Bibliometric analysis of the 100 most-cited papers about the role of gut microbiota in irritable bowel syndrome from 2000 to 2021

Over the last few decades, gut microbiota research has been the focus of intense research and this field has become particularly important. This research aimed to provide a quantitative evaluation of the 100 most-cited articles on gut microbiota and IBS and highlight the most important advances in this field. The database Web of Science Core Collection was used to download the bibliometric information the top 100 most-cited papers. Microsoft Excel 2021, CiteSpace, VOSviewer, R software, and an online analytical platform (https://bibliometric.com/) were was applied to perform bibliometric analysis of these papers. The total citation frequency in the top 100 article ranged from 274 to 2324, with an average citation of 556.57. A total of 24 countries/regions made contributions to the top 100 cited papers, and USA, Ireland, and China were the most top three productive countries. Cryan JF was the most frequently nominated author, and of the top 100 articles, 20 listed his name. Top-cited papers mainly came from the Gastroenterology (n = 13, citations = 6373) and Gut (n = 9, citations = 3903). There was a significant citation path, indicating publications in molecular/biology/immunology primarily cited journals in molecular/biology/genetics fields. Keywords analysis suggested that the main topics on gut microbiota and IBS were mechanisms of microbiome in brain-gut axis." Behavior" was the keyword with the strongest burst strength (2.36), followed by “anxiety like behavior” (2.24), “intestinal microbiota” (2.19), and “chain fatty acid” (1.99), and “maternal separation” (1.95). This study identified and provided the bibliometric information of the top 100 cited publications related to gut microbiota and IBS. The results provided a general overview of this topic and might help researchers to better understand the evolution, Influential findings and hotspots in researching gut microbiota and IBS, thus providing new perspectives and novel research ideas in this specific area.


Introduction
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain associated with altered stool form or frequency [14].To date, the specific etiology and pathogenesis of IBS remain unclear.Over recent decades, extensive research has indicated that the pathogenesis of IBS is complex and multifactorial, including genetics, physiological and psychological stress, abnormal brain-gut axis, altered gut microbiota, neuroimmune dysfunction, and infections [5,19,39].Epidemiologic and demographic studies indicated that there is substantial regional variation in prevalence of IBS, and the average prevalence among individual countries ranged from 1.1% in France and Iran to 35.5% in Mexico [44].Although the prevalence of IBS varies dramatically in different geographic locations, IBS leads to a large economic burden due to enormous direct and indirect costs [2].
On the one hand, extensive research suggested that IBS could often co-occur with mental disorders such as anxiety symptoms and depression via influencing the brain-gut axis, making its diagnosis and treatment challenging [15,16].On the other hand, it is believed that alterations in brain structure and function are involved in the generation of clinical symptoms of IBS [6,20,47].Recent evidence has highlighted the importance of the dysbiosis of gut flora in the pathophysiology of IBS [1,31].To further understand the role of the intestinal microbiota in the pathophysiology of IBS, several studies have characterized this complex microbial community in IBS patients.Gut microbiota plays an essential role in maintaining intestinal homeostasis and protecting intestinal epithelial barrier integrity.It has been reported that disrupted intestinal permeability is one of the factors important to the development of IBS [10].Peng L et al. found that microbiota-derived shortchain fatty acids (SCFAs) are crucial for the maintenance of intestinal epithelium physiology and intestinal barrier function [34].Mucin-degrading bacteria such as ruminococcus torques and ruminococcus gnavus are shown to be related to the severity of bowel symptoms in IBS [28,45,46].Furthermore, data suggested that there is a relative abundance of proinflammatory bacterial species in IBS patients, such as Enterobacteriaceae [51].An increasing body of research has illustrated that Veillonella and Ruminococcus abundance are increased while Faecalibacterium abundance was decreased in fecal samples from patients with IBS [29,38,40].However, the lack of an efficient IBS treatment, as well as the high diversity of the interventions, strongly suggest that the pathophysiology of the disease is not yet fully elucidated.
An important but challenging task for researchers is to identify the most influential work in a specific area.
Citation analysis is a bibliometric method to identify documents with the greatest impact on research and the clinical community, and can help predict the hotspots and trends within a certain research area [13].Citation count is an important indicator reflecting publications' impact.
In the present study, we performed a bibliometric analysis of the 100 most-cited papers about the role of intestinal microbiota in IBS to identify the most influential work in this area.The analysis is of great importance to look into the distribution of articles and authors in this field, which would provide readers with a comprehensive overview of the most important works in this enormous field.

