BL52); CV6: Qihai (CV6); CV9: Shuifen (CV9); CV12: Zhongwan (CV12); EX-HN3: Yintang (EX-HN3); GB34: Yanglingquan (GB34); GB36: Waiqiu (GB36); GB37: Guangming (GB37); GB40: Qiuxu (GB40); GB41: Zulinqi (GB41); GV20: Baihui (GV20); HT7: Shenmen (HT7); EX-B2: Jiaji (EX-B2); KI3: Taixi (KI3); KI6: Zhaohai (KI6); LI4: Hegu (LI4); LI11: Quchi (LI11); LR3: Taichong (LR3); PC6: Neiguan (PC6); SJ6: Zhigou (SJ6); SP4: Gongsun (SP4); SP6: Sanyinjiao (SP6); SP9: Yinlingquan (SP9); SP14: Fujie (SP14); ST25: Tianshu (ST25); ST27: Daju (ST27); ST32: Futu (ST32); ST33: Yinshi (ST33); ST34: Liangqiu (ST34); ST35: Dubi (ST35); ST36: Zusanli (ST36); ST37: Shangjuxu (ST37); ST38: Tiaokou (ST38); ST40: Fenglong (ST40); ST42: Chongyang (ST42); ST44: Neiting (ST44).

4.3. “Synergistic effect” of acupoints

Is acupuncture affected by the superposition of acupoints? Is the superposition of acupoints equal to the superposition of efficacy? By analyzing the literature, we found that not only is the compatibility of acupoints diverse, but their curative effects also differ (supplementary Figure 2). Zhong et al ⁶⁹ designed a study to observe differences in the immediate effect on bowel movement when acupuncture was administered at different points. Forty healthy volunteers were divided into 3 groups: the Tianshu (ST25) + Dachangshu (BL25), Quchi (LI11) + Shangjuxu (ST37) and Tianshu (ST25) + Dachangshu (BL25) + Quchi (LI11) + Shangjuxu (ST37) groups. Regrettably, the results showed no significant difference in each group. Xu et al ⁷⁰ injected atropine into mice to induce a model of gastrointestinal propulsion function weakening. The propulsion rate of the gastrointestinal tract was selected as an outcome to observe the effect of EA at “Neiguan (PC6)”, “Pishu (BL20)”, and “Zusanli (ST36)” and the effects of single points, double points and triple points. Among these mice, the Neiguan (PC6) group, Zusanli (ST36) group, Neiguan (PC6) + Zusanli (ST36) group and Pishu (BL20) + Zusanli (ST36) group showed significant promotion of gastrointestinal propulsive function, while the Neiguan (PC6) + Pishu (BL20) group exhibited only slight promotion. Amazingly, the combination of Neiguan (PC6) + Pishu (BL20) + Zusanli (ST36) displayed an antagonistic effect. As such, the antagonistic effect of acupoints exists objectively. Further study found that the synergistic and antagonistic effects of acupoint compatibility may be manifested in the pathological state of the organism but not the physiological state. In view of these findings, future research should focus on exploring the mechanisms of the differences between compatible acupoints and a single acupoint.

4.4. Relationship and differences between “special effects”/“co effects”/“synergistic effects”

Acupoints have specificity. “Huang Di Nei Jing” records that “those who have inside and must form outside”. When the body suffers from disease or injury, corresponding acupoints are believed to be activated and manifest in several sensitized forms, including expansion of the receptive field, pain sensitization, and heat sensitization. Such phenomena are believed to gradually disappear concomitantly with recovery from the disease. Hence, under the condition of disease, acupoints show changes in functional states such as sensitization, which is the action point of acupuncture to improve the state of the body.⁷¹

Acupoint not only has a two-way regulatory effect on gastrointestinal motility but also has a “coeffect”. On the one hand, acupuncture can improve intestinal motility by altering both excitatory and inhibitory enteric neurons,⁷² and regulating different functional states (constipation and diarrhoea) of the same disease. On the other hand, the same acupoint also has an overall regulating effect on the body under the action of different acupuncture and moxibustion methods (stimulus parameters). Compared with 2, 15, or 100 Hz, only Tianshu (ST25) with 2/100 Hz could improve the motility of postoperative ileus.⁷³ Similarly, compared with shallow needling, the effect of deep needling Tianshu (ST25) was not only stable but also showed more benefit in the complete spontaneous bowel movements, symptom scores and satisfaction scores.⁷⁴

Acupoint combination is based on TCM theories and is an acupoint selection method that can integrate the specific effects of different acupoints to produce “synergistic effects” for better clinical efficacy. Physicians of past dynasties have summed up the methods of acupoint allocation, such as “Shu-mu” and “He-mu”. These combinations are thought to be the embodiment of syndrome differentiation and treatment administration and a crucial component of acupuncture prescriptions and the basis of acupuncture manipulation.⁷⁵

In the near future, it is necessary to further study whether the same acupoint will play a specific targeting role in different disease states and investigate the “single point special effect”; to study whether the same acupoint will produce an overall adjustment effect under the same disease state and to investigate the “single point co effect”; to study whether multiple acupoints will play a synergistic targeting role in the same type of disease state; and to investigate “multiacupoint synergistic effects”.

4.5. Limitations

In this study, acupoint selection was determined to be very important for disease treatment, such as differences in acupoint location, meridians, dominant nerve segments or related organs. However, acupuncture manipulation has been overlooked compared with other factors. Acupuncture manipulation is an extensive concept that includes duration, frequency, angle, depth and other aspects. The variation in acupuncture manipulations by different acupuncture operators in these studies, although EA is mostly used, the intervention frequency is different, which makes it difficult to achieve uniform standards for acupuncture manipulation. Whether the impact of acupuncture manipulation on therapeutic efficacy is significant is a great question for acupuncture researchers. The present study only selected acupoints as representative factors to investigate the impact of acupoint compatibility on the efficacy of acupuncture, which has certain limitations.

In conclusion, based on an analysis of the published literature investigating FGIDs, we summarized that the optimal EA acupuncture technique at different acupoint combinations seemingly progressed pathological symptoms to normal states, suggesting that single/ compatible acupoints potentially have significant influential roles in the effect of acupuncture on these diseases. For the core acupoints, including Tianshu (ST25), Zusanli (ST36), and Shangjuxu (ST37), the correlation emphasizes the application of special acupoints, meridian points and nerve segments, and the two-way regulatory effect found in this study is often used as the basis of acupoint selection and acupoint prescription for treatment of FGIDs.

To optimize the acupoints for FGIDs, our team will design an RCT, select patients with IBS as research subjects, and attempt to randomly control multiple groups of acupoints. Through comparing the curative effect among the acupoint groups, the best combination of acupoints will be evaluated, which could provide a reference for clinical practice. We hope that future studies can focus on the characteristics of single/ compatible acupoints and acupuncture techniques to investigate how “special effects”/“coeffects”/ “synergistic effects” can achieve a positive result in clinical practice.

5. ACKNOWLEDGEMENTS

We thank LI Xia, SUN Runquan, ZHENG Hui, YE Kun, WANG Xin, WANG Xuefei and LI Zhigang for their valuable assistance. WANG Xin, WANG Xuefei and LI Zhigang conceived of the study. LI Xia, SUN Runquan and YE Kun are involved in the conception, design, and critical revision for this study. ZHENG Hui is responsible for revising the manuscript. All authors read and approved the final manuscript. SUN Runquan and LI Zhigang are co-corresponding authors.