Bibliometric and visual analysis of intestinal ischemia reperfusion from 2004 to 2022

Background Intestinal ischemia/reperfusion (I/R) injury is a common tissue-organ damage occurring in surgical practice. This study aims to comprehensively review the collaboration and impact of countries, institutions, authors, subject areas, journals, keywords, and critical literature on intestinal I/R injury from a bibliometric perspective, and to assess the evolution of clustering of knowledge structures and identify hot trends and emerging topics. Methods Articles and reviews related to intestinal I/R were retrieved through subject search from Web of Science Core Collection. Bibliometric analyses were conducted on Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio). Results A total of 1069 articles and reviews were included from 2004 to 2022. The number of articles on intestinal I/R injury gradually plateaued, but the number of citations increased. These publications were mainly from 985 institutions in 46 countries, led by China and the United States. Liu Kx published the most papers, while Chiu Cj had the largest number of co-citations. Analysis of the journals with the most outputs showed that most journals focused on surgical sciences, cell biology, and immunology. Macroscopic sketch and microscopic characterization of the entire knowledge domain were achieved through co-citation analysis. The roles of cell death, exosomes, intestinal flora, and anesthetics in intestinal I/R injury are the current and developing research focuses. The keywords “dexmedetomidine”, “proliferation”, and “ferroptosis” may also become new trends and focus of future research. Conclusion This study comprehensively reviews the research on intestinal I/R injury using bibliometric and visualization methods, and will help scholars better understand the dynamic evolution of intestinal I/R injury and provide directions for future research.


Introduction
Intestinal ischemic injury occurs in various situations during clinical practice, such as arterial embolism, strangulated hernia, colon cancer, intestinal torsion, blood poisoning, mesenteric dysfunction, and hypovolemic shock (1). During the interruption of blood supply, mitochondrial dysfunction and metabolic disturbances of energy deficiency damage intestinal cells (2, 3); the end of ischemia is often accompanied by tissue reperfusion, which further aggravates intestinal damage (4).
This process is usually accompanied by an intense inflammatory response and massive neutrophil recruitment (5). The release of inflammatory factors and the recruitment of neutrophils cause extensive intestinal epithelial cell death (6), resulting in impaired intestinal mucosal barrier function, which involves distant organs such as lungs, liver, and kidneys (7)(8)(9). Consequently, bacteria and endotoxins from the intestinal lumen can transit through the damaged intestinal mucosal barrier to the circulatory system (10), inducing systemic inflammatory response syndrome or even multi-organ failure (11). Microcirculatory disorders and organ damage after intestinal I/R are complex pathological processes involving metabolic damage and oxidative stress (2). Metabolic damage is mainly manifested in ischemia, where vascular closure or obstruction leads to intracellular hypoxia, impairing the expression of mitochondrial respiratory chain ATP synthase and thus resulting in reduced ATP synthesis and ATP deficiency (12,13). At the same time, the microcirculatory dysfunction caused by I/R injury may initiate multi-organ damage, organ fibrosis, and even organ failure (14). Hence, prevention and treatment of intestinal I/R injury are crucial, given its potential to cause severe deterioration of the patient's physiological status and its high incidence and mortality in surgical applications.
With the rapid advances in basic medicine of cell death (15), intestinal flora (16), microRNA (17), and various omics (18,19), many academic journals have published articles on preventing or reducing intestinal I/R injury. However, few attempts have been made to systematically analyze the scientific results and current status of this field from a global perspective. Therefore, a suitable visualization method is urgently needed to reveal the global status, future trends, and hot spots of intestinal I/R injury research.
Since the emergence of the bibliometric field in the 1960s, the open science movement is considered the most critical change in bibliometrics. The free sharing of various scientific results on the Web has influenced the practice of bibliometrics at all levels, including data, infrastructure, definition, and collection of metrics. Bibliometric methods can be used to explore the impacts of the research fields, researchers, and specific papers, or to identify documents that are particularly influential in each research field (20)(21)(22). Recently, the results of bibliometric analysis have been applied to medical fields such as cancer (23), stroke (24), critical care medicine (25), and anesthesiology (26). However, there is still a gap in the bibliometric studies on intestinal I/R injury. Therefore, this review systematically analyzes the studies on intestinal I/R injury to assess the current status and hot spots of this field.

