Mapping the global research landscape and hotspots of traditional herbal medicine for inflammatory bowel disease: A bibliometric analysis

Jiaxin Dong; Jiawen Dou; Lixia Zhu; Linhao Zhang; Yang Bo; Zhongyi Liang; Xianghe Meng; Xiujiang Wang; Tan Wang; Mengmeng Sun; Xinyue Zhang; Min He

doi:10.1097/MD.0000000000044003

. 2026 Apr 24;105(17):e44003. doi: 10.1097/MD.0000000000044003

Mapping the global research landscape and hotspots of traditional herbal medicine for inflammatory bowel disease: A bibliometric analysis

Jiaxin Dong ^a, Jiawen Dou ^b,^c, Lixia Zhu ^b,^c, Linhao Zhang ^d, Yang Bo ^e, Zhongyi Liang ^f, Xianghe Meng ^g, Xiujiang Wang ^h, Tan Wang ^h, Mengmeng Sun ^b,^c, Xinyue Zhang ⁱ, Min He ^b,^c,^*

PMCID: PMC13124398 PMID: 42071868

Abstract

Traditional herbal medicine, which utilizes herbal materials for complementary, alternative, and integrative therapies, has seen increasing application across diverse medical fields in recent decades, including the treatment of inflammatory bowel disease (IBD). To our knowledge, no bibliometric analyses have been conducted over the past 3 decades to evaluate the global research landscape of herbal medicine applications in IBD treatment. We performed a bibliometric analysis of scientific publications indexed in the Web of Science database in the past 3 decades (1990–2023), focusing on studies related to IBD treatments involving herbal medicines, including decoctions, formulas, herbal plants, and natural derivatives. By our analysis, China emerged as the most productive country in this field, with Nanjing University of Chinese Medicine contributing the highest number of publications. Hsiao Chung-Der was identified as the most prolific author, while Markus F. Neurath ranked as the most cited author. Journals such as Frontiers in Pharmacology, Journal of Ethnopharmacology, and Evidence-Based Complementary and Alternative Medicine were not only the top publishers but also the most frequently cited sources. Our analysis further revealed that the most widely used herbal decoctions and herbal plants exhibit shared molecular targets and signaling pathways with therapeutic potential against IBD. This study provides a systematic, visualized, and objective evaluation of research trends, offering insights to guide future investigations in this field.

Keywords: bibliometrics analysis, herbal therapy, inflammatory bowel disease, networks pharmacology, visualization

1. Introduction

The inflammatory bowel disease (IBD), include subcategories of Crohn’s disease (CD) and ulcerative colitis (UC), is a refractory chronic intestine inflammatory illness with typical symptoms including weight loss, diarrhea, and rectal bleeding.^[1] The incidence and prevalence rates of IBD have been steadily rising globally in recent years, to be reaching to 21,00,000 IBD patients in our nation by 2044 and is showing a trend of youthfulness.^[2] IBD patients’ daily life and work efficacy are significantly impacted by the frequent attacks and difficult treatments, and these factors frequently result also in depressive and anxious feelings. Such a difficult problem has threatened to affect the entire world.^[3] Environmental variables,^[4] genetic factors, familial inherited disorders,^[5] daily food,^[6] etc, may all contribute to the development of IBD. In vivo homeostasis disruption, autophagy and apoptosis risk,^[7] the distribution of tight junction proteins in intestinal epithelial cells,^[8] immune system dysfunction,^[9] abnormal lipid metabolism,^[10] increased endoplasmic reticulum stress (ERS),^[11] and disturbed intestinal flora^[12] are currently known IBD pathogenesis factors. The current clinical medical care for IBD treatment mainly involves mainly the application of glucocorticoids, 5-amino salicylic acid, as well as immunosuppressive drugs. However, none of these medications would be free from the side effects of drug resistance and gut flora dysbiosis.^[13] Therefore, there is an urgent need to discover more drug candidates from herbal plants and natural products based on pharmacological studies, in order to antagonize the complex and intractable nature of IBD.

An increasing number of drug candidates have been identified and the potential therapeutic effects of herbal plants have been increasingly applied and confirmed, thanks to the fast-expanding global pharmaceutical industry, which has garnered scholars all over the world with significant attention and a desire for further study. Herbal plants as complementary and alternative medicine offer advantages such as being holistic, multi-targeting, hypotoxic, and having few negative effects, which would be beneficial for treating intractable IBD.^[14] According to China’s ancient classic prescriptions, Fuzi-ganjiang,^[15] Huang-lian Jie-du decoction,^[16] Huangqin decoction,^[17] Jianpi Qingchang decoction,^[18] Qinghua Changyin,^[19] Pyungwi-sa,^[20] and Tou Nong San^[21] are all recorded as effective in treating digestive tract illnesses, particularly intestinal illnesses. An increasing number of clinical investigations and scientific experiments have recently reported the potential of traditional Chinese medicine (TCM) formulas in treating IBD. Some recent studies have summarized the potential of TCM formulas in treating IBD, while earlier assessments largely relied on manual reading and summarizing by readers. A systematic analysis, visualized data interpretation, and objective, rigorous evaluation and discussion are needed.

Bibliometrics is a mathematical and statistical approach used to understand the structure, distribution, relationships, and changing trends of data. It provides qualitative and quantitative evaluations, as well as insights into research hotspots and trends within a specific scientific field.^[22,23] Although there are a growing number of studies focusing on TCM in treating IBD (such as experimental and meta-analytic publications), systematic bibliometric analyses on this topic remain limited. Therefore, this research employs bibliometrics to describe the current state of TCM in the treatment of IBD and to explore future research hotspots and perspectives, offering guidance for future academic directions as well as the creation and improvement of clinical recommendations for IBD. Our study innovatively bridges a critical gap in systematic bibliometric analyses of herbal therapies for IBD over the past 3 decades, achieving unprecedented academic breakthroughs through multidimensional innovations.

2. Materials and methods

2.1. Documental searching strategy and data collection

The database was used for raw data collection. In this study, the Web of Science Core Collection of Clarivate Analytics as the core database was used, which serves as the gold standard for bibliometric analysis, providing authoritative journal coverage from 1945 to the present (>21,000 SCI/SSCI) and unique citation network depth (such as highly cited literature tracking and author collaboration network analysis), fully supporting trend mining over a 30-year span. Simultaneously, adopting a standardized process (importing into CiteSpace in text document mode for analyzing) and publicly available analysis tool parameters (CiteSpace clustering threshold, etc) ensured comprehensive data quality, reproducibility, and methodological rigor.^[24-26] Using such a database, we have designed a search strategy with strict Boolean logic including 3 queries, in order to include the targeted relevant documents pertaining to our topics as widely as possible (Table 1). In summary, publications encompassing traditional herbal medicine and those studying IBD based on animal models were incorporated. The search period ranges from January 1990 to May 2023. The data was then exported per each document package with 500 publication records and was then integrated into a single file and imported into CiteSpace (version 6.2.R4) for further data preprocessing, analysis and visualization. To maintain data quality and avoid duplication, we used the “Remove Duplicates” feature for redundancy elimination during processing in the output directory located in the “output” section of the Web of Science tab. This methodical process was crucial for preparing the dataset for subsequent analysis, ensuring precision and uniqueness. The processed dataset was then seamlessly integrated into the Bibliometrix R package program within R-Studio software (127.0.0.1:4623) for subsequent computational bibliometric exploration. Data of good quality and acceptance by preliminary evaluation were further used for analysis and visualization. All literature searches in this study were conducted within the same day to avoid errors caused by daily database updates. The detailed literature screening process and analysis methods are illustrated in Figure 1.

Table 1.

Retrieval strategy for the Web of Science database.

Query Number	Search strategy with Boolean logic
Query#1	((((((((((((((ALL = (Chinese medicine)) OR ALL = (TCM)) OR ALL = (Chinese medicinal)) OR ALL = (CM)) OR ALL = (granule)) OR ALL = (decoction)) OR ALL = (essential oil)) OR ALL = (herb)) OR ALL=(herbs)) OR ALL = (herbal)) OR ALL = (plant)) OR ALL = (plants)) OR ALL = (planta medica)) OR ALL = (prescription)) OR ALL = (prescriptions)
Query#2	(((((ALL = (inflammatory bowel disease)) OR ALL = (IBD)) OR ALL = (ulcerative colitis)) OR ALL = (UC)) OR ALL = (Crohn’s disease)) OR ALL = (CD)
Query#3	((((ALL = (zebrafish)) OR ALL = (mouse)) OR ALL = (mice)) OR ALL = (rat)) OR ALL = (rats)
Query#4	#1 AND #2 AND #3

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CD = Crohn’s disease, CM = Chinese medicine, TCM = traditional Chinese medicine, UC = ulcerative colitis.

