Introduction
Functional bowel disorders (FBDs) are highly prevalent worldwide, afflicting more than one-third of the population, with irritable bowel syndrome (IBS) being the most prevalent FBD (5–10%).1 The symptoms (abdominal pain, diarrhea, constipation, etc.) can greatly impair one’s quality of life, both physically and psychologically.2 The research fields of FBDs and the intestinal microbiota have made great progress. The Rome Foundation has played a critical role in creating and updating the diagnostic criteria for FBDs from Rome I in 1994 to Rome IV in 2016.3 Simultaneously, the Human Genome Project (started in 1990) and, more recently, the Integrative Human Microbiome Project (completed in 2019) have provided significant insight into microbiota-host interactions (Fig. 1).4–6 Of importance, recent studies have shown that the intestinal microbiota is causally related to FBDs.7,8 Further, novel microbiota-targeted treatments for FBDs, such as probiotics, prebiotics, synbiotics, and even fecal microbiota transplantation (FMT), are considered promising therapies for FBDs.9 However, there are still many challenges in this research field. The pathogenesis and pathophysiology of FBDs, mechanism of microbiota-host interaction, and causality between microbiota and disease require further research.10
Scientometric analysis involves the combination of mathematics, visualization, and philosophizing to observe the knowledge growth, disentangle complex knowledge networks, and trace the latest trends in research frontiers.11 Over the past two decades, there has been a substantial increase in the number of published studies on the intestinal microbiota in FBDs. Various published studies have conducted scientometric analyses to understand the relationships between the intestinal microbiota and inflammatory bowel disease, obesity, cancer, etc.12–14 However, there are few scientometric articles pertaining to FBDs and the intestinal microbiota. Zyoud et al.15,16 analyzed the productive countries in this field and preliminarily discussed two trends regarding the microbiome in IBS (research spanning 2000–2019) and the microbiome-gut-brain axis (research spanning 2009–2018). Neither of these two studies employed burst detection of keywords and references, which is a powerful method to detect hotspots and trace trends, nor did they construct dual-map overlays or perform structural variation analysis to infer possible research frontiers. To the best of our knowledge, no comprehensive scientometric analyses related to FBDs and the intestinal microbiota have been performed. The aim of this current article was to survey the current status of progress, understand the current knowledge base, and trace the possible frontiers in the fields of FBDs and the intestinal microbiota using scientometric analysis. The findings presented here could facilitate further research and innovation.
Materials and methods
Search strategy
Web of Science contains the most comprehensive and complete citation network among all scientific databases and provides overall data sources for bibliometric software. Therefore, a comprehensive search was conducted using the citation index database Web of Science (WoS) Core collection™ (©2022 Clarivate) with the Science Citation Index Expanded (SCI-EXPANDED) database (2007–present), Current Chemical Reactions (CCR-EXPANDED) database (1985–present), and Index Chemicus (IC) database (1993–present). The most recent version of the Web of Science database was made available in December 2022. Literature retrieval and data downloads were performed on a single day, June 26th, 2023, to reduce the bias incurred by database updates. According to the Rome IV criteria published in 2016, FBDs are classified into six distinct categories: IBS, functional constipation, functional diarrhoea, functional abdominal bloating/distention, unspecified FBD, and opioid-induced constipation.17 Search strategy syntax was combined with medical subject headings (MeSH) and entry terms. First, the PubMed MeSH database was used to determine the MeSH words and entry terms. Then, the search strategy was employed in Web of Science; only documents defined as “articles”, “proceeding papers”, or “early access” in Web of Science were included in the analysis; other documents, such as letters, meeting abstracts, or editorials were excluded. As different languages cannot be analyzed within the one bibliometric analysis, the article language was restricted to English. Boolean logic was used to connect search words or formulas as follows.