Data sources
Our bibliometric analysis is based on the Web of Science Core Collection (WOSCC), the most widely-used and convincing dataset for bibliometrics today (27,28). WOSCC has the most comprehensive set of data fields to support our most comprehensive analysis. We used "intestinal ischemia reperfusion" (Topic) OR "intestinal ischaemia reperfusion" (Topic) OR "mesenteric ischaemia reperfusion"(Topic) as a search tool to retrieve literature. The categories included 1010 papers, 59 reviews, 46 conference papers, 4 online publications, and 1 data paper. We limited our search to papers and reviews, resulting in 1069 documents. All of the above documents were in English.

Data collection
All results were searched on WOSCC using the above formula and exported as plain text literature in formats txt and csv. The literature search was conducted on May 1, 2021 to prevent possible bias introduced by database updating.

Data analysis
Visual analysis was performed on Microsoft Excel 365, Bibliometrix (R-Tool of R-Studio) (29), VOSviewer (30), and CiteSpace (31). The advantages and disadvantages of the above econometric analysis software were also discussed in recent literature, and thus were not elaborated here (32). CiteSpace 6.1.R2 Advanced was used to visually analyze country distribution, institution distribution, subject area distribution, keyword timeline, references, keywords, and literature bursts from the above-extracted data. On VOSviewer 1.6.18, we visually analyzed country distribution, institution distribution, and author distribution from the extracted data. With Bibliometrix (R-Tool of R-Studio), we visually analyzed country distribution, references, and keywords using R-Studio.
Since all raw data used here were obtained from public databases, no ethical review was required.

Publication output and temporal trend
As a complex pathophysiological process, intestinal I/R has been studied since the second half of the last century (33). Given that the object of analysis should be current and cutting-edge, we set the publication time to be about 19 years or since 2004. The number of articles per year published during the selected period was variable, fluctuating from 30 to 80 (Figure 1). The annual citation frequency in this field generally rose over the past 20 years, with 2,470 citations in 2020, which was onethird more than that in 2019. The annual number of articles and the frequency of citations within the 20 years peaked to 79 documents in 2020 and 3,038 citations in 2021 respectively.

Distributions of countries/regions and institutions
At present, 46 countries or regions are involved in intestinal I/R research, which are mainly from the northern hemisphere. There are only Brazil, Argentina, Australia, and New Zealand studied intestinal I/R in the southern hemisphere. The proportion approximately is less than 10% (4/46).What's more, the links between countries is concentrated in the northern hemisphere. Brazil in the southern hemisphere is relatively active and maintains a high frequency of communication with Europe and the United States (Figure 2A). China had the most significant number of publications with 414 (34.33%), followed by the United States with 184 (15.26%) and Turkey with 126 (10.45%) ( Table 1). In terms of total association strength, the United States (88), Germany (33), and China (33) were the strongest and invested more efforts to intestinal I/R research. The top two countries in terms of the number of publications totaled nearly half of the total number. The top ten institutions in terms of literature output are shown in Table 2. Zhongshan University had the most significant number of publications (76, 6.30%), followed by Dalian Medical University (50, 4.15%) and São Paulo University (27, 2.24%). Similarly, Sun Yatsen University had the strongest total association strength in this field. Meanwhile, Sun Yat-sen University, Technion-Israel Institute of Technology, University of São Paulo, Southern Medical University, Wuhan University, the Federal University of São Paulo, and Ohio State University all rank in the top 10 in terms of the number of articles and association intensity and should have conducted extensive research in this field.
There is a general lack of cooperation among countries and among institutions in intestinal I/R research, given the limited communication targets, and multiple clearly-differentiated communication scopes in this field. The different colors between nodes analyzed on VOSviewer each indicate a collection of intimacy (30). The countries or regions can be divided into ten sets according to the intimacy of cooperation ( Figure 2B). It is a interesting information that, Turkey is a self-contained collection, with only the United States. In contrast, analysis of the country relationship network on CiteSpace showed the periphery of nodes representing the United States, China, England, Germany, Italy, France, and Spain had purple circles in the network, indicating these countries are highly influential in this field (Supplementary Figure 3). These influential countries, except China and France, are located in different groups ( Figure 2B). In terms of research focus and collaboration, FIGURE 1 Trends in the publication and citation frequency of intestinal I/R-related literature (2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021)(2022). The number of publications fluctuates between 30 and 80, with a maximum value in 2020 and an average of more than 66 in the last decade. The overall upward trend in citation frequency is observed.    (Supplementary Figure 4).