Search strategies and data extraction
The relevant data included in this study were downloaded from the Science Citation Index Expanded (SCI-EXPANDED) of Clarivate Analytics Web of Science Core Collection (WoSCC).As the most prestigious global database, WoSCC can provide detailed information needed for bibliometric software and is commonly used in bibliometric analysis [9,49,50].The search strategies were built on previous literature: TS = (IBS OR "irritable bowel syndrome*" OR "irritable bowel" OR "irritable colon" OR "irritable bowel disease") AND TS = (gastrointestinal OR gut OR intestinal OR bowel) AND TS = (microbiome OR microbiota OR microorganism OR microbe) [8,48].Literature in WoSCC published from January 2000 to December 2021 was systematically searched.Document retrieval and recording were completed on 27 September 2022 to avoid bias caused by the database update.Only original articles and reviews with full manuscripts were considered for bibliometric analysis, without language limitation.Two researchers independently screened the title, abstract and document type, if necessary, reading the full article for a more detailed assessment, to confirm if it should be included.We download the 100 most influential articles' records, in the "Full Record and Cited References" form WoSCC in.TXT format.The impact factors of each journal were retrieved from the latest Journal Citation Reports 2021.

Data analyses and visualization
Descriptive statistical analysis and diagrams generation were performed with Microsoft Excel 2021 and R software (v 4.2.1).An online analytic platform (https: //bibliometric.com/) was selected to perform cooperation networks among countries.VOSviewer, developed by Van Eck and Waltman, is a powerful bibliometric tool that can clearly construct network of institutions, keywords, authors, and so on [12].
In this study, the download data was import into VOSviewer to create an institutional cooperation network, co-authorship network of authors, and the term co-occurrence network.In the network map developed by VOSviewer, various nodes represented different elements, such as institutions, authors and keywords.The thickness of the connecting line between nodes represented link strength of the co-authorship and co-occurrence, which could be weighted by a quantitative indicator called Total Link Strength (TLS).Co-authorship analysis reveals collaboration patterns between countries and institutions.In co-occurrence analysis, the relatedness of items is determined based on the number of documents in which they occur together and the color indicates different clusters.Besides, CiteSpace software was used to construct the dual-map overlay of journals and identify the keywords with the strongest burst strength [7].

Analysis of publications and citations
As shown in Fig. 1, all of the 100 top-cited studies were published between 2000 and 2019.The detailed information about the 100 most influential publications was recorded in Supplementary Table 1.The number of citations for the top 100 articles ranged from 274 to 2324 citations, with a median citation of 429 and an average citation of 556.57.The total number of citations was 55,657.It was worthy to focus on the top three studies.The first study titled "Gut Microbiota in Health and Disease," which was published in Physiological Reviews in 2010 and had also been cited 2324 times.The second top-cited paper was published in the Nature Reviews Neuroscience in 2012, titled "Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour" and has also been cited 2213 times.The paper titled "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve" published in 2011 by the Proceedings of the National Academy of Sciences of the United States of America, and was cited 1909 times.

Analysis of the most productive countries
As can be seen in Fig. 2, a total of 24 countries/regions worldwide contributed to the top 100 most-cited documents, with 16 countries/regions had more than 3 articles.Supplementary Table 2 shows the USA dominated in this field with 33 of the 100 papers and 15,356 citations at an average citation count of 465.33.Ireland ranked second, contributing 27 papers, with 17,520 citations and an average citation count of 648.89.Followed by Canada, contributed 19 articles, with 13,348 citations and an average citation count of 702.53.Wales had the highest average number of citations per publication (864.5).

Institutions analysis
As for institutions, a total of 219 institutions contributed to the top 100 articles.Of them, University College Cork produced the most top-cited articles (n = 25), followed by McMaster University (n = 12).University of California-Los Angeles and University of Helsinki ranked 3 with 10 publications (Supplementary Table 3).Institutional co-authorship analysis was represented in Fig. 3

Analysis of journals
Table 1 listed the relevant journal of the 100 articles.The Gastroenterology published most of the 100 articles (n = 13), with 6373 citations, followed by GUT , which published nine papers that had 3903 citations.American Journal of Gastroenterology, Biological Psychiatry, British Journal of Nutrition, Nature Reviews Gastroenterology & Hepatology, and Proceedings of The National Academy of Sciences of The United States of America took third place with three publications, and had 1519, 1705, 2359, 1636, 3199 citations, respectively.