#1. Topic = “Irritable Bowel Syndrome*” OR “Colonic Diseases, Functional” OR “Irritable Colon” OR “Mucous Colitides” OR “Mucous Colitis” OR IBS. / (21848)
#2. Topic = “Functional constipation” OR “Constipation” OR “Opioid-Induced Constipation*” OR “Narcotic Bowel Syndrome*” OR “Opioid-Induced Bowel Dysfunction*”. / (19919)
#3. Topic = “Functional Diarrhoea” OR “Functional Abdominal Bloating” OR “Functional Abdominal Distention” OR “Functional Bowel Disorder*”. / (696)
#4. Topic = “Gastrointestinal Microbiome*” OR “Gut Microbiome*” OR “Gut Microflora” OR “Gut Microbiota*” OR “Gastrointestinal Flora” OR “Gut Flora” OR “Gastrointestinal Microbiota*” OR “Gastrointestinal Microbial Communit*” OR “Gastrointestinal Microflora” OR “Gastric Microbiome*” OR “Intestinal Microbiome*” OR “Intestinal Microbiota*” OR “Intestinal Microflora” OR “Intestinal Flora” OR “Enteric Bacteria”. / (89631)
#5. #1 OR #2 OR #3. / (38860)
#6. #4 AND #5. / (2924)
All publications in this field were published between 2007 and 2023. Further analysis was performed after data cleansing. The scientometric indicators included year distribution, countries, institutions, authors, journals, categories, keywords, and references.
Scientometric analysis
Data analysis was performed using CiteSpace 6.2. R2 (64-bit) beta-© 2003–2023 Chaomei Chen (Built on April 3, 2023) (http://cluster.cis.drexel.edu/~cchen/citespace ) with Java 17.0.6+9-LTS-190 (64-bit). Geographic visualization was performed using SCImago Graphica Beta 1.0.19 (www.graphica.app ). VOSviewer software (www.vosviewer.com , Van Eck & Waltman version 1.6.18) and Pajek64 portable software (http://mrvar.fdv.uni-lj.si/pajek/ , Andrej Mrvar & Vladimir Batagelj version 5.17) were used to facilitate the analysis, mapping, and digital visualization of keyword co-occurrences in the titles and abstracts of the publications. Microsoft Office Excel 2019 (Redmond, United States) was used to analyze the frequencies and percentages of productive countries, institutions, authors, and publications.
In CiteSpace, the G-index was chosen to analyze the node types of categories (without Pathfinder) and keywords (with Pathfinder), respectively. The top 50 most cited or observed items from each slice were selected for the analysis of co-citation references (with Pathfinder) and structural variation analysis (with Pathfinder), respectively. Specifically, the G-index in each slice was calculated as follows: g2 ≤ k∑i ≤ gci, k ϵ Z+; to include more or fewer nodes, the algorithm increased or decreased the scale factor k = 25. Pathfinder with pruning sliced networks and merged networks was chosen to simplify the synthesized network and highlight its significant characteristics. Citation and co-citation networks were plotted from articles published in a one-year time interval. Structure variation analysis was plotted in a two-year time interval. All clusters were constructed based on the log-likelihood ratio algorithm, and keywords were extracted from the articles using CiteSpace software. Modularity Q > 0.3 reflected significant clustering; Weighted Mean Silhouette (WMS) > 0.7 reflected convincing clustering. Other parameters were set to default values. The journal dual-map overlay analyses were performed using the “JCR Journal Maps” function in CiteSpace.
As this study was a scientometric analysis of the published literature, ethics approval was not required.