Distributions of authors and co-cited authors
The authors of the retrieved literature were analyzed, and the top 10 aX2uthors ranked by the number of publications and frequency of citations were found ( Table 3

Distribution of journals
Journal of Surgical Research (IF 2.192), and Shock (IF 3.454) were the first and second most published and co-cited journals ( Table 4). World Journal of Gastroenterology (IF 5.742) was the third most published journal, and Journal of Immunology (IF 5.422) was the third most-cited journal. Six of the top ten journals ranked by the number of publications were also among the top ten journals in terms of co-citation frequency, and these journals should have high prestige in intestinal I/R. The journals with the most publications were 1 in Q1 and 5 in Q2, and the journals with the most co-citations were 3 in Q1 and 5 in Q2 (Table 4), indicating these journals have a high academic reputation in the field. The journals were divided by the co-citation frequency into 4 clusters ( Figure 5). Articles from journals within the same cluster are more likely to have similar research directions or a specific internal logic (36). Journal of Surgical Research, and Shock, the top two journals in terms of co-citation frequency, clearly tend to be co-cited with more frequently cited journals,

Distribution of subject areas
Analyzing the published literature on intestinal I/R and the subject areas of interest enables us to identify the current research habits and scenario applications in intestinal I/R. By tracking the subject areas of the journals published and cited, we linked the visualization in Figure 6A. The colored paths between the citing journals on the left and the cited journals on the right reflect the citation relationship among different fields. The orange and green paths show that the literature on intestinal I/R is mainly published in the disciplinary fields: "4. MOLECULAR, BIOLOGY, IMMUNOLOGY" and "2. MEDICINE, MEDICAL, CLINICAL". The literature related to both disciplines is more likely to be published in "8. MOLECULAR, BIOLOGY, GENETICS" and "5. HEALTH, NURSING, MEDICINE". The discussion of intestinal I/R was published or cited in basic medicine, clinical applications, and health care.
Then the literature was analyzed on CiteSpace to refine the citation relationships among subject areas ( Figure 6B). The subject "SURGERY" is the most frequently cited. Subjects "SURGERY", "CELL BIOLOGY", "IMMUNOLOGY", "MEDICINE", "RESEARCH & EXPERIMENTAL", "PHARMACOLOGY & PHARMACY", "BIOCHEMISTRY & MOLECULAR BIOLOGY", "PHYSIOLOGY", "TOXICOLOGY", "BIOPHYSICS", "BIOTECHNOLOGY & APPLIED MICROBIOLOGY", and "CHEMISTRY, MULTIDISCIPLINARY" are marked with purple circles in the diagram. Results show in the study and research on intestinal I/R, the knowledge of the subjects mentioned above and is even indispensable and shall be given some importance. As shown in Figure 6A, the literature in the subject "IMMUNOLOGY" is mostly referenced by "SURGERY" and "GASTROENTEROLOGY & HEPATOLOGY". "HEPATOLOGY" and "BIOPHYSICS" are referenced by "MEDICINE, RESEARCH & EXPERIMENTAL". The literature was clustered by subject areas (Figure 6C) into totally six clusters. The more important clusters are #0, covering "ENDOCRINOLOGY & METABOLISM", "MICROBIOLOGY", "GASTROENTEROLOGY & EXPERIMENTAL", "GASTROENTEROLOGY & HEPATOLOGY", with the keyword inflammation; #1, covering "TRANSPLANTATION", "IMMUNOLOGY", and "SURGERY", with the keyword proliferation. Interestingly, cluster #3 covers the subject areas "AGRICULTURE, MULTIDISCIPLINARY", "CHEMISTRY, APPLIED" and " FOOD SCIENCE & TECHNOLOGY", with the keyword naringin, and may be a collection of disciplines related to the study of components in food. Cluster #5 covers the subject areas "SPORT SCIENCES", "MEDICAL LABORATORY TECHNOLOGY", "MEDICINE, GENERAL & INTERNAL", and "TOXICOLOGY", and the keyword is rat, which may focus on the animal behavior in intestinal I/R, toxicological response to interventional drugs, and model evaluation.