Figure 1. — Flowchart of the literature screening process. IBD = inflammatory bowel disease, CD = Crohn’s disease, CM = Chinese medicine, KEGG = Kyoto Encyclopedia of Genes and Genomes, TCM = traditional Chinese medicine, WoSCC = Web of Science Core Collection.

2.2. Data processing and visualization

In the bibliometric analysis, VOSviewer (Version 1.6.19) and Bibliometrix were used to obtain and filter appropriate parameters, and to further analyze the numerical distribution of publications and citations by year, countries, prominent institutions, journals, authors, partner collaborations, and the most frequently used keywords. The open-sources software package Bibliometrix (Biblioshiny) plugged in the R language environment (R language).

The detailed parameter settings for CiteSpace (version 6.2.R4) were as follows: the time span is set from January 1990 to May 2023, with a time slice of 1 year. Pruning: pathfinder was selected as the cutting method; default settings were used for the remaining settings. This study used CiteSpace 6.2.R4, which selects keywords for node selection and conduct timeline analysis and keyword co-occurrence analysis. Under 1 cluster of keyword timeline, only 1 keyword was retained per year, using an adjusted γ (gamma) value of 0.5. There were a total of 310 emergent keywords, and the top 20 words related to animal models among these emergent words were selected. For VOSviewer software, the parameter settings were as follows: The minimum threshold for the number of publications from countries/regions, institutions, and authors was set to 5, 5, and 10, respectively. The timeline model for animal models only retains relevant animal models.

2.3. “Components–targets–pathway” networks construction based on network pharmacology

Based on the filtered results from the bibliometric analysis, the core functional targets of the most frequently used top 3 herbal plants against IBD were further analyzed. To do this, chemical components of these 3 herbal plants were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP, https://tcmsp-e.com/browse.php?qc=herbs), respectively. Oral bioavailability ≥ 30% and drug-likeness^[27] ≥ 0.18 were set as the threshold. Then, the UniProt database (https://www.uniprot.org/) was utilized to extract the potential gene targets of the filtered chemical components, by matching protein target names to their corresponding official gene symbols. The IBD-related target genes were also retrieved at the same time, by searching the keywords “inflammatory bowel disease,” “ulcerative colitis,” and “Crohn’s disease” from 3 public databases: GeneCards (https://www.genecards.org/), Online Mendelian Inheritance in Man (https://omim.org/), and Therapeutic Target Database (https://idrblab.net/ttd/); the results from these databases were combined to remove duplicate information. A Veen diagram of the common target genes shared by the plants and IBD disease was drawn based on Jvenn (https://bioinformatics.com.cn). Meanwhile, the construction of a “components–targets–pathway” correlation network against IBD disease was further established and visualized using the Cytoscape software (Version 3.9.1). Finally, pathways associated with these core target genes were enriched using Kyoto Encyclopedia of Genes and Genomes analyses based on Metascape database (https://www.metascape.org).

3. Results

3.1. Basic information

A total of 6828 documents written in English were acquired using the key strategy as mentioned in Table 1. The time span was from January 1990 to May 2023. A total of 1480 sources were involved in publishing these articles with an annual growth rate of 15.8%, among which 6395 primary experimental articles and 211 review papers were included. A total of 28,144 authors have published these articles, with an average citation per document of 28.38%. Among these, 25 were single-author articles, and the international coauthorship reached 24.79%. A detailed description is provided in Table 2.

Table 2.

Main Information of extracted data.

	Description	Results
Basic information	Timespan	1990:2023
	Sources (journals, books, etc)	1480
	Annual growth rate %	15.8
	Document average age	6.65
	Average citations per doc	28.38
	References	2,32,932
	Documents	6828
	Keywords plus	14,319
	Author’s keywords	13,966
Author details	Authors	28,144
	Authors of single-authored docs	25
	Single-authored docs	28
	Co-authors per doc	8.45
	International co-authorships %	24.79
Document types	Article	6395
	Article; book chapter	2
	Article; early access	61
	Article; proceedings paper	59
	Article; publication with expression of concern	1
	Article; retracted publication	1
	Correction	9
	Editorial material	6
	Letter	6
	Meeting abstract	62
	Proceedings paper	5
	Review	211
	Review; book chapter	3

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3.2. Corresponding authors’ country and affiliations

The corresponding author(s) is responsible for project design, communication and contact for manuscript submission, final proofreading, as well as financial organization and applications. Thus, the analysis according to their works is important and may reflect frontier hotspots in the academic area. In this study, we have analyzed the data to find out the most relevant corresponding authors based on his/her country and affiliation, the number and frequency of their total published articles, number of single country publications (SCP), number of multiple country publications (MCP), as well as the international joint publication rate (MCP ratio). From our database, there are in total 112 countries that published their works in this research area. We have found that China remained in the top position with a total of 3205 articles (2720 SCP and 485 MCP). The United States scored in the second position with a total of 1311 articles (846 SCP and 465 MCP). The detailed information for the top ten corresponding authors in our ranking list is displayed in Table 3.

Table 3.

Corresponding author’s country.

Rank	Country	Articles number (percentage)	SCP	MCP	Freq (article number/total articles)	MCP_Ratio (MCP/article number)
1	China	3205 (46.94%)	2720	485	0.469	0.151
2	United States	1311 (19.20%)	846	465	0.192	0.355
3	Brazil	348 (5.10%)	276	72	0.051	0.207
4	Korea	221 (3.24%)	191	30	0.032	0.136
5	India	160 (2.34%)	133	27	0.023	0.169
6	Canada	155 (2.27%)	73	82	0.023	0.529
7	Japan	134 (1.96%)	97	37	0.02	0.276
8	Germany	122 (1.79%)	55	67	0.018	0.549
9	Italy	93 (1.36%)	58	35	0.01s4	0.376
10	United Kingdom	89 (1.30%)	45	44	0.013	0.494

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Freq = frequency, MCP = multiple country publications, SCP = signal country publications.

From the analysis on the most relevant institutions, we found that 8 out of the top 10 institutions were from China, while the other 2 were from the United States. The Nanjing University of Chinese Medicine, Guangzhou University of Chinese Medicine and Shanghai University of Chinese Medicine stand in the top 3 positions, with total articles number of 528, 489, and 364, respectively (Table 4).

Table 4.

The top 10 list of affiliations.

Rank	Country source	Institutions	Counts
1	China	Nanjing Univ Chinese Med	528 (7.73%)
2	China	Guangzhou Univ Chinese Med	489 (7.16%)
3	China	Shanghai Univ Tradit Chinese Med	364 (5.33%)
4	China	Shanghai Jiao Tong Univ	362 (5.30%)
5	United States	Univ Calif Daviss	340 (4.98%)
6	China	Zhejiang Univ	307 (4.50%)
7	China	Fudan Univ	287 (4.20%)
8	United States	Univ Calif San Diego	282 (4.13%)
9	China	Huazhong Univ Sci And Technol	246 (3.60%)
10	China	Sun Yat Sen Univ	231 (3.38%)

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3.3. Countries and institutions linkage

Using the VOSviewer on the dataset of the found articles, the cooperation relationship between countries and between institutions were analyzed and visualized, based on corresponding author’s information. The visualization showed that the European as the most focused cooperative area, developed wide cooperative networks with countries (Fig. 2A). While when classified with countries, China and United States ranked to the top 2 of the most published articles, which have great cooperations of with other countries (Fig. 2B). As shown in Figure 2C, 18 institute clusters were generated based on their belonging countries as well as their cooperation works, using the institute database which published more than 5 articles. Among these institute clusters, the biggest cluster is the Chinese institution group (including mainly Chinese Academy of Sciences, China Medical University, Shanghai University of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine)and the United States institution group (including mainly University of California Davis and University of California San Diego).

Figure 2. — Network visualization of articles related to the IBD treated with TCM, based on corresponding author’s information. (A, B) cooperation networks among countries; (C) cooperation networks among institutions. IBD = inflammatory bowel disease, TCM = traditional Chinese medicine.