Results
Global trends and international collaborations
A topic search for FBDs (Rome IV) and intestinal microbiota resulted in 2,924 records published between 2007 and 2023. Publications in this field exhibited a growing trend from 21 to 434 records between 2007 and 2022 (Fig. 2a). This indicates increasing interest and research efforts in this field. China (n = 685, 23.43%) and the United States (n = 672, 22.98%) were among the most productive countries, followed by the United Kingdom (n = 276, 9.44%), Italy (n = 225, 7.69%), and Australia (n = 164, 5.61%) (Fig. 2b). Categorization of the records by year revealed that the most productive year was 2022; the publication trend of the United States was flatter than that of China between 2016 and 2022 (Fig. 2c). Geographical visualization of the international collaboration network showed that the most frequent collaborations occurred between the United States and European countries (e.g., Sweden and the United Kingdom), and between the United States and China (Fig. 2d, e).
Publication analysis of related institutions and authors
The most productive institution was the University of College Cork (n = 143, 4.89%), followed by the University of California System (n = 84, 2.87%), and University of London (n = 69, 2.36%) (Fig. 3a); almost all productive institutions were located in Europe or the United States, which indicates stronger scientific prowess aggregated in these areas. The most productive author was Cryan JF (n = 74, h-index = 121), followed by Dinan TG (n = 66, h-index = 123), Quigley EMM (n = 40, h-index = 67), and Gasbarrini A (n = 35, h-index = 89) (Fig. 3b); most of the productive authors were from Europe, the United States, and China. Thus, the institution and author analyses showed that the strongest scientific expertise in this field was mainly distributed within Europe, the United States, and China.
Publication analysis of productive journals and cited journals
The most productive journal on the field of FBDs and the intestinal microbiota was Nutrients (n = 123, 4.21%), followed by World Journal of Gastroenterology (n = 74, 2.53%) and Neurogastroenterology and Motility (n = 74, 2.53%) (Fig. 3c). Among the top 10 citing journals, there were three journals with impact factors > 10, including Gut Microbes (n = 51, 1.74%, IF2022 = 12.2), Gastroenterology (n = 32, 1.09%, IF2022 = 29.4), and Gut (n = 29, 0.99%, IF2022 = 24.5). Based on the number of cited publications, Gastroenterology (n = 2,364) ranked first, followed by Gut (n = 2,186) and Plos One (n = 1,794) (Fig. 3d). Among the top 10 cited journals, there were four journals with impact factors > 10, including Gastroenterology, Gut, Nature (n = 1,450, IF2022 = 64.8), and Proceedings of the National Academy of Sciences of the United States of America (n = 1,339, IF2022 = 11.1). The journal analysis showed that co-cited journals had higher impact factors than citing journals, indicating that there is a strong knowledge base within this field, but deeper and more novel research is still required.
Categories and dual-map overlay analysis of publication portfolio
Category analysis in this field between 2007 and 2023 showed that Gastroenterology & Hepatology held the dominant leading position (n = 793, 27.12%) and maintained increasing momentum, while Nutrition & Dietetics (n = 404. 13.82%) and Microbiology (n = 401, 13.71%) exhibited a continuous increase; Neurosciences (n = 287, 9.82%) and Pharmacology & Pharmacy (n = 251, 8.58%) exhibited similar tendencies (Fig. 3e, f). The dual-map overlay was established by Chen and Leydesdorff to reveal the patterns of a scientific portfolio by providing a global map of scientific literature at the disciplinary level. Dual-map overlay analyses of publication portfolios, with one overlay of citing journals and another of cited journals, can explicitly and simultaneously depict the sources and targets of citations.18 Such analyses provide an understanding of the input and output of knowledge flow, as well as the inheritance and development of scientific domains. In this study, the journal dual-map overlays for the field between 2007 and 2023 were drawn using the “JCR Journal Maps” function of CiteSpace. Based on the citation links shown in the journal dual-map overlays, the starting position of the citing trajectory was predominated by publications in the molecular/biology/immunology and medicine/medical/clinical disciplines, whereas the ending position of the trajectory appeared to be influenced by activities in the molecular/biology/genetics and health/nursing/medicine disciplines (Fig. 4). Thus, the dual-map overlay analyses indicated that the FBDs/intestinal microbiota research field is multidisciplinary, and interdisciplinary efforts are required to address important research questions.