Authors analysis
The top 10 authors involved in the top 100 publications were listed in Table 2.The list was led by Cryan JF from the University College Cork, who participated in 20 of the top 100 articles.Followed by Dinan TG (n = 18), and Clarke G (n = 9) also come from this University.Figure 4A presents the annual outputs of these top 10 authors between 2006 and 2019.As the leading researchers of this field, Cryan JF and Dinan TG had been publishing articles for years in a row.As presented in Fig. 4B, a total of 55 authors with a minimum limitation of more than two publications were identified and analyzed with the help of VOSviewer.Cryan JF, Dinan TG and Stanton C were the top three authors with the greatest TLS, and located at the central position in the network map.

Distribution of journals
The dual-map overlay of the journals stands for the topic distribution of journals (Fig. 5A).On the left side of the map represents the network of citing journals and the labels show the disciplines of the citing journals; the network of cited journals is on the right side of the dual map, and the labels on it denote the disciplines to which the cited references belong.As shown in Fig. 5A, the yellow path indicates publications in molecular/biology/immunology primarily cited journals in molecular/biology/genetics fields.In Fig. 5B, source dynamics show that most of relevant papers published in the Gastroenterology (n = 13) and Gut (n = 9), both of them maintain the overall growth trend in recent years.on the above principles, we detected the research dynamic and structure of the discipline via keyword co-occurrence analysis.The more frequently a keyword occurred, the larger the sphere is.As shown in Fig. 7A.Hot keywords include probiotics, microbiota, stress, depression, gut microbiota, irritable bowel syndrome, brain-gut axis, inflammation, etc.The research frontiers in a certain field can be identified by keywords with the strongest burst strength.Keywords burst earlier indicate that researchers focused on this area in early years, while burst closer to the present denote the topic has suddenly attracted attention recently.From Fig. 7B, the top five keywords identified are "behavior," "anxiety like behavior," "intestinal microbiota," "chain fatty acid," and "maternal separation" with the burst strength of 2.36, 2.24,2.19,1.99,1.95,respectively."Helicobacter pylori" and "placebo controlled trial" are the earliest keywords to burst, and the most recent burst keywords include "chain fatty acid," "Parkinson's disease," and "early life stress."

Future direction
Figure 8 displays the current principles and landscape of gut microbiota in IBS.The disrupted brain-gut axis is of great importance in the pathogenesis of IBS.The specific mechanisms by which the intestinal flora affects mental and physical health has not been fully elucidated, and is a direction for future research.

Discussion
With the rapid development of high-throughput sequencing technology and bioinformatics efforts, an increasing body of literature has demonstrated that intestinal microbiota has a profound impact on host health by regulating intestinal homeostasis.Although IBS is not directly life-threatening, it can have a serious impact on patients' life quality and mental health [18].Besides, multiple recent studies have consistently revealed that the gut microbiota plays a substantial role in IBS [36,42].Thus, it is crucial to understand the progress and evolution about the role of intestinal microbiota in IBS.However, such information is very limited.In this study, the top 100 most influential documents in this field were selected for research data and bibliometric analysis was carried out to systematically explore the research output dynamics, hotspots, and frontiers of this field.It can help researchers accurately grasp basics, broaden the horizon, and learn status quo of current research efforts.
As is seen from Fig. 2, these influential outputs characterized by international cooperation and witnessed a multi-national cooperation network with the USA and Ireland as the core.The USA and Ireland were the leading country with most top papers and have the most specialists (Supplementary Table 2).Additionally, more than half of the top 10 institutions were from these two countries (Supplementary Table 3).In addition, some European countries such as the Netherlands, Sweden, and Canada in North America have also made outstanding contributions in the field.In 2005, an article written by Finland researcher Malinen E revealed that there was extensive individual variation in the gastrointestinal (GI) microbiota between IBS group and control group devoid of GI symptoms, significant differences were found in Clostridium coccoides subgroup and Bifidobacterium catenulatum group among IBS patients and controls [29].Besides, Kassinen A et al. characterized the differences in GI microbiota between patients with IBS and control subjects by extensive high-throughput 16S ribosomal RNA gene cloning and sequencing of clones in 2007 [22].These studies indicated that fecal microbiota is significantly altered in IBS.Although the molecular mechanisms underlying these alterations are poorly understood, targeting the composition and metabolic function of intestinal flora has become a new option for the treatment of IBS.In recent years, many countries have contributed substantially in this field.Studies have shown that probiotics can not only reduce the symptoms of patients suffering from IBS but also alleviated depression and increases quality of life in patients with IBS [32,35].The VOSviewer software was used to visualize the relationship between each institution in this The top-cited studies within the research field were more likely to be published in high-impact journals such as

