Quality of Evidence Supporting the Role of Acupuncture for the Treatment of Irritable Bowel Syndrome

Objectives To systematically collate, appraise, and synthesize the current evidence on acupuncture for irritable bowel syndrome (IBS). Methods Systematic reviews (SRs)/meta-analyses (MAs) of acupuncture for IBS were searched in eight databases. For quality evaluation of the enrolled studies, Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) was used for methodological quality, Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) for reporting quality, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for evidence quality. Results Ten studies were included in our review. According to AMSTAR-2, only one study met all the criteria and was rated as high methodological quality, and the rest were rated as low or very low methodological quality. According to the PRISMA checklist, most of the items were fully reported, with the exception of Q5 (protocol and registration), Q8 (search), and Q27 (funding). With the GRADE system, no outcome measure was rated as high quality. Conclusions Acupuncture may be a promising therapy for IBS. However, this conclusion must be treated with caution since the quality of SRs/MAs providing evidence is generally low.


Introduction
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurrent abdominal pain accompanied by abnormal or altered defecation habits [1]. From country to country, the prevalence of IBS ranges from 1.1% to 45.0% [2], with global estimates of 11.2% [3] in Rome, 5.9% in China [4], and 7.1% in the United States [3].
is disorder not only has a marked negative impact on quality of life (QOL) and work productivity but also increases medical healthcare costs and imposes a huge socioeconomic burden [5,6]. It is reported that the annual direct cost per patient due to IBS is estimated to be $348 to $8,750 and the indirect cost is $355 to $3,344 [7]. e pathophysiology of IBS is poorly understood and is currently thought to represent a complex interplay among the gut microbiota, mucosal immune system, impaired mucosal barrier function, visceral hypersensitivity, gut motility, and alterations in the gut-brain axis [8][9][10]. e conventional medication (CM) recommended to alleviate the symptoms include antispasmodics, fiber supplementation antidepressants, and probiotics [2,8]. However, the effects are limited and accompanied by various side effects [11]. As a nonpharmacological treatment technique, acupuncture is believed to be beneficial to IBS based on the theory of the visceral hyperalgesia theory of the central nervous system. Acupuncture is becoming more widely used, and the number of published systematic reviews (SRs) and meta-analyses (MAs) has increased, but the evidence they provide for acupuncture for IBS is not always consistent. SR/MA is considered the gold standard for assessing the effectiveness of clinical interventions; however, high-quality SRs/MAs can provide reliable evidence, while low-quality SRs/MAs might instead mislead clinical decision-making [12]. us, there may be a gap between evidence-based clinical implementation of acupuncture and its actual implementation in real-world dynamics. Clinical decision-making requires a comprehensive overview of the available evidence in order to identify potential benefits and harms of the intervention [13]. Within this framework, the overview of SRs/MAs is a relatively new approach, which aims to summarize and evaluate the strength of the evidence provided in multiple SRs/MAs [14]. By mapping the evidence in the real-world implementation field of acupuncture, an umbrella review will help draw a clear link between the need to address uncertainty and advancing clinical knowledge a priori [15]. erefore, we conducted this study.

Methods
e Cochrane criteria and the statements of Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) [16] were followed to carry out this overview. e protocol was registered in PROSPERO (CRD42021228185).

Strategy for Search.
PubMed, Cochrane Library, Web of Science, Embase, Chinese Scientific Journal Database, CNKI, VIP, and Wanfang were systematically searched from inception to July, 2021. Irritable bowel syndrome, acupuncture, systematic review, and meta-analyses were used as search key terms. A search strategy used for PubMed is shown in Table 1.

Criteria Used to Consider Studies.
e studies that met the following criteria were included: (1) SRs/MAs based on randomized controlled trials; (2) the Rome I-IV criteria were adopted as diagnostic criteria for IBS; (3) the experimental intervention was acupuncture or a combination of acupuncture plus medications and the control intervention was Sham acupuncture or CM; and (4) outcome measures should be effective rate, recurrence rate, IBS symptom scores, IBS-QOL, and Symptom Severity Scale of IBS (IBS-SSS). e studies that met the following criteria were excluded: (1) duplicate publications; (2) updated SRs/MAs; (3) dissertations without peer review; and (4) the control intervention that included acupuncture.

Literature Selection and Data Extraction.
Literature selection and data extraction were carried out by two independent authors, respectively. For literature selection, titles and abstracts were first screened and then, the full text of potentially relevant studies was further reviewed to determine eligibility. In addition to the outcomes of metaanalyses, data regarding the characteristics of the studies and subjects, details of the treatments, and methods of the SRs/ MAs were extracted. Any discrepancies were resolved by discussion.