Analysis of the co-occurrence of keywords
In VOSviewer, the minimum number of occurrences of a keyword was set at eight; 596 of the 8,108 keywords met the threshold. The keywords were divided into seven clusters using VOSviewer; the greatest diameter and the hottest density of circles belonged to the keyword “intestinal microbiota” (links = 594), followed by “irritable bowel syndrome” (links = 592) and “probiotics” (links = 553) (Fig. 5a, b). CiteSpace was used to further analyze the characteristics of the keywords. The merged network contained 645 keywords with 6,743 links between 2007 and 2023. The Top20 keywords with the highest count in Citespace were coincided with those in VOSviewer (Supplementary Table 1). Citation burst analysis is a powerful means to trace the development of a research focus. The top 25 keywords with the strongest citation bursts are shown in Figure 6. The bursting keyword with the highest strength was gastrointestinal microbiota (23.03), followed by antibiotic-associated diarrhea (19.3) and anxiety-like behavior (17.88). The bursting keywords with the latest duration time from 2021–2023 included gastrointestinal microbiome, receptor, serotonin, and metabolism. The analysis of bursting keywords indicated that research in this field has evolved from preliminary analyses mainly of the microbiota to in-depth analyses of pathophysiological mechanisms, diagnostic biomarkers, and treatment of the intestinal microbiota in FBDs.
Citation and co-citation analysis of references
A document co-citation network was constructed from the dataset. The merged network contained 475 references cited with 2,603 links between 2007 and 2023. The top-ranked items by citation count were Tap J et al.19 (166 citations), followed by Pittavanon R et al.20 (147 citations) and Simren M et al.21 (138 citations) (Supplementary Table 2). The analysis of the top 10 cited articles revealed three predominant subjects: 1) updates on the current understanding of FBDs;17,21 2) utilization of the latest sequencing technology to unveil the relationship between the intestinal microbiota and FBDs;19,20 and 3) preliminary studies of the effects of microbiota-targeted treatment on FBDs.22
Citation bursts of references reflect the development of a research focus. The top 10 references with the strongest citation bursts from 2016 to 2023 included Pittayanon R et al.,20 Tap J et al.,19 and Lacy BE et al.17 (Fig. 7). Citation bursts of the top 10 references showed that the research frontier was focused on three overarching topics: 1) the pathophysiological mechanisms of the microbiota-gut-brain;23 2) exploration of microbial-related mechanisms and biomarkers of FBDs;24 and 3) clinical trials of microbial-targeted treatments (including FMT, probiotics, low FODMAP diet with or without probiotics).25,26
Structural variation analysis of citing articles with the highest cluster linkage
Structure variation analysis focuses on the novel boundary-spanning connections introduced by a new article.27 For this study, a two-year time interval was chosen, and the knowledge map was visualized from 2007–2023. The merged network contained 329 references cited with 333 links between 2007 and 2023 (Modularity Q = 0.8868, WMS = 0.9668). The cluster linkage parameter measures the overall structural variation and is better at predicting the citation count of a new article; thus, it was used as an indicator of intellectual impact in this research. The top-ranked item by cluster linkage was Browne PD et al.28 with a cluster linkage of 899.28, followed by Bootz-maoz HH et al.29 and Vervier KK et al.30 The top five citing original articles with the highest cluster linkage from 2020–2023 are listed in Supplementary Table 3. These articles were in greater boundary-spanning co-citation connections in the baseline network, connecting clusters #1 fecal microbiota transplantation, #9 IBS, #8 low FODMAP diet, and #13 microbiota (Fig. 8). The above critical articles serve as a bridge connecting different subfields and constitute integrated knowledge mapping. These studies mainly explored the efficacy of microbiota-targeted treatment including FMT and diet on IBS.