Gastroenterology, Gut, American Journal of Gastroenterology, Biological Psychiatry, Nature Reviews Gastroenterology & Hepatology, Proceedings of The National Academy of Sciences of
The United States of America, suggesting that these journals are prone to publishing research of gut microbiota in health and disease.Meanwhile, it can be seen that most of these papers are from journals with high-impact factor value, indicating that the topic is considered of high value by academics worldwide.The results of bibliometric analysis also support the well-known convention that highquality studies are often published in high-impact factor journals, which in turn maintains the high-impact factor of these journals.Additionally, in addition to gastroenterology and microbiology, several studies published in these journals belonging to other fields such as psychiatry and physiology.These findings offer substantial support for the strong correlation between brain-gut axis and IBS.Numerous groundbreaking advances regarding gut microbiota have been made in these research directions.O'Mahony SM et al. designed a study to assess the effect of early life stress on the brain-gut axis, they found that early life stress could result in an altered brain-gut axis, which might be used for investigating potential mechanistic insights into stress-related disorders including depression and IBS [33].Burokas A and colleagues reported that chronic prebiotic treatment exhibited both antidepressant and anxiolytic effects in mice, this therapeutic effect was primarily based on normalizing the intestinal flora and reducing chronic stress-induced elevations in corticosterone and proinflammatory cytokine levels [4].A clinical trial performed in the England investigated the clinical efficacy of prebiotic trans-galactooligosaccharide (GOS) in IBS.Clinical study results showed that the prebiotic significantly improved anxiety scores in IBS patients and was effective in alleviating symptoms by stimulating gut bifidobacteria [41].Overall, there is growing appreciation for the influences and mechanisms of gut microbiota in brain-gut axis.According to the current study results, the main action mechanisms of probiotics, including promoting the colonization and normalization of perturbed intestinal microbial communities; competitive exclusion of pathogens; production of volatile fatty acids, which could interact with the brain-gut axis by regulation of endocrine and neurologic functions [37].Despite great progress has been made in recent decades, further research to elucidate the precise molecular mechanisms of probiotic actions is warranted.The major contributors (shown in Fig. 4), such as Cryan JF, Dinan TG, and Clarke G come from the same institution University College Cork.Their long-lasting efforts and closer collaboration have driven the development of this hotpot.Through a network of co-authors, the cooperative relationships among researchers are fragmented, indicating that most scholars prefer to cooperate with authors in a certain circle, especially from the same institution.As a result, it is necessary for research institutions and authors to strengthen cooperation with researchers in other countries and institutions.
The distribution of the journals (Fig. 5A) demonstrates the studies of gut microbiota in IBS are increasingly reliant on molecular/biology/immunology field.As shown in Fig. 5B, some journals such as Gastroenterology and Gut have continued to remain influential in this research area.Interestingly, in addition to the field of digestive system, relevant studies were also published in the field of psychiatry.One possible explanation could be that a large proportion of patients with IBS have been observed to have high rates of anxiety and depression symptoms.The gut microbiota plays a crucial role in the communication between the intestine and central nervous system (CNS), also known as the microbiota-gut-brain axis, and is also an important signal for maintaining intestinal homeostasis [17,27].The wide application of probiotic for the treatment of IBS and depression suggested that targeting gut microbiota with probiotics may have a therapeutic potential for disease related to the brain-gut axis.
Through the analysis of high-frequency terms and phrases extracted from the titles and abstracts, the top 100 most-cited papers covered a wide range of topics regarding gut microbiota and IBS.As shown in Fig. 6, these terms or phrases including gut microbiota, irritable bowel syndrome, probiotics, microbiota, stress, depression, microbiome, anxiety, brain-gut axis, serotonin, inflammation, and inflammatory bowel disease appeared more frequently in the top 100 publications.From these terms, we briefly summarized the current attentions of this topic mainly focus on the clinical application of probiotics in IBS and depression.The next research hotspot in this field may revolve around the keyword brain-gut axis.Meanwhile, targeting gut microbiota in IBS and depression is gradually being valued in Fig. 7A.Keywords with higher burst strength may become the new turning point, which can lead us to find emerging hotspots and frontiers of the field.Figure 7B showed that earlier studies paid more attention on the links between gut microbiota and gastrointestinal symptom.However, more and more studies have increasingly focused on the role of intestinal flora in the brain-gut axis in the latest research.Actually, microbiota-gut-brain axis is one of the research frontiers.Beginning with the concept of the brain-gut axis, the interdependence between gastrointestinal tract and brain has been implicated in gut microbiome with increasing clinical applications.With the recent development of various techniques for microbiome analysis, there has been a rapid increase in the number of relevant preclinical and clinical studies on animals and human subjects.Various psychiatric symptoms including psychotic and depressive symptoms could alter the composition of the gut microbiome.Conversely, the resided microbiome influences psychological factors by means of their metabolites, either acting directly on the brain or through the synthesis of various neurotransmitters [3,11,25].
How peripheral gut microbes are associated with emotions and cognitive function is not yet clear.However, it is hypothesized that interactions occur through multiple signal pathways, such as microbial metabolites, immune system, and gut hormone signaling [21].Kelly JR et al. reported that fecal microbiota transplantation (FMT) from depressed patients to microbiota-depleted rats can lead to typical psychosocial and behavioral characteristics, including anhedonia and anxiety-like behaviors [23].Therefore, highlighting the role of microbiomes has great potential for the treatment of psychological and gastrointestinal disorders in future.
Fig. 8 The landscape of gut microbiota in IBS IBS usually co-morbid anxiety and depressive disorders and the latter characterized by elevated levels of inflammatory markers including interleukin IL-6, tumor necrosis factor alpha (TNFα), and C reactive protein (CRP) [26,43].Although series of studies proved that the gut microbiome played an important role in the treatment of IBS and depression via the microbiome-gut-brain axis.However, there are still some problems remain elusive, the exact role of the intestinal flora in the pathogenesis of depression and anxiety is unknown and the downstream physiological mechanisms by which gut microbes influence human behavior remain unclear.Due to the complexity of the intestinal flora itself, the mechanisms of its interaction with the body had not been fully elucidated, and the exact mechanism of participating in the metabolism of the body was still unclear, which needed to be investigated in further studies.