Highly cited reference analysis
Therapeutic Effects of Xanthine Oxidase Iinhibitors: Renaissance Half A Century after Discovering Allopurinol (Pacher et al.) (37) had the highest number of citations (843) ( Table 5). This paper is based on allopurinol and its active metabolites, which are promising drugs for treating ischemic and other tissue and vascular injuries, inflammatory diseases, and chronic heart failure. This paper is aimed to describe their therapeutic application in various pathophysiological FIGURE 5 Visualization of the relationship between co-cited journals. One node represents one journal, and the area means the citation frequency. Sizes of nodes are reflected with co-citations. While the highly-cited articles reflect the high recognition of their authors in the field, the first four highly-cited articles were published over ten years ago, indicating that the research in the last decade is likely to involve the application of tools Clustering module value (Q value), using in CiteSpace cluster analysis, it is generally considered that Q > 0.3 means that the clustering structure is significant, shown line 10 in top left of (C). The average contour value of clustering (S value), in line 11, it is generally considered that S > 0.5 clustering class is reasonable and S > 0.7 means that the clustering is convincing.  (42). The relationship among the studies was analyzed on CiteSpace, and was found to have a specific time factor of publication, marking the literature with an explosive citation frequency ( Figure 7A). The earliest bursting articles were earlier than 2001. The number of explosive studies and the citation frequency of published studies peaked in 2008. The number of cited incendiary studies is correlated to the frequency of citations of published studies in the same year. The studies with high citation frequency account for a higher percentage among all the high explosive studies. The studies with high citation frequency are more likely to be cited as high incendiary literature, which confirms the correlation between explosive research and citation frequency to a certain extent. It is indicated that the research focus in the field may revolve around a specific hot spot for a while. The clustering of the relational network of the literature (Figure 7B) yielded totally 17 co-reference clusters. The cluster with the highest number of publications is #0, and the specific common keyword with a high number of publications is acute lung injury. The most relevant study is Effect of Montelukast on Acute Lung Injury

Keyword analysis
As a core summary of article contents, keywords can be used to analyze the frontiers of results in intestinal I/R (48). The keywords that appeared more than 100 times in the order of frequency were ischemia/reperfusion (349 times), intestinal I/R (218 times), intestine (208 times), oxidative stress (144 times), inflammation (100 times), and five others ( Table 6). The five keywords also have high association strength in the domain (all greater than 1500). Among the top 20 keywords, it is tentatively speculated to have more apparent connections. For instance, ischemia/reperfusion, intestinal I/R, ischemia, and intestinal ischemia all involve the description of intestinal I/R and its related or similar pathophysiological processes; intestine, lung injury, intestinal injury, and injury may focus on the organs affected by intestinal I/R and the resulting injuries. Other keywords are oxidative stress, antioxidants, nitric-oxide, neutrophil, and inflammation with cytokine and NF-κb. Similar relationships may exist. Figure 8 shows the network relationship diagram of keyword co-occurrence. The thicker line between the keyword points in each section means the more frequent co-occurrence (48). The different colors of the nodes represent different clusters, and the intestinal I/R field is co-categorized into 10 clusters, reflecting the possible ten research directions. These clusters, with apparent associations among the top 20 highoccurrence keywords, are in general agreement. In the purple cluster, oxidative stress and antioxidant are solidly related with apoptosis, autophagy, and related pathways such as nrf2 and sirt1. In the green cluster, inflammation is associated with neutrophil, immune-related concepts such as complement, and barrier-related concepts such as tight junction. The yellow cluster covers injury, lung injury, liver injury, acute pancreatitis, and other organ injury-related keywords. The orange cluster includes organs such as lung, liver, curcumin, ileum and kidney. In the cyan cluster, ischemia/reperfusion, intestine, and injury show no more obvious association, and are too closely connected to other collections, presumably because it is the standard part of the research direction of the field. In the red cluster, mouse, nitric oxide, experimental model, shock, and sepsis may describe the current situation of intestinal I/R on sepsis and shock research. The brown cluster covers gene expression. The pink cluster (proliferation), and the scarlet cluster (dexmedetomidine) seem to have less number of keywords, which may be emerging research directions.
The keyword burst can also reflect some emerging academic trends and new topics in the field, which can be used to predict the direction of cutting-edge research and reveal potential hot spots in the field (49). The top 25 keywords with high citation bursts in intestinal I/R are shown in Figure 9A. The highest keyword is "protect", followed by "nitric oxide" and "apoptosis". "Nitric oxide synthase" had the longest burst time and was the earliest burst among the top 25 keywords. Conversely, "preservation", "necrosis factor alpha", "nitric oxide" and "mucosa" all had shorter outbreaks. The keywords that are still in the burst status are "lung injury", "damage", "autophagy", "protection", "mucosa", "protect", "apoptosis" and "cell death", which represent some of the current hotspots in the field.
Timeline views of the intestinal I/R co-citation network were made with CiteSpace (Figure 9B), which can be seen as emergence, popularity, and decline of hotspots (50). From 2004 to 2010, the strong influence keywords were focused, and were mainly inflammation, ischemia/reperfusion injury, lung injury, model, acute lung injury, activated protein c, rat, expression, reperfusion injury, protect, disease, tolllike receptor, myocardial ischemia, mesenteric ischemia, and immune response. Cluster #1 arose first with the keyword ischemia/reperfusion injury, showing a discovery history  Discussion CiteSpace 6.1.R2 Advanced, VOSviewer 1.6.18, and R-bibliometrix were used to analyze the data of 1069 articles on intestinal I/R between 2004 and 2022 from the Web of Science, and evaluate the spatial and temporal distributions, author contributions, core articles, research hotspots and frontiers of the field based on these data.