Discussion
The aim of this study was to provide a comprehensive perspective on the knowledge base and frontier in the overlapping fields of FBDs and the intestinal microbiota using scientometric analysis. The publications on this topic exhibited a growing trend from 2007–2022, which may be explained by three major factors. First, the high incidence of FBDs globally and their effects on quality of life have raised the attention of both the public and researchers. Second, the pathophysiology of FBDs is still largely unknown and there are no effective treatments. Third, since the National Institutes of Health (NIH) launched the Human Microbiome Project in 2008,5 a number of projects, such as the China Microbiome Initiative and the European MetaHIT project, have been set up and sponsored many research projects. These national programs have profoundly contributed to the development of multi-omics technology and research on the relationships between the human microbiome and diseases. These internal and external promoting factors have prompted scientists to delve deep and attempt to disentangle the links between FBDs and the intestinal microbiota.
Through scientometric analysis, the current study identified three main research frontiers, as described below.
Microbiome-metabolites-mechanisms in FBDs
Many studies have explored and revealed alterations in the intestinal microbiota (e.g., Bacteroides,31Erysipelatoclostridium,32 etc.) and effects of microbial metabolites (e.g., short chain fatty acids,33 bile acids,34 etc.) on gut motility, intestinal barrier function, visceral sensation, immune activation, and the nervous system in FBDs.35 In addition, the microbiota-gut-brain axis has attracted significant attention in recent years and has been found to modulate the function of both the enteric and central nervous systems.36 However, mechanistic studies of complex gut-brain communication in FBDs are still in their infancy.37 More in-depth studies are needed to bridge the gap between human and animal studies, to clarify the complex network of microbiome-metabolites-mechanism in FBDs, and to turn microbiome findings into clinical applications.
Microbiota-related biomarkers for diagnosing and distinguishing the severity of FBDs
FBDs diagnosis mainly depends on symptoms and stool consistency. Although some studies have identified microbiome biomarkers of FBDs,19,32 there are currently no robust biomarkers for the identification and classification of FBD severity.38 It is necessary to develop non-invasive microbial biomarkers not only for diagnosis but for targeted treatment. Therefore, patients with depleted health-related microbes or metabolites could benefit from non-invasive diagnostic tools and microbial-targeted treatments to counterbalance the defects caused by FBDs.39
Investigation of the cellular and molecular mechanism of microbiota-targeted treatments towards FBDs for precision medicine
Microbiota-targeted treatments include direct methods such as FMT, and indirect ones such as dietary intervention using low FODMAP, reshaping the gut microbiome into a healthier status. However, microbiota-targeted treatments have heterogeneous effects and linked mechanisms remains poorly understood. A meta-analysis showed that a low FODMAP diet significantly reduced global IBS symptoms,40 while another study showed that low FODMAP was associated with unfavorable changes in the gut microbial composition.41 FMT is promising as a powerful therapy for Clostridium difficile infection,42 but its effects are also not yet convincing. A randomized, double-blind clinical trial conducted by Johnsen PH et al. showed that FMT could relieve the symptoms of IBS patients,43 while Halkjaer SI et al. showed that FMT is no better than a placebo in improving symptoms and quality of life.44 Notably, microbiota-targeted treatments are not without risk, including uncertain impacts on the recipient’s immune system and disease transmission.45,46
The current article employed scientometric methods to comprehensively analyze the knowledge base and viable frontier of research in the overlapping fields of FBDs and the intestinal microbiota. However, there are several limitations of this study that should be noted. First, the Web of Science database was exclusively employed for the scientometric analysis, and this may have caused literature selection bias. Second, open access analysis in this field showed that All Open Access (n = 1,945, 66.52%), followed by Gold (n = 1,171, 40.05%), Free to Read (n = 283, 9.68%), and Gold-Hybrid (n = 279, 9.54%). There might be a citation bias or even citation stacking in the process. Finally, scientific networks constantly change over time, which could influence the bibliometric results. Thus, the findings of the current article could be greatly influenced by time factors.