Limitations
However, several limitations of this study should be noted.First, the data sources analyzed in our research were limited to the WoSCC database, thus, papers were not collected in the WoSCC database were ignored.However, WoSCC is an authoritative and comprehensive database which can depict most of the information to carry out bibliometric analysis.Secondly, it should be noted that studies published in earlier years are likely to be frequently cited over time, while recently-published papers, even if high-quality, may not have yet obtained comparable visibility owing to the time factor.Thirdly, the academic influence of an article could not be fully reflected by citations alone.Citation counts are generally considered a measure of utilization and contribution to published articles in current academic research, so it is of great importance for bibliometric analysis.Lastly, the bibliometric analysis results typically fall behind the actual research situation because of the continuous updating of the WoSCC database.
In spite of this, we still believe that this work can be applied to present the overall situation and general trend in this field.

Conclusion
Overall, this current study highlights the 100 top-cited studies between gut microbiota and IBS.The Ireland and USA were the dominant country in terms of the number of documents and institutions associated with the 100 articles.At present, the research focus of this field is gut-brain axis, which is closely related to the pathogenesis of IBS.The information may help researchers quickly understand the historical progress of this topic, and continued in-depth studies in this area will provide insight into a better understanding of the gut microbiota in IBS.
, only institutions with more than three documents were included.Of the 15 institutions met the threshold, University of California-Los Angeles (TLS = 41), University College Cork (TLS = 34), McMaster University (TLS = 33), and Wageningen

Fig. 1 3
Fig. 1 Number and citations of top-cited publications from 2000 to 2021

Fig. 2 Fig. 3
Fig.2The network map of countries that involved in this research area

Fig. 4 A
Fig. 4 A Top 10 authors' production over time.B Network visualization map of author co-authorship analysis

Fig. 5 A
Fig. 5 A The dual-map overlay of journals.B The annual growth trends of the journals

Fig. 6 Fig. 7 A
Fig. 6 Cloud map of author keywords

Table 1
Journals of the 100 most-cited articles in the field of gut microbiota and IBS Ranked according to the number of total publications

Table 2
Top 10 authors with the most publications