General distribution
The overall performance of intestinal I/R over the last 19 years was highly volatile, with the number of publications maximizing in 2020 and with a high publication profile in the previous two years. In contrast, the frequency of citations increased and tended to accelerate recently. The publication number and citation frequency can broadly describe the development of a field (Figure 1). We conclude that intestinal I/R, a long-established topic since the mid-20th century, has kept active in the first 19 years of the 21st century because it remains a severe challenge for physicians and patients in clinical practice.
China and the United States are the top two countries ranked by the number of publications and frequency of citations in intestinal I/R ( Table 2). In terms of centrality and strength of association, the United States has the most decisive influence and vital linkage in the field. Spain and Italy have smaller numbers of publications but enjoy a high impact in the field, indicating their research results are generally considered as high-quality. Other high-impact countries are China, Germany, and England (Supplementary Figure 3). As the country with the most significant number of publications, China is also influential. However, the number of publications does not match with the centrality of other high-impact countries. In terms of the average frequency of citations per article, China (18.22) is still at a deficit position compared to other influential countries, such as the United States (37.46), Germany at (26.45), and England (22.2), and is even below the average level of 22.06 too many. There is a difference of about 1589 times in catching up with the world average, and the 4th most cited country exceeds the total citation frequency of Turkey. To catch up with the average citation level of the United States, it takes about 7,965 citations to exceed its citation frequency. However, contrary to the view at the national perspective, as far as institutions are concerned, China has 5 of the top 6 institutions in publications, and 4 of the top 10 institutions in citations ranked by association intensity, the first of which is Sun Yatsen University in Guangdong, China ( Table 2). The lack of national influence and the differences in Chinese dominance among institutions suggest that Chinese authors need to actively become international and improve their research quality and reference value. Moreover, there is a shortage of Chinese research in intestinal I/R that is good enough to be recognized and evaluated by the world. Similarly, we should recognize that international and inter-institutional cooperation in intestinal I/R is lacking (Figure 2B and Supplementary Figure 3). In addition to the apparent subgroups, no institution has a centrality over 0.1. We suggest that the field of intestinal I/R should strengthen cross-discipline and actively organize international conferences to attract researchers from more countries and institutions. And scientists should also apply basic research in the field of intestinal I/R to clinical trials and attract more doctors from hospitals to strengthen the links between institutions. Furthermore, Dalian Medical University has no links to other institutions (Supplementary Figure 4). When national and institutional barriers against communication can be broken down, the advantages between influential countries complement each other, and the platform for research is expanded, which will bring obvious benefits for the long-term progress of research in the field.
Supported by the data, Liu Kx has been the most prolific author in the field of intestinal I/R in the last 19 years, and early methodological and mechanistic discussions covered oxidative stress (228 citations, 7 articles), ischemia pre/post-conditioning (236 citations, 7 articles), and anesthetic drugs (318 citations, 5 articles). The most cited author is Chiu Cj, whose pioneering Chiu's Score for intestinal injury assessment is widely used to judge the quality of intestinal I/R studies. Mallick Ih is the most cited author directly related to research in this field, with 535 citations for his Summary of Protective Strategies for Intestinal I/R Injury in 2004, followed by two gastroenterology  Table 3). In addition, Tian Xf is the most cited author, with five studies on oxidative stress reaching 382 citations before 2016. A single article involving ferroptosis-induced intestinal injury in 2019 was cited 199 times recently. The scholars mentioned above have undoubtedly significantly contributed to the development of this field. Interestingly, Chiu Cj, as the most co-cited author, is not a researcher in the field, which is odd. In addition, we find 3 of the top 10 co-cited authors are from Louisiana State University, which may be an important institution for research in the field.
Reviewing the top 20 journals in terms of publication volume or co-citation frequency ( Table 4), we find most of them are clinical journals, such as Journal of Surgical Research, World Journal of Gastroenterology, Transplantation Proceedings, and Gastroenterology. Some are essential medical journals, such as Journal of Immunology, which support and complete one of our inferences in "Distribution of Subject Areas" (Figure 6A). Only World Journal of Gastroenterology division is higher than Q3, and IF is not lower than 5. The results in the field need to be improved in terms of quality. In conclusion, most of the journals in this field have IF higher than World Journal of Gastroenterology (IF 5.742) and Journal of Immunology (IF 5.422), and the highest IF among the frequently cited journals is Gastroenterology (IF 22.682). We clustered the citation relationships of the journals, and found frequent associations among journals within subgroups, but not as apparent as associations among institutions or authors (Figure 5), which is partly because the authors maintained good academic habits and read and thought widely about results at different levels.