3.4. Author collaborations

The phenomena of 2 or more authors being co-cited in the same body of literature is known as author co-citation, and it can be used to identify highly prominent research groups and shed light on the academic community within the field.^[28-30] Considering that not only do corresponding authors but also collaborations among all authors may make important contributions and have great impacts on the research field, networks to visualize author collaborations was conducted in this study. We found that among the 28,144 authors listed in the public database, there were a total of 149 authors who published more than 10 articles in this research area. Based on their family names, the top 10 authors on the ranking list were from Asian countries (e.g. Chinese), while all their collaborators originated from non-Asian regions (Tables 5 and 6). This reveals the importance of international cooperations in this research area and may also highlight the increasingly widespread international attentions to TCM activities. From the analysis conducted using the VOSviewer, we found that the authors with highest publication output mainly come from China, the United States, New Zealand, Germany, and Japan, among others. (Fig. 3A), and the top 3 most popular journals for their publications are Frontiers in Pharmacology, Journal of Ethnopharmacology, and Evidence-based Complementary and Alternative Medicine (Fig. 3B).

Table 5.

The top 10 list of authors related to TCM in the treatment of IBD.

Rank	Author	Counts (%)	Average citation per item	Countries/regions	Citations	Total link strength
1	Hsiao, Chung-Der	30 (0.44%)	16.42	China	542	98
2	Zhang, Wei	28 (0.41%)	12.94	China	427	41
3	Fan, Heng	27 (0.40%)	20.33	China	671	163
4	Li, Yan	27 (0.40%)	16.03	China	529	75
5	Chen, Wei	23 (0.34%)	10.48	China	346	24
6	Liu, Yang	22 (0.32%)	13.00	China	429	26
7	Quintans-Junior, Lucindo J	21 (0.31%)	17.03	Brazil	562	97
8	Wang, Ying	21 (0.31%)	12.12	China	400	35
9	Wang, Jing	21 (0.31%)	12.03	China	397	34
10	Wang, Yan	21 (0.31%)	12.33	China	407	33

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IBD = inflammatory bowel disease, TCM = traditional Chinese medicine.

Table 6.

The top 10 list of co-cited authors.

Rank	Co-cited author	Citations	Location	Total link strength
1	Neurath, Markus F	343	Germany	4874
2	Wirtz, Stefan	282	Germany	3788
3	Ng, Siew C	215	China	3263
4	Cooper, Harry S	191	United States	2434
5	Ungaro, Ryan C	179	United States	2807
6	Baumgart, D C	178	Germany	2282
7	Strober, Warren	173	United States	2311
8	Podolsky, Daniel K	155	United States	2059
9	Danese, Silvio	154	Italy	2238
10	Kaplan, Gilaad G	152	Canada	2429

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Figure 3. — Visualization of authors’ networks. (A) networks among the collaborated authors. (B) Networks among authors-countries-journals.

3.5. Annual production and their relevant sources

Our data collected the information relating to herbal medicine treatments on IBD from 1990 to 2023. There were only 2 articles published in 1990, after which there was a relative flat growth trend until 2002. From 2002 to 2021, the annual production of articles in this area increased significantly and reached a peak in 2022 with a maximum of 851 publications (Fig. 4A). These publications originated from 1480 sources. From the analysis we found that the top 3 most relevant sources are Journal of Ethnopharmacology (ISSN:0378-8741), Frontiers in Pharmacology (ISSN:1663-9812), and Evidence-Based Complementary and Alternative Medicine (ISSN: 1741-427X [Print] ISSN: 1741-4288 [Online]), which are preferred by authors and recorded 221, 136 and 121 articles respectively (Fig. 4B). A table listing the top 10 Journals preferred by authors, with their detailed information is provided (Table 7).

Figure 4. — Information of article publication volume and relevant journals in the herbal medicine treatment on IBD. (A) Number of annual article publications. (B) The top 10 relevant sources for authors publications. IBD = inflammatory bowel disease.

Table 7.

The top 10 preferred sources for publications.

Journal name	Documents	ISSN	Category (JCR)	IF2022
Journal of Ethnopharmacology	221	0378-8741	Q1	5.195
Frontiers in Pharmacology	136	1663-9812	Q1	5.988
Evidence-Based Complementary and Alternative Medicine	121	1741-427X	Q4	2.65
International Immunopharmacology	110	0268-4012	Q1	30.2
Scientific Reports	105	2045-2322	Q2	4.996
PLoS One	96	1932-6203	Q2	3.752
Phytomedicine	85	0944-7113	Q1	6.656
Biomedicine and Pharmacotherapy	79	0753-3322	Q1	7.419
Frontiers in Immunology	73	1664-3224	Q1	8.786
World Journal of Gastroenterology	73	1007-9327	Q2	5.374

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JCR = journal citation reports.

3.6. Analysis for global citations

The outcomes of scientific research are the developed theories, discoveries, and explorations based on previously published references. Thus, the citations which mention the previous references reflect the inheritance and improvement of science and technology in a certain research field. In this study, we extracted the important information and analyzed the top 10 cited journal sources, the top 10 cited countries, the annual number of citations, and the top 10 global cited articles among the most cited articles (Fig. 5).

Figure 5. — Analysis for global citations. (A) Average citations per year; (B) most local cited sources; and (C) most cited countries.

From our analysis, a flexible increase in the average annual citation number occurred, and a peak appeared in 2008 with an annual citation number of 6.3. For the most frequently locally cited sources, Gastroenterology (ISSN: 0016-5085, IF2022 = 33.883), Nature (ISSN:0028-0836 IF2022 = 64.80), P Natl Acad Sci USA (ISSN:0027-8424 IF2022 = 12.779) were listed in the top 3, with total citation volumes of 5235, 4819, and 4562 respectively. For the counties contributing to the sources of the most cited articles, articles originating in the United States were cited most, with a total volume of 68,441 citations in total and an annual average of 52.4 citations. China ranked second, with a total volume of 62,889 citations and an annual average of 19.9 citations. Brazil ranked third, with a total volume of 7379 citations and an annual averge of 21.5 citations.

Next, we analyzed the top 10 global cited documents, as shown in Table 8. The most cited article was a review published in the journal of Autophagy (ISSN:1554-8627, IF2022 = 13.3) with a total of 3037 citations, published by Klionsky DJ in 2012, entitled “Guidelines for the use and interpretation of assays for monitoring autophagy.” In this article the author summarized the autophagy process and mediators, and also summarized some compounds isolated from herbal plants which act as autophagy inducers.

Table 8.

3.7. Analysis of keywords and co-occurrence map for frontiers

3.7.1. Keyword cluster analysis and trend topics

A cluster analysis was conducted using all the keywords extracted from the document database and visualized by CiteSpace. Using the Log-likelihood Ratio with the Feature-based algorithm, keyword co-occurrence maps serves as the basis for keyword clustering, which identifies various cluster labels to pinpoint the research hotspots.^[31-33] The clustering results were rigorously validated through modularity (S-value) and silhouette coefficient (Q-value) analyses, enabling a robust evaluation of the model’s efficacy and significance. Our model achieved an S-value exceeding 0.6 performance and a Q-value approaching 0.3 demonstrating that the internal themes within each category exhibit remarkable focus, thereby ensuring strong intra-class credibility. Beyond statistical validation, the clustering accuracy underwent dual manual verification processes to conclusively prove its reliability.

As shown in Figure 6A, there are a total of 8 clusters displayed in the visualized cluster map, indicating 8 research directions. From the first several clusters, we can conclude that the current topics in this research area focus mainly on the following: IBD modeling, such as Dextran sulfate sodium salt (DSS)-induction and mice/rat offsprings; essential oil and herbal plants treatments; mechanisms; such as oxidative stress and inflammations; interaction between brain-intestine axis: such as gut microbiota, hippocampal neurogenesis and brain neurogenic inflammation.

In addition, a trend topic analysis of the keywords with timespans was also conducted, in order to gain further insights into the trends herbal research on treating IBD. As shown in Figure 6B, the main keywords were focused on local tissue lesions starting in 2003. With the development of this research area, free radicals, arachidonic acid, and lipid peroxidation have widely studied as research topics over a relative long period (2008–2018). Notably, keywords relevant to natural compounds (e.g., berberine), gut microbiota (especially akkermansia muciniphila), as well as genetic and protein research, have emerged as the current research hotspots of herbal treatment for IBD over the past 5 years (2018–2023).

3.7.2. Co-occurrence map among cellular and animal models

It is important to gather more detailed information by analyzing the most frequently used words mentioned in the collected database, such analysis helps to understand more detailed research topics in this academic area. By filtering and analyzing the keywords, high frequently occurring keywords in different time periods can reflect, to some extent, the research hotspots and developmental trends. The selection of applied experimental models determines the further understanding of disease mechanisms, safety and efficacy evaluations of herbal plants, as well as therapeutic mechanisms interpretations, thus reflecting indirectly the development and hotspot trends of a research field.

In this study, we further analyzed the experimental models (including cellular models and animal models) that were used in this research field, by extracting information from the keywords of articles. Cellular and animal models were mentioned in 1747 articles, yielding 3500 keywords from these articles. As shown in Figure 7, the rodent model (mainly rat and mouse models) and cellular models were the most frequently used models for the studies on herbal therapies against IBD during the period from 1993 to 2010. Through timespan analysis, the zebrafish has been increasingly widely used and has shown high occurrence in this research field recently. This may be due to the various advantages of zebrafish, such as their utility in studying herbal therapeutic effects.^[34] Our analysis also reveals that the research interests have turned from traditional organ (brain, intestine, colitis, etc,) pathology to bacteria (intestinal bacteria/microbiome, stem cells) studies, which have become an increasingly popular topic interest in recent years. More detailed information on the cellular model and the co-occurrence analysis results is displayed in the Tables S1 and S2, Supplemental Digital Content, https://links.lww.com/MD/R691.

Figure 7. — Timespan of the applied cellular and animal models.

3.7.3. Co-occurrence map among herbal decoctions, herbal plants and among natural products

The most important objective in this study was to explore the most frequently used active herbal plants and natural products for the IBD treatment. From our analysis by filtering the top 3000 keywords, we further retrieved keywords related to decoctions, herbal plants and components that appeared in the document data. A total of 98 articles on 16 herbal decoctions, 56 articles on 12 single herbal studies, and 251 articles on 26 natural products were extracted into our final list. Co-occurrence analysis was further conducted in 3 ways: using the herbs contained in the extracted decoctions lists; or using those mentioned in single herb studies; or or combining all data together, respectively. The top 15 frequently used decoctions with their herbal compositions are displayed in Table S3, Supplemental Digital Content, https://links.lww.com/MD/R691. The co-occurrence of the filtered decoctions and those of the filtered herbs were listed in the Table 9. The correlation networks between decoction and herbal compositions, as well as the networks among herbs, were displayed in the Figure 8. As shown in Table 9 and Figure 8, the most frequently used herbal plants for IBD treatment in our final combined analysis was Glycyrrhizae Radix Et Rhizoma, which is frequently used for harmonizing herb combinations according to the Chinese medicine theories. The high frequency may be due to the fact that most herbal decoctions prefer this harmonizing herb, either for toxicity reduction or activity enhancement. Such a preference leads this harmonizing herb to rank even above other “sovereign drugs.” However, such a plant is seldom used as a principal herb or studied in a single herb research on IBD. The next top 3 herbs in our final combined list that are the frequently used for IBD treatments are Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma (Panax ginseng). These herbs are considered as “sovereign drug” (or principal herb) in decoctions, according to the Chinese medicine theories. In addition, although Panax ginseng does not rank in the top 5 for its application in decoctions, it is still the most frequently studied herbal plant in single herb research. This might explain why Panax ginseng rose into the top 5 in our final combined list. Nevertheless, it strongly indicates its potential efficacy against IBD. Besides the Panax-ginseng, we also found that another ginseng species, Panax notoginseng was listed. This suggests the therapeutic potential of ginseng species plants in treating IBD.^[35] For natural products, quercetin, berberine, curcumin, resveratrol and capsaicin were considered as the top 5 active compounds. Quercetin and berberine, the most frequently studied monomers, are abundant in various plants including Coptidis Rhizoma and Scutellaria-baicalensis. These results align with the co-occurrence analysis results of decoctions and single herbs.

Table 9.

Top 15 herbal decoctions, herbal plants and natural products for IBD treatments.

Decoctions	Published articles	Herbs in decoctions	Published articles	Single herbs	Published articles	Combined ranking^*	Published articles	Monomers	Published articles
Gegen Qinlian	14	Glycyrrhizae Radix Et Rhizoma	65	Panax ginseng	15	Glycyrrhizae Radix Et Rhizoma	70	Quercetin	32
Pulsatilla	13	Coptidis Rhizoma	64	Scutellaria-baicalensis	6	Coptidis Rhizoma	64	Berberine	26
Huangqin	12	Scutellaria-baicalensis	56	Panax-Notoginseng	5	Scutellaria-baicalensis	62	Curcumin	21
Shaoyao	9	Paeoniae Radix Alba	21	Citrus	4	Panax ginseng	29	Resveratrol	17
Qingchang Wenzhong	8	Jujubae Fructus	20	Officinalis	4	Paeoniae Radix Alba	21	Capsaicin	14
Sophorae	7	Aucklandiae Radix	20	Phaseolus-vulgaris l	4	Jujubae Fructus	20	Saponins (ginsenosides)	11
Lizhong	6	Zingiberis Rhizoma	18	Qing-dai	4	Aucklandiae Radix	20	Lignans	11
Banxia xiexin	5	Rhei Radix Et Rhizoma	16	Salvia-miltiorrhiza	4	Zingiberis Rhizoma	18	Anthocyanins	10
Sanhuang	5	Phellodendri Chinensis Cortex	16	Astragalus-membranaceus	3	Rhei Radix Et Rhizoma	16	Baicalin	10
Sini	4	Sophorae Flavescentis Radix	16	Concanavalin-a	3	Phellodendri Chinensis Cortex	16	Ellagic acid	9
Huanglian	3	Ginseng Radix Et Rhizoma	14	Arctium-lappa	2	Sophorae Flavescentis Radix	16	Genistein	9
Huang-lian-jie-du	3	Puerariae Lobatae Radix	14	American ginseng	2	Panax Notoginseng	16	Paeoniflorin	7
Jianpi Qingchang	3	Pulsatillae Radix	13			Puerariae Lobatae Radix	14	Proanthocyanidins	7
Danggui	2	Fraxini Cortex	13			Pulsatillae Radix	13	Naringenin	6
Dahuang Mudan	2	Notoginseng Radix Et Rhizoma	11			Fraxini Cortex	13	Glycyrrhizic acid	5

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IBD = inflammatory bowel disease.

Combined analysis: Decoctions + single herb.

Figure 8. — Correlation networks of herbs on IBD treatment. (A) networks between decoction and herbal compositions and (B) networks among herbs. IBD = inflammatory bowel disease.

3.7.4. Potential mechanisms based on burst analysis

After excluding the keywords related to herbal plants and animal models, keywords relevant to mechanisms were further extracted from the document data and visualized for co-occurrence analysis. From this analysis, the most frequently appearing keywords were related to mechanisms of IBD treatment with herbs (Table 10). Among these keywords, lipid peroxidation, intestinal barrier, and free radicals showed the highest co-occurrence, which were listed in the top 3. Besides these mechanisms, most of the rest were linked to inflammatory response and cytokine pathways.

Table 10.

Most frequent keywords extracted based on burst analysis (top 15).

Entity	Strength	Begin	End
Lipid peroxidation	16.0896	2004	2011
Intestinal barrier	11.0032	2019	2023
Free radicals	10.8648	2006	2011
Nitric oxide synthase	10.8427	2005	2013
Tumor necrosis factor	9.7077	2006	2011
NF kappa b	9.3163	2015	2016
Network pharmacology	8.7753	2021	2023
Intestinal inflammation	7.2746	2009	2017
Autophagy	6.8316	2019	2023
Protein kinase c	6.7912	2005	2011
Nlrp3 inflammasome	5.5853	2021	2023
TNF α	3.9464	2009	2012
Immunity	3.5979	2020	2023
Proliferation	3.4579	2009	2011
Il-10	2.8914	2016	2018

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TNF α = tumor necrosis factor-α.

3.7.5. “Components–targets–pathway” networks of the top 3 herbal plants for IBD treatments based on network pharmacology

Considering that the Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma (Panax ginseng) are frequently used in herbal decoctions and have been frequently reported for their potential effects against IBD, we further analyzed the potential targets for IBD disease that they shared.

First, a total of 48, 143 and 190 ingredients were identified from the Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma respectively, by searching the TCMSP database. After filtering under the conditions of Oral bioavailability ≥ 30% and drug-likeness ≥ 18%, 11, 31 and 15 ingredients were filtered from each herb. A total of 51 bioactive ingredients were obtained after removing the duplicates (Table 11). Based on the TCMSP, 173, 117, and 109 potential target genes were matched for Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma respectively. After removing duplicate gene targets, 257 gene targets remained for further analysis.

Table 11.

Basic information of active components of Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma.

Source	Active ingredient	OB (%)	DL
Coptidis Rhizoma	Berberrubine	35.74	0.73
Coptidis Rhizoma	(R)-Canadine	55.37	0.77
Coptidis Rhizoma	Berlambine	36.68	0.82
Coptidis Rhizoma	Corchoroside A_qt	104.95	0.78
Coptidis Rhizoma	Magnograndiolide	63.71	0.19
Coptidis Rhizoma	Palmatine	64.6	0.65
Coptidis Rhizoma	Worenine	45.83	0.87
Coptidis Rhizoma	Quercetin	46.43	0.28
Coptidis Rhizoma	Berberine	36.86	0.78
Coptidis Rhizoma, Scutellariae Radix	Epiberberine	43.09	0.78
Coptidis Rhizoma, Scutellariae Radix	Coptisine	30.67	0.86
Scutellariae Radix	Acacetin	34.97	0.24
Scutellariae Radix	Wogonin	30.68	0.23
Scutellariae Radix	(2R)-7-hydroxy-5-methoxy-2-phenylchroman-4-one	55.23	0.2
Scutellariae Radix	Baicalein	33.52	0.21
Scutellariae Radix	5,7,2,5-Tetrahydroxy-8,6-dimethoxyflavone	33.82	0.45
Scutellariae Radix	Carthamidin	41.15	0.24
Scutellariae Radix	Dihydrobaicalin_qt	40.04	0.21
Scutellariae Radix	Eriodyctiol (flavanone)	41.35	0.24
Scutellariae Radix	Salvigenin	49.07	0.33
Scutellariae Radix	5,2′,6′-Trihydroxy-7,8-dimethoxyflavone	45.05	0.33
Scutellariae Radix	5,7,2′,6′-Tetrahydroxyflavone	37.01	0.24
Scutellariae Radix	Skullcapflavone II	69.51	0.44
Scutellariae Radix	Oroxylin a	41.37	0.23
Scutellariae Radix	Panicolin	76.26	0.29
Scutellariae Radix	5,7,4′-Trihydroxy-8-methoxyflavone	36.56	0.27
Scutellariae Radix	Neobaicalein	104.34	0.44
Scutellariae Radix	Dihydrooroxylin	66.06	0.23
Scutellariae Radix	Sitosterol	36.91	0.75
Scutellariae Radix	Norwogonin	39.4	0.21
Scutellariae Radix	5,2′-Dihydroxy-6,7,8-trimethoxyflavone	31.71	0.35
Scutellariae Radix	ent-Epicatechin	48.96	0.24
Scutellariae Radix	bis[(2S)-2-ethylhexyl] benzene-1,2-dicarboxylate	43.59	0.35
Scutellariae Radix	Moslosooflavone	44.09	0.25
Scutellariae Radix	5,7,4′-trihydroxy-6-methoxyflavanone	36.63	0.27
Scutellariae Radix	5,7,4′-trihydroxy-8-methoxyflavanone	74.24	0.26
Scutellariae Radix	Rivularin	37.94	0.37
Scutellariae Radix, Ginseng Radix Et Rhizoma	Diop	43.59	0.39
Scutellariae Radix, Ginseng Radix Et Rhizoma	Stigmasterol	43.83	0.76
Scutellariae Radix, Ginseng Radix Et Rhizoma	Beta-sitosterol	36.91	0.75
Ginseng Radix Et Rhizoma	Inermin	65.83	0.54
Ginseng Radix Et Rhizoma	Kaempferol	41.88	0.24
Ginseng Radix Et Rhizoma	Aposiopolamine	66.65	0.22
Ginseng Radix Et Rhizoma	Deoxyharringtonine	39.27	0.81
Ginseng Radix Et Rhizoma	Dianthramine	40.45	0.2
Ginseng Radix Et Rhizoma	Arachidonate	45.57	0.2
Ginseng Radix Et Rhizoma	Frutinone A	65.9	0.34
Ginseng Radix Et Rhizoma	Ginsenoside rh2	36.32	0.56
Ginseng Radix Et Rhizoma	Ginsenoside-Rh4_qt	31.11	0.78
Ginseng Radix Et Rhizoma	Girinimbin	61.22	0.31
Ginseng Radix Et Rhizoma	Suchilactone	57.52	0.56
Ginseng Radix Et Rhizoma	Fumarine	59.26	0.83

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DL = drug-likeness, OB = oral bioavailability.

Second, using the GeneCards, IBD-related target genes were collected (7050 targets to IBD, 5332 targets to UC, and 5019 targets to CD). From the Therapeutic Target Database, IBD-related target genes were collected (68 targets to IBD, 41 targets to UC, and 42 targets to CD). Additionally, the Online Mendelian Inheritance in Man database provided also some IBD-related target genes (544 targets to IBD, 7 targets to UC, and 23 targets to CD). After combining and deduplicating targets from all databases, a total of 10,064 target genes were obtained and integrated into our final list for further analysis. The overlapping targets between these 3 and the IBD were input into a Veen diagram, generating 156, 96, and 89 overlapping co-targets between each herb and IBD. Ultimately, there were 38 overlapping identified target genes were identified across all herbs and IBD, indicating their shared potential therapeutic targets these herbs shared for IBD treatments (Fig. 9).

Figure 9. — Veen diagram of potential target genes among the top 3 herbal plants against IBD disease. (A) overlapping identified target genes between *Coptidis Rhizoma* and IBD. (B) overlapping identified target genes between *Scutellariae Radix* and IBD. (C) overlapping identified target genes between *Ginseng Radix Et Rhizoma* and IBD. (D) overlapping identified target genes among all herbs and IBD disease. CR = *Coptidis Rhizoma*, IBD = inflammatory bowel disease, PG = *Ginseng Radix Et Rhizoma*, SR = *Scutellariae Radix*.

Third, the overlapping target genes of IBD, herbs, and their active ingredients of herbs were imported into the cytoscape software to constract a “Components–Targets–Pathway” network, depicting the complex relationship between the IBD and the herbal treatments. In total, there are in total 320 nodes and 1128 edges were generated in the networks, combing the 51 identified bioactive compounds, 257 potential target genes and 38 overlapping IBD targets (Fig. 10).

Figure 10. — “Components–Targets–Disease” network. Orange rectangle refers 3 herbal plants, purple V refers IBD, light orange circle refers herbal plant chemical components, light purple diamond refers overlapping target genes, light green circle refers herbal plants especial target genes. IBD = inflammatory bowel disease.

Finally, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed to elucidate the core functions and enriched pathways of the topanti-IBD genes from the 3 herbs. Overlapping target genes from each single herbal plant against the IBD were analyzed via Metascape. Five pathways were shared by all 3 herbs for IBD treatment: cancer, lipid and atherosclerosis, chemical carcinogenesis – receptor activation, amebiasis, and Nuclear factor kappa-B (NF-κB) signaling pathway (Fig. 11). Our results suggest that these 3 herbs exert intestinal protective effects and therapeutic roles against IBD by inhibiting cell proliferation and cancer-related pathway, alleviating lipid accumulation, reducing inflammatory responses, and angiogenesis inhibitors.

Figure 11. — Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of *Coptidis Rhizoma*, *Scutellariae Radix*, and *Ginseng Radix Et Rhizoma* in the treatment of IBD. (A) *Coptidis Rhizoma*-IBD. (B) *Scutellariae Radix*-IBD. (C) *Ginseng Radix Et Rhizoma*-IBD. (D) Venn diagram shows that the top 3 herbs shared 5 core pathways against the IBD. CR: *Coptidis Rhizoma*, KEGG = Kyoto Encyclopedia of Genes and Genomes PG: *Ginseng Radix Et Rhizoma*, SR: *Scutellariae Radix*.

4. Discussion

Both the bibliometric analysis and the network pharmacology are the research technologies that based on the big public database and bioinformatics under the theory of integrative systems thinking. Our study combined the bibliometric analysis and network pharmacology analysis, in order to screen potential important information that widely used for the IBD treatments. With the help of bibliometric analysis, the global trend of herbal plants and decoctions applications on IBD treatment was well analyzed, and the mostly used herbal decoctions and the most contributed herbal plants were further filtered. With the application of the network pharmacology, “components–targets–pathway” networks of the filtered top 3 herbal plants for IBD treatments can be further analyzed. This combination of different database can help with a better understanding the principles and principles of the TCM formula, as well as their potential mechanisms.

4.1. Current understanding status of the IBD

The IBD is a comprehensive recurrent chronic intestinal inflammation for its onset and development. Long term IBD patients have higher risks of colorectal cancer and atherosclerosis, compared to the general population.^[36,37] From our bibliometric analysis, the understanding of IBD is highly referred to the characterization of the high level of reactive oxygen species with inflammatory and immune response, and by the highly dysfunctional intestinal flora. To date, the pathogenesis of IBD involves dysregulated autophagy, disrupted gut microbiota, and ERS.^[38] Under normal conditions, autophagy is suppressed by mechanistic target of rapamycin complex 1-mediated inhibition of ULK1-FIP200 coupling but activates during nutrient deprivation or oxidative stress.^[39,40] In IBD, impaired mTOR-dependent autophagic flow and reduced expression of autophagy-related genes (e.g., immune-related guanosine triphosphatase M protein [IRGM], Unc-51 like autophagy activating kinase 1 [ULK1], X-box binding protein-1 [XBP-1], ATG13, ATG16L1, nuclear receptor binding factor 2 [NRBF2]) contribute to intestinal epithelial damage, barrier dysfunction, and inflammation^,[38,41,42]. ERS exacerbates pathology by triggering unfolded protein response, leading to ferroptosis and defects in tight junction proteins, resulting in microvilli shortening and inflammatory infiltration,^[43-45]. Additionally, disrupted gut microbiota composition – marked by reduced Firmicutes, increased Bacteroides, and metabolic imbalances – interacts with autophagy defects, particularly through mutations in ATG16L1 and nucleotide binding oligomerization domain containing 2, impairing bacterial sensing and immune regulation.^[46-49] In summary, IBD arises from intertwined dysfunctions in inflammatory signaling, oxidative stress, autophagy, ERS, and microbial homeostasis, which are recent research hotspots awaring researchers interests. Patients with such a complex disease are eager more effective and therapies for systematic regulations of the body homeostasis.

4.2. Herbal therapies for IBD

The IBD disease is attracting researchers’ attention in its pathological mechanisms, as well as its treatments explorations. The current therapeutic strategies of the IBD have revolutionized into combined therapies owing to the emerged “therapeutic ceiling.”^[50] As an important alternative therapeutic method, the herbal medicine (or TCM) is attracting more and more attention on disease treatments including the IBD treatment, with various advantages such as high dose tolerance with relative low toxicities, long history with specific medical theories and clinical experiences, as well as their personalized optimizations for prescriptions. Such personalized therapeutic strategy is more responsible to improve the accuracy and efficacy of treatments of diseases. From our analysis, we filtered top 15 decoctions that were reported and used for the IBD treatments, many of which shared the same herbal plants and were reported with anti-inflammatory, anti-oxidative, immuno-regulatory activities and can induce apoptosis. For instance, ten out of the 15 decoctions for the IBD treatment filtered by our database contain the herb of Coptidis Rhizoma. These decoctions are as the following: the Gegen-Qinlian decoction, Pulsatilla decoction, Qingchang-Wenzhong decoction, Shaoyao decoction, Banxia xiexin decoction, Huanglian decoction, Huang-lian-jie-du decoction, Jianpi Qingchang decoction, Sanhuang decoction, and Danggui decoction. We also found that among these herbal decoctions, Coptidis Rhizoma, Scutellariae Radix and Ginseng Radix Et Rhizoma (Panax ginseng) are frequently used as “sovereign drug” (or principal herb) in herbal decoctions and are frequently reported with their potential against the IBD.

The Gegen Qinlian decoction as the most popularly used herbal formular for the IBD treatment contains Puerariae Lobatae Radix, Scutellariae Radix, Coptidis Rhizoma, and Glycyrrhizae Radix Et Rhizoma. It is reported to alleviate various pathological symptoms of the IBD including weight loss, shortened colon length, inflammatory response and the disrupted microscopic intestinal tissue structure. The Gegen Qinlian decoction can also restore the diversity and community landscape of gut microbiota, as well as metabolic profiles.^[51] The Pulsatilla decoction contains 4 herbal plants including Coptidis Rhizoma as its main herbal composition, and is reported to reduce the secretion of pro-inflammatory cytokines, to restore changes in tight junction proteins in colon tissue, to promote autophagy by activating adenosine 5′-monophosphate activated protein kinase (AMPK) phosphorylation and inhibiting mTOR expression, thus to repair the intestinal epithelial barrier in DSS-induced IBD mice.^[52,53] Interestingly, another study filtered the Pulsatilla decoction, Gegen Qinlian decoction and Taohua (Peach blossom) decoction as the most relevant formulas for treating the typical IBD symptom by big data mining and zebrafish-based activity assessment, which are partially consistent with our research.^[54] The Qingchang Wenzhong decoction, which displayed also in our final list, is reported to regulate the intestinal stem cell-mediated epithelial proliferation, accelerate intestinal mucosal healing, and regulate the dysregulated gut microbiota and metabolism.^[55] The Sanhuang decoction contains Coptidis Rhizoma, Scutellariae Radix and Rhei Radix Et Rhizoma as its main herbal compositions, which alleviates the IBD symptoms by inhibiting oxidative stress, protecting mucosal barrier, and regulating gut microbiota in DSS-induced mice model.^[56] All these may indicate the strong potential of the Coptidis Rhizoma on regulating the IBD-induced intestinal disturbance.

It is reported that the Coptidis Rhizoma exerts its therapeutic effects on IBD mainly by inhibiting oxidative stress, resisting injury, protecting the intestinal mucosal epithelial barrier, regulating helper T cells, and antibacterial through phosphatidylinositol 3-kinase/AKT and T helper 17 differentiation signaling pathways.^[57,58] The berberine as one of the main active components in the Coptidis Rhizoma is one of the TCMs with research hotspots for IBD in recent years. It plays anti-inflammatory effect by regulating the AMPK/MTOR/ULK1 to promote autophagy and to inhibit the expression and secreting of lysozyme,^[59] and is reported to be active against the IBD by downregulating the insulin like growth factor 2 mRNA binding protein 3 expression thus inhibits proliferation and induces G0/G1 phase arrest in colorectal cancer cells.^[60] In addition, the berberine has also various effects, including reducing serum lipid levels, improving vascular endothelial proliferation, antagonizing lipid accumulation,^[61] and activating mitochondria autophagy that caused by oxidative stress.^[62] Currently, more and more researchers are focusing on the intestinal microbiota disorders that caused by the IBD. The berberine is reported to alleviated colitis related colorectal tumors by reshaping the gut microbiota variations,^[63] restoring intestinal microbiota homeostasis,^[64] reducing the abundance of pathogenic bacteria and increasing the content of beneficial bacteria.^[65] Recently, in order to better adapt the development of TCM, and to solve the problems such as solubility and low oral utilization, new materials for pharmaceuticals raise the researchers’ interests and applied also to the IBD treatments. For instance, ursodeoxycholic acid-berberine supramolecular nanoparticles which using the berberine and active ingredient of Calculus Bovis as raw materials is reported to be active against the IBD.^[66] Meanwhile, the nano-emulsion of Coptidis Rhizoma combined with Magnolia officinalis can alleviate the inflammation and restore the intestinal morphology in DSS-induced mice model.^[67]

Not only decoctions containing the Coptidis Rhizoma, many other herbal plants exert similar multi-target therapeutic advantages in treating the IBD disease. From our analysis, we also found that in the top 15 list of the most applied decoction for IBD treatment, 6 out of 15 decoctions contains the ginseng species plants, either the Ginseng Radix Et. Rhizoma (root from Panax ginseng C. A. Meyer), or the Notoginseng Radix Et Rhizom a (root from Panax notoginseng(Burk.)F.H.Chen). The activity of Panax ginseng Meyer is reported to depend on its main active components – ginsenosides which have multiple functions including: participating the glycolysis and pentose phosphate pathways and regulating the epidermal growth factor receptor, signal transducer and activator of transcription 3 and AKT1 pathways^[68]; inhibiting inflammatory response by regulating the toll-like receptor/NF-κB and mitogen-activated protein kinase (MAPK) pathways^[69]; inhibiting the DNA synthesis of the colorectal cancer cells by regulating the reactive oxygen species/c-Jun N-terminal kinase (JNK)/tumor protein p53 pathway^[70]; and binding with the NLRP and participating in the MAPK signaling pathways, etc,.^[71] The Shaoyao (peony) decoction can alleviate the colitis symptoms in DSS-induced IBD mice, including inhibiting levels of pro-inflammatory cytokines, reducing immune cell infiltration into colon tissue, inhibiting signal transduction and promotion of signal transducer and activator of transcription 3 and NF-κB, and improving epithelial integrity by regulating epithelial cell apoptosis and epithelial permeability.^[72] The total glucosides from Shaoyao decoction can reduce inflammatory response, inhibit myeloperoxidase activity, and even enhance systemic immune functions by balancing Th17/regulatory T immune disorders.^[73] In addition, more and more components and natural product(s) from herbal plants are reported to be active against the IBD symptoms by regulating multiple pathways,^[74,75]. In summary, the above research as examples may indicate the overall and multi-target therapeutic advantages of the TCM.

From our further analysis by systems pharmacology, we found that the filtered top 3 herbal plants by the bibliometric analysis play intestinal protective effect and play therapeutic roles against the IBD by mainly inhibiting cell proliferation and cancer-related pathway, alleviating lipid accumulation, reducing inflammatory productions and as angiogenesis inhibitors. These pathways of herbs in regulating the IBD disease filtered by our analysis were widely supported that can be regulated by the herbal interventions. First, the IBD is a chronic disease characterized by the long-term inflammation in intestine. Many researchers have reported that the inflammatory pathways can be inhibited by some herbal plants and their active ingredients (e.g., Coptidis Rhizoma, Scutellariae Radix, Panax ginseng, Panax notoginseng, Shaoyao (peony), etc).^[76-78] Second, besides the inflammatory characterization, epidemiology shows higher incidence of intestinal cancer in long term IBD patients than normal populations.^[79] This means that the IBD shared many cancer pathways with the intestinal cancer disease. The treatments by these highly reported herbs in our study may indicate their systematic interventions against the disease, instead of the “one disease - one target - one drug” thinking. These systematic interventions may benefit to patients that alleviate not only the acute symptoms, but also may delay the cancer risk by the long-term damage of IBD. This is being convinced by more and more studies recently. For instance, 20 (S)–protopanaxadiol is a metabolite of ginsenosides from Panax quinquefolius L. and Panax ginseng C.A. Meyer, which has anticancer activity in colon cancer cells by targeting NF-κB, JNK, and MAPK/extracellular regulated protein kinase signaling pathways.^[80] The Scutellariae Radix and one of its main components – baicalein can enhance the efficacy of 5-fluorouracil against the colon cancer, by inhibiting cell proliferation signaling pathways.^[81] Coptidis Rhizoma and its main bioactive component – berberine, can inhibit tumor by downregulating the cancer targets of checkpoint kinase 1, Polo like kinase 1, and aurora kinase B.^[82] Additionally, our enrichment of pathways also found that the potential activity of the top 3 herbs against the IBD by regulating the lipid and atherosclerosis pathways. Lipid metabolism is considered with close link to inflammation and cardiovascular diseases. In fact, it is indeed reported that the IBD patients are with more incidence of ischemic heart disease occurrence.^[83] Meanwhile, the downregulated apolipoprotein C3 and increased serum lipoprotein lipase was reported freshly indicating the dysregulated triglycerides metabolism in IBD patients.^[84] The Scutellariae Radix and its active component baicalein can hemostatic glucose and lipid metabolism by upregulating AMPK and peroxisome proliferator-activated receptor-γ pathways, which is considered as a favorable candidate for the prevention and treatment of metabolic syndrome.^[81] The efficacy of Yiqi Huoxue Huatan formula (containing Scutellariae Radix, Astragali Radix, Salviae Miltiorrhizae Radix Et Rhizoma and Hirudo Nipponica Whitman) has been proved to inhibit inflammation and atherosclerosis by regulating the SRC proto-oncogene (SRC)/NF-κB, lipid and Apelin (generated by adipocytes, which is a ligand of Apelin receptor expressed in the central nervous system and cardiovascular system) signaling pathways, and effective components were further screened.^[85]

4.3. The emerging zebrafish model as hotspots for assessing toxicity and efficacy of drug candidates

Rodents are commonly used to interpret immune responses and inflammatory processes in many diseases. Nowadays, more than 30 rodent models have been developed for inducing IBD. Spontaneous mutants, genetic induction, chemical reagent induction, and T cell transfer are the 4 main experimental methods for inducing the IBD models. However, due to the high cost and the requirement for ethical considerations, rodent and other mammalian models are still with many challenges and limitations for large-scale drug screening analysis.^[86] As a vertebrate model organism, zebrafish (Danio rerio) have various advantages including cheap, occupying small space, fast reproducing, and laying a large number of eggs, which has led to a boom in drug academic research. Importantly, zebrafish genome sequencing reveals high similarities with other vertebrates including humans. In addition, zebrafish’s adaptability to gene manipulation allows for the use of technologies such as transgenic, protein overexpression, genome editing, or large-scale genome mutagenesis.^[27,87,88]

Zebrafish has become an indispensable model organism in inflammatory physiology and pathology research. So far, the chemical reagent induction is the most welcome approach for IBD modeling, either applied in larvae or adult zebrafish.^[89] For instance, zebrafish larvae have been used as an attractive model for anti-inflammatory drug screening and composite therapies, by utilizing chemical damage to contralateral nerve cells.^[90] Zebrafish larvae exposed to trinitrobenzene sulfonic acid, or dextran sulphate sodium (DSS) exhibit impaired intestinal homeostasis and inflammation, which is similar to human IBD.^[91,92] In addition, oxazolone and lipopolysaccharides can all be used as chemical inducers for zebrafish IBD modeling.^[93] In addition to chemical inducers, high cholesterol diet feeding strategy selectively induces infiltration of bone marrow cells in the zebrafish larval intestine, making it suitable for drug screening discovery work. The transgenic fluorescent zebrafish marking specific neutrophils or macrophages are also wildly used to monitor acute inflammatory responses throughout a fully functional innate immune system in the entire biological environment, by utilizing the unique clarity of zebrafish larvae.^[94] A recent study screened and characterized 6 natural monomers from herbal decoctions based on zebrafish IBD model, which are considered as potential drug candidates against the IBD.^[54] Such zebrafish IBD models are being increasingly applied for phytotherapy studies, which certainly contribute and speed up the drug screening and discoveries.

Taken together, our bibliometric study revealed the emerging model organism zebrafish in recent 10 years, which is gradually becoming a hot experimental model. This research in phytotherapies for IBD treatments gave a systematic and visualized interpretation, as well as an objective and rigorous evaluation and discussion, on the spatial and temporal distribution of countries, institutions, researchers, and the internal organization of the published knowledge base. This may provide new focus and directions of academic research in the future.

5. Conclusion

In this research, we utilized the bibliometric analysis to visualize the published articles during the past 3 decades, which related IBD treatments by phytotherapies including herbal decoctions, herbal plants and natural products. By combined multiple analysis results from Bibliometrix, VOSviewer and CiteSpace, our results indicate an increased number of annual publications in this field in recent years and China was dominant in this research field. The published articles were with great collaborations among institutions and countries, especially with the institutes in United States and in European countries. This may show increasing global interests of the phytotherapies against the IBD and show more and more acceptance on the transferred theories “multiple targets towards multiple (integrative) treatments” from “one target fits all.” From our analysis, we also found that the disease models are transferring from the traditional cellular and rodent models to the aquatic vertebrates (e.g., zebrafish). The most frequently studied mechanisms refer to the lipid peroxidation, intestinal barrier and free radicals. The gut microbiota studies (especially the akkermansia-muciniphila)are represented the current research hotspots of herbal treatment on the IBD in the past 5 years. The most frequent herbs used in the IBD treatment are ginseng species and the Scutellaria-baicalensis, and Coptidis Rhizoma which targets and pathways in common were further analyzed by network pharmacology.

Acknowledgments

The authors acknowledge the directors of Changchun University of Chinese Medicine for supporting this research.

Author contributions

Conceptualization: Mengmeng Sun, Min He.

Funding acquisition: Zhongyi Liang.

Project administration: Zhongyi Liang.

Supervision: Zhongyi Liang, Xiujiang Wang, Mengmeng Sun, Min He.

Writing – original draft: Jiaxin Dong, Jiawen Dou.

Writing – review & editing: Lixia Zhu, Linhao Zhang, Yang Bo, Xianghe Meng, Tan Wang, Xinyue Zhang.

Supplementary Material

medi-105-e44003-s001.pdf^{(208.6KB, pdf)}

Abbreviations:

AMPK: adenosine 5′-monophosphate activated protein kinase
ATG13: Autophagy related 13
ATG16L1: autophagy related 16 like 1
CD: Crohn’s disease
DSS: dextran sulfate sodium salt
ERS: endoplasmic reticulum stress
FIP200: focal adhesion kinase family interacting protein of 200 kD
IBD: inflammatory bowel disease
JNK: c-Jun N-terminal kinase
MAPK: Mitogen-activated protein kinase
MCP: multiple country publications
NF-κB: Nuclear factor kappa-B
NO: Nitric oxide
NOD2: nucleotide binding oligomerization domain containing 2
SCP: single country publications
TCM: traditional Chinese medicine
TCMSP: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform
UC: ulcerative colitis
ULK1: Unc-51 like autophagy activating kinase 1

Min He appreciate the financial support by the Pilotscale Selection Project of Colleges and Universities in Changchun City [No.24GXYSZZ10] and the Open Scientific Project of Institute of Basic Theory for Chinese Medicine, China Academy of Chinese Medical Sciences (No. YZX-202207). Bo Yang was supported by the Education Department of Jilin Province (grant number JJKH20241052KJ). Zhongyi Liang was supported by the Jilin Province Health Technology Capability Enhancement Project (grant number 20223C039).

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Dong J, Dou J, Zhu L, Zhang L, Bo Y, Liang Z, Meng X, Wang X, Wang T, Sun M, Zhang X, He M. Mapping the global research landscape and hotspots of traditional herbal medicine for inflammatory bowel disease: A bibliometric analysis. Medicine 2026;105:17(e44003).

JD and JD contributed to this article equally.

Contributor Information

Jiaxin Dong, Email: dongjiaxin@hotmail.com.

Jiawen Dou, Email: d18843228475@163.com.

Lixia Zhu, Email: a15066816125@163.com.

Linhao Zhang, Email: zhangxy01@ccucm.edu.cn.

Yang Bo, Email: yangbo@ccucm.edu.cn.

Zhongyi Liang, Email: 86513619@163.com.

Xianghe Meng, Email: wishtech_loong@163.com.

Xiujiang Wang, Email: wangtan@ccucm.edu.cn.

Tan Wang, Email: wangtan@ccucm.edu.cn.

Mengmeng Sun, Email: sunmm@ccucm.edu.cn.

Xinyue Zhang, Email: zhangxy01@ccucm.edu.cn.

Min He, Email: hemin@ccucm.edu.cn.

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Supplementary Materials

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[R1] [1].Nobrega VG, de Novais Silva IN, Brito BS, Silva J, Silva MCM, Santana GO. The onset of clinical manifestations in inflammatory bowel disease patients. Arq Gastroenterol. 2018;55:290–5. [DOI] [PubMed] [Google Scholar]

[R2] [2].Shao BL, Yang WJ, Cao Q. Landscape and predictions of inflammatory bowel disease in China: China will enter the Compounding Prevalence stage around 2030. Front Public Health. 2022;10:11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] [3].Travis S, Feagan BG, Peyrin-Biroulet L, et al. Effect of adalimumab on clinical outcomes and health-related quality of life among patients with ulcerative colitis in a clinical practice setting: results from inspirADA. J Crohns Colitis. 2017;11:1317–25. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R4] [4].Sanmarco LM, Chao C-C, Wang Y-C, et al. Identification of environmental factors that promote intestinal inflammation. Nature. 2022;611:801–9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] [5].Kalla R, Adams AT, Nowak JK, et al. Analysis of systemic epigenetic alterations in inflammatory bowel disease: defining geographical, genetic and immune-inflammatory influences on the circulating methylome. J Crohns Colitis. 2023;17:170–84. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] [6].Lewis JD, Abreu MT. Diet as a trigger or therapy for inflammatory bowel diseases. Gastroenterology. 2017;152:398–414.e6. [DOI] [PubMed] [Google Scholar]

[R7] [7].Pott J, Kabat AM, Maloy KJ. Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice. Cell Host Microbe. 2018;23:191–202.e4. [DOI] [PubMed] [Google Scholar]

[R8] [8].Zhao S, Xia J, Wu X, et al. Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish. Nat Commun. 2018;9:1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] [9].Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019;20:970–9. [DOI] [PubMed] [Google Scholar]

[R10] [10].Koutroumpakis E, Ramos-Rivers C, Regueiro M, et al. Association between long-term lipid profiles and disease severity in a large cohort of patients with inflammatory bowel disease. Dig Dis Sci. 2016;61:865–71. [DOI] [PubMed] [Google Scholar]

[R11] [11].Kaser A, Lee A-H, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743–56. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] [12].Li SY, Xu K, Cheng Y, et al. The role of complex interactions between the intestinal flora and host in regulating intestinal homeostasis and inflammatory bowel disease. Front Microbiol. 2023;14:21. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] [13].Speight RA, Mansfield JC. Drug advances in inflammatory bowel disease. Clin Med (London, England). 2013;13:378–82. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R14] [14].Yuan S, Wang Q, Li J, et al. Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment. Chin Med. 2022;17:1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] [15].Huang CQ, Dong J, Jin X, et al. Intestinal anti-inflammatory effects of fuzi-ganjiang herb pair against DSS-induced ulcerative colitis in mice. J Ethnopharmacol. 2020;261:112951. [DOI] [PubMed] [Google Scholar]

[R16] [16].Yuan Z, Yang L, Zhang X, Ji P, Wei Y. Therapeutic effect of n-butanol fraction of Huang-lian-Jie-du Decoction on ulcerative colitis and its regulation on intestinal flora in colitis mice. Biomed Pharmacother. 2020;121:109638. [DOI] [PubMed] [Google Scholar]

[R17] [17].Yang Y, Chen G, Yang Q, et al. Gut microbiota drives the attenuation of dextran sulphate sodium-induced colitis by Huangqin decoction. Oncotarget. 2017;8:48863–74. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] [18].Zheng L, Zhang Y-L, Dai Y-C, et al. Jianpi Qingchang decoction alleviates ulcerative colitis by inhibiting nuclear factor-kappa B activation. World J Gastroenterol. 2017;23:1180–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Mapping the global research landscape and hotspots of traditional herbal medicine for inflammatory bowel disease: A bibliometric analysis

Jiaxin Dong, MM

Jiawen Dou, MM

Lixia Zhu, MM

Linhao Zhang, MM

Yang Bo, MD

Zhongyi Liang, MM

Xianghe Meng, MB

Xiujiang Wang, MD

Tan Wang, MD

Mengmeng Sun, PhD

Xinyue Zhang, MM

Min He, PhD

Abstract

1. Introduction

2. Materials and methods

2.1. Documental searching strategy and data collection

Table 1.

Figure 1.

2.2. Data processing and visualization

2.3. “Components–targets–pathway” networks construction based on network pharmacology

3. Results

3.1. Basic information

Table 2.

3.2. Corresponding authors’ country and affiliations

Table 3.

Table 4.

3.3. Countries and institutions linkage

Figure 2.

3.4. Author collaborations

Table 5.

Table 6.

Figure 3.

3.5. Annual production and their relevant sources

Figure 4.

Table 7.

3.6. Analysis for global citations

Figure 5.

Table 8.

3.7. Analysis of keywords and co-occurrence map for frontiers

3.7.1. Keyword cluster analysis and trend topics

Figure 6.

3.7.2. Co-occurrence map among cellular and animal models

Figure 7.

3.7.3. Co-occurrence map among herbal decoctions, herbal plants and among natural products

Table 9.

Figure 8.

3.7.4. Potential mechanisms based on burst analysis

Table 10.

3.7.5. “Components–targets–pathway” networks of the top 3 herbal plants for IBD treatments based on network pharmacology

Table 11.

Figure 9.

Figure 10.

Figure 11.

4. Discussion

4.1. Current understanding status of the IBD

4.2. Herbal therapies for IBD

4.3. The emerging zebrafish model as hotspots for assessing toxicity and efficacy of drug candidates

5. Conclusion

Acknowledgments

Author contributions

Supplementary Material

Abbreviations:

Contributor Information

References

Associated Data

Supplementary Materials

ACTIONS

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