Quality Assessment.
Quality assessment was carried out by two independent authors. e Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) [17], PRISMA tool, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [18] were used to evaluate the methodological quality, reporting quality, and evidence quality, respectively. Any discrepancies were resolved by discussion. Figure 1, the literature search identified 243 citations, and after removing the duplicates, 173 citations were further eliminated, 167 of which were excluded. Finally, 10 studies [19][20][21][22][23][24][25][26][27][28] met the inclusion criteria. Table 2, 10 MAs published from 2010 to 2020 were enrolled in this overview. Half of these studies were published in English, with the number of trails ranging from 6 to 41 and the subjects ranging from 664 to 3440. e experimental intervention was mainly acupuncture or a combination of acupuncture plus medications, and the control intervention was mainly Sham acupuncture or CM characteristics.

Methodological Appraisal.
According to AMSTAR-2, only one review met all items and was rated as high methodological quality, and the rest were rated as low or critically low methodological quality. Key items affecting the methodological quality were item 2 (established protocol), item 4 (comprehensive search strategy), and item 7 (a list of excluded trails). Further details are shown in Figures 2 and 3.

Reporting Quality Appraisal.
According to PRISMA checklists, most of the items were fully reported in these included reviews, with the exception of Q5 (protocol and registration), Q8 (search), and Q27 (funding). Further details are given in Table 3.

Evidence Quality
Classification. 25 outcome indicators regarding the effects of acupuncture for IBS were extracted from the included studies. With GRADE, 12 outcome indicators were rated as moderate quality and the rest were rated as low or critically low quality. e risk of bias, imprecision, inconsistency, and publication bias were the main reasons for evidence degradation (Table 4).

Effect of the Interventions.
Relative effects of the outcome indicators regarding the effectiveness of acupuncture for IBS are shown in Table 4. Two studies [20,23] compared the effects of acupuncture and Sham acupuncture, and reportedly no statistically significant difference was found in effective rate, IBS-QOL, or IBS-SSS. Nine studies [19,20,[22][23][24][25][26][27][28] compared the effects of acupuncture and CM, and results revealed that patients receiving acupuncture therapy showed a greater improvement in effective rate, recurrence rate, weekly defecation, IBS symptom scores, IBS-QOL, and IBS-SSS than patients receiving CM. One study [21] compared the effects of acupuncture plus Chinese herbal medicine and CM, and results revealed that patients receiving combination therapy reported a significantly greater improvement in effective rate and abdominal pain than patients receiving CM.

Safety of the Interventions.
One study [19] reported the meta-analysis results in adverse effects, and no statistically significant difference was found between patients treated with acupuncture and CM.

Discussion
Treatment of IBS focuses on symptom management to maintain daily functioning and improve QOL. However, due to significant side effects of prescribed medications, some sufferers do not take multiple CM but instead turn to complementary and alternative therapies for remedy [11,29]. A number of SRs/MAs have investigated the efficacy of acupuncture for IBS patients. e purpose of this study was to systematically collate, appraise, and synthesize the evidence published in recent years.
Ten SRs/MAs regarding to the efficacy of acupuncture for IBS were finally included. From the meta-analysis results of these studies, patients reported that acupuncture had a greater benefit on IBS symptoms than CM. However, these findings must be considered cautiously, given the limitations on methodological quality, reporting quality, and evidence quality of the included studies. According to AMSTAR-2 and PRISMA checklists, most of (80%) the included studies did not establish a protocol, which could undermine the rigor of the study and increase the risk of bias. For literature search, 60% studies only provided the search keywords but no specific search strategies, which could lead to publication  bias and undermined the credibility of the results. Moreover, 90% studies did not provide the lists of excluded trails, which may undermine the transparency of the study process. According to the GRADE tool, no outcome indicators provided high-quality evidence, indicating that the metaanalyses results of the included studies may differ from the true results. e risk of bias for the enrolled trails of the included studies was the main reason for evidence degradation. Further analyses found common limitations of the enrolled trails as follows: only randomization was mentioned without the randomization method; the allocation was not concealed; and only single blinding was implemented. erefore, the basic factor leading to the decline in the quality of evidence was the low methodological quality of the enrolled trails. It was believed that well-designed and implemented randomized controlled trials were considered to be the gold standard to avoid the risk of bias [30]. Furthermore, almost all of the included SRs/MAs indicated that acupuncture seemed to have a significant clinical efficacy for IBS; however, most authors did not wish to draw clear conclusions due to low methodological quality or the small size of the enrolled trails.
Pain Research and Management   Pain Research and Management e action mechanism of acupuncture for IBS includes regulating the gastrointestinal motility, reducing visceral hypersensitivity, regulating the brain-intestine axis, reducing low-level intestinal mucosal inflammation, promoting intestinal microflora balance, and adjusting psycho-psychological status [31]. IBS is a gastrointestinal disorder in which intestinal spasm causes abdominal pain, hypermotility leads to diarrhea, and hypomotility leads to constipation. us, for the purpose of treatment, IBS can be divided into three types: constipation-predominant, diarrhea-predominant, or mixed [32]. Animal experiments revealed that acupuncture stimulation of IBS-D model rats effectively improved diarrhea symptoms in rats, and it was found that the mRNA and protein expression of APQ8 in the rat colon tissue was reduced, while the protein expression of VIP was increased [33]. For patients with IBS-C, electroacupuncture stimulation of Zusanli can promote contraction of the patient's colon ends and accelerate colonic transit, which in turn improves constipation symptoms [34]. ese results suggest that acupuncture has a bidirectional regulatory effect on intestinal motility in IBS patients. Furthermore, EA intervention can ameliorate the fecal property in IBS-C rats, which may be associated with its function in inhibiting the expression of colonic CGRP and SP proteins [35]. Visceral hypersensitivity is considered an important pathological mechanism in the development of IBS. It is reported that EA can alleviate visceral hypersensitivity in IBS-D and IBS-C rats by regulating the expression level of TRPV1 in the colon [35,36]. e brain-gut axis was a complex, bidirectional signaling system between the central nervous system and the gastrointestinal system. It is reported that acupuncture could improve intestinal motility and visceral sensitivity by modulating brain-gut peptide levels in the central nervous system, gut, and blood [31]. Furthermore, electroacupuncture decreases 5-HT and CGRP, increases NPY in the brain-gut axis in rat models of IBS-D [37], and increases the number of neurons in the myenteric plexus of IBS-C rats [38]. Posttraumatic stress disorder (PTSD) is thought to be associated with IBS and is a common comorbidity [39]. It is reported that acupuncture can affect the autonomic nervous system, and the prefrontal as well as limbic brain structures, enabling it to relieve the symptoms of PTSD [40]. Activation of the immune system was strongly associated with IBS, and acupuncture could downregulate the expression of serum IL-18, TNF-α, and IL-23 in IBS patients, thus playing an immunoregulatory role [41]. e overgrowth of intestinal flora may be an important factor in the induction of IBS [42]. It is reported that acupuncture treatment may modulate intestinal bacteria and the psychological state tends to balance to relieve the symptoms of IBS [31,43]. However, there is still a lack of evidence on the regulation of intestinal microbiota in IBS through the use of acupuncture.
is overview would provide some useful information on unique treatments in clinical practice for physicians in the management of IBS, thus providing more treatment options for IBS patients. However, we found that the majority of the included reviews were of poor quality, which could result in them having low credibility. Furthermore, the AMSTAR-2 tool, PRISMA checklist, and the GRADE system are highly subjective.
us, different reviewers may have their own independent judgments on the evaluation results. Even with two independent reviewers in this study, subjective factors or errors cannot be completely eliminated. Finally, there is limited evidence for the efficacy of acupuncture for IBS subtypes, especially IBS-C. Further clinical and mechanistic studies of acupuncture for IBS subtypes are still necessary.

Conclusion
Acupuncture may be a promising treatment for IBS, and it could be used as an adjunct in clinical settings to improve efficacy. However, this conclusion must be treated with caution since the quality of SRs/MAs providing evidence is generally low.

IBS:
Irritable bowel syndrome SR: Systematic review MA: Meta-analysis AMSTAR-2: Assessment of Multiple Systematic Reviews 2 PRISMA: Preferred Reporting Item for Systematic Reviews and Meta-Analyses GRADE: Grading of Recommendations, Assessment, Development, and Evaluation QOL: Quality of life SSS: Symptom Severity Scale CM: Conventional medication.

Data Availability
All analyses were based on previously published studies.

Consent
No informed consent was required.

Disclosure
Jinke Huang and Mengxiong Lu are the co-first authors.

Conflicts of Interest
e authors declare that there are no conflicts of interest.

Authors' Contributions
Jinke Huang and Mengxiong Lu initiated the study design and drafted the manuscript. Both these authors have contributed equally to this work. Jinxin Ma, Jing Ma, Xiangxue Ma, Yitian Wang, Yijun Zheng, and Kunli Zhang helped with implementation to this work. All authors read and approved the final manuscript. Fengyun Wang and Xudong Tang contributed to the methodology, review, and editing of the manuscript. All authors read and approved the final manuscript.