Hotspots and frontiers
Keyword analysis is beneficial to grasping the core contents and frontiers of a research field (51). In the existing studies, the main keywords are "intestine", "oxidative stress", "inflammation", "apoptosis", "lung injury", "rat", "cytokine", "nitric oxide", "antioxidant" and "bacterial translocation" ( Table 6). These keywords and their relationships are often closely associated with the research hotspots regarding intestinal I/R process mechanisms, such as the relationship among inflammation, intestinal barrier and vascular permeability. The manifestations are in-situ organ and distant organ damages and the pathway mechanisms of oxidative stress. Intestinal I/R therapies include ischemic pre/post-treatment, hydrogen resuscitation, transcriptional inhibition, and related drugs such as anesthetic drugs (Figure 8). However, deriving of the above hotspots still need years of keyword data support, and the timeliness is yet unsatisfactory. We unfolded the analysis through the time of highly explosive keywords. In recent years, lung injury and various cell death such as apoptosis, autophagy, and ferroptosis caused by intestinal I/R are also worthy of attention. Despite the lack of explosive trend in flora, exosomes, or TLR, there are a certain number of studies on discussion of intestinal I/R in the last three years.
The cell death modalities currently explored in intestinal I/R are apoptosis, pyroptosis, ferroptosis, autophagy, NETosis, and necrotizing apoptosis. In the last few years, metformin, which is used extensively to study autophagy, has been discussed in intestinal I/R for its possible involvement in pyroptosis via the TXNIP-NLRP3-GSDMD pathway (52). Research on autophagy in intestinal I/R shows multiple signaling pathways play a role. For instance, paeoniflorin activation of LKB1/AMPK pathway and mTOR signaling is positively correlated with, and the JAK2/STAT3 signaling pathway is negatively associated with the occurrence of autophagy (53)(54)(55). Some pathways may exhibit other effects while promoting autophagy. Postischemic treatment through the Akt/GSK-3β/Nrf2 pathway can inhibit oxidative stress and make autophagy accompanied by positive antioxidant effects (56). The transcription factor Nrf2 in its pathway may be involved in multiple cell death modalities, including apoptosis. In intestinal I/R, Nrf2 plays a protective role as it can regulate SLCA11 and HO-1 to limit ferroptosis to attenuate secondary acute lung injury, and can modulate TERT and SLC7A11 to weaken secondary acute liver injury (57). With oxidative stress imbalance as an essential death phenotype, ferroptosis has an oxidative stressrelated upstream similar to Nrf2. ACSL4 was first identified in intestinal I/R to play a role in ferroptosis-mediated injury via ischemia production (41). Administration of apigenin-7-Oβ-d-(-6 -p-coumaroyl)-glucopyranoside prevented ferroptosis in intestinal vascular endothelial cells by inhibiting the downstream Nrf2 of HO-1 and MAO-B (58). Intriguingly, inhibitors of the apoptosis-associated protein p53 similarly inhibited ferroptosis in intestinal I/R (42). Furthermore, SIRT3mediated deacetylation of PRDX3 attenuated intestinal I/R apoptosis while alleviating oxidative mitochondrial damage (59). In contrast, mitochondrial autophagy in a diabetic mouse model exacerbated intestinal I/R damage (60), while the miR-665-3p/ATG4B/autophagy regulatory axis had antiinflammatory and anti-apoptotic effects (61). All these shreds of evidence implicitly and inconspicuously point to the possible correlation and mutual checks and balances among apoptosis, autophagy, and ferroptosis in intestinal I/R. Interestingly, a similar concept has recently been proposed for PANoptosis, whereby cell-bound inflammatory cytokines initiate a cell death process that is highly interconnected with pyroptosis, apoptosis and necroptosis through signaling induced by death-containing structural domains of receptors (62,63). Two recent discoveries are that NETosis is also involved in the development of intestinal I/R along with necrotic apoptosis, and that HMGB-1, a DAMP, can induce NETosis and thus exacerbate acute lung injury induced by intestinal I/R (64). Surprisingly, bacterial invasion can reduce the NETosis-caused damage (65). Recently, how thrombus recombinant protein, a neutralizer of NETs, attenuates NETosis in intestinal I/R was investigated (66). Reports on necroptosis show that mtDNA-STING is involved in necrosis of the intestinal epithelium following intestinal I/R (67). The livers will be secondary to HMGB-1-associated necrosis and polarization of Kupffer cell M1 (68).
Given that intestinal I/R occurs surgically on patients under anesthesia, the possible effects of anesthetic drugs and their resulting individual mental status on intestinal I/R shall be evaluated. There are many relevant studies recently, which cover the medications of propofol, dexmedetomidine, etomidate, remifentanil, and sevoflurane. Propofol, a general anesthetic, is seemingly protective in intestinal I/R through PI3K/Akt and NF-κB pathways (69,70). Similarly, etomidate and sevoflurane may have NF-κB protective pathways in intestinal I/R (71,72). In contrast, remifentanil promotes PDIA3 expression by activating p38MAPK to inhibit oxidative and endoplasmic reticulum stress in intestinal I/R (73). Dexmedetomidine, commonly used as an anesthetic sedative, is the most carefullystudied anesthetic drug in terms of the effects on intestinal I/R. As for intestinal injury mechanisms, dexmedetomidine may inhibit p38MAPK, and TLR4/MyD88/NF-κB signaling pathways and activate Jak/STAT signaling pathways, attenuating intestinal injury (74)(75)(76). Reportedly, dexmedetomidine pretreatment alleviates intestinal vascular barrier injury and is clarified to attenuate distal liver injury (77).
Furthermore, the hepatoprotective effect of dexmedetomidine was enhanced by the combination of irisin (78). The protective effect of dexmedetomidine on acute lung injury, a hot topic at this stage, was recently discussed in a rat model (79). Dexmedetomidine can protect acute lung injury probably because inhibition of NLRP3 inflammatory vesicles in lung tissues or the activation of PI3K/Akt leads to the upregulation of cannabinoid receptor 2 and subsequent effects (80). In addition to total organ damage, other research topics of dexmedetomidine are mitochondriarelated oxidative stress and endoplasmic reticulum stress. Dexmedetomidine promotes mitochondrial translocation of telomerase reverse transcriptase, protecting enteric glial cells and reducing oxidative stress from intestinal injury (81). The action mechanism of dexmedetomidine on mitochondria is strongly related to the SIRT family, which inhibits endoplasmic reticulum stress-induced pyroptosis in intestinal epithelial cells via SIRT1 expression (82). Moreover, the SIRT3-dependent regulation of the PINK1/HDAC3/p53 pathway can inhibit mitochondrial damage and apoptosis in enteric glial cells (83).
In a very complex microbial environment, the intestine maintains a dynamic equilibrium through mucosal and other barriers to interact with the flora, which is highly susceptible to disruption by intestinal I/R. The role of the intestinal flora and metabolites in intestinal I/R has attracted increasing attention recently. Flora can attenuate NETosis in acute mucosal injury in intestinal I/R (65). Preoperative fasting by mimicking clinical requirements for patients was performed before the mouse model of intestinal I/R, and its alteration of flora metabolites was found beneficial for resisting intestinal I/R injury (84). Specific flora such as Bifidobacterium bifidum PRL2010 can attenuate intestinal I/R injury (85), and altered schaedler flora affected leukocyte adhesion in intestinal I/R injury (86). In terms of specific mechanisms, the flora metabolite pravastatin drives IL-13 release from type II innate lymphocytes via IL-33/ST2 signaling and attenuates intestinal I/R injury (87). Capsiate activates TRPV1 and Gpx4 expression, and inhibits intestinal I/R-induced ferroptosis (15).
Other frontiers of our focus are exosome and TLRrelated studies. Current technology allows the isolation of intestine-derived exosomes in the mouse intestinal I/R model, which facilitates subsequent studies (88). Intestine-derived exosomes can stimulate microglia and affect memory deficits after intestinal I/R (89). Classically, the main components of exosomes are believed to contain miRNAs, among which miRNA-26b-5p can target DAPK1 to inhibit apoptosis of intestinal mucosal cells in intestinal I/R (90). miR-665-3p can attenuate inflammation and apoptosis in intestinal I/R via the ATG4B-autophagy regulatory axis (61). miR-34a-5p activation of SIRT1 signaling attenuates reactive oxygen species accumulation and apoptosis (46). Therefore, the protection of intestinal I/R by intestine-derived exosomes may be a new potential therapy for intestinal I/R injury. In addition, TLR, with 11 family members, recognizes PAMP receptors and equally recognizes DAMP receptors. The role and mechanism of TLR4 in intestinal I/R injury are widely studied and reported (91). More scholars start to focus on the parts and tools of other TLR members in intestinal I/R. In terms of PAMP receptors, Lactobacillus murinus can promote IL-10 release from M2 macrophages through activation of TLR2 signaling, thereby attenuating intestinal I/R injury (16). In terms of DAMP receptors, intestinal I/R leads to increased expression of extracellular RNA, which is further a potential risk molecule for activating TLR3 to trigger or even exacerbate intestinal I/R injury (92).

Limitations
We statistically analyzed the trends, hot spots, and frontiers in intestinal I/R over the last 20 years by using three software programs: CiteSpace, VOSviewer, and R-bibliometrix. The discussion in this review still has many limitations. All literature data here are only from Web of Science. Although the timely and dynamic updating, authority, and extensiveness of the Web of Science helped us to obtain abundant literature to support the analysis, we cannot exclude the possibility of leaving out a part of the results about intestinal I/R that other data engines cannot ignore. In addition, our analysis relies heavily on the accumulation of literature data over time and the homogeneity within keywords. In consideration of analysis softwares have not enough to hadle the defect of data, we analyzed the most recent period, and screened some different results. However, we still unavoidably missed some frontier hot spots in intestinal I/R.

Conclusion
In this study, we reviewed the 19 years of research on intestinal I/R using bibliometric analysis, and analyzed the development of this field in space-time, internal logic, current situation, hot spots, and frontiers from multiple perspectives.
Undoubtedly, the United States and China are the core competencies of intestinal I/R research. However, there is an extraordinary lack of communication between the two sides and even among the possible subgroups, institutions and authors. Among all the authors, Liu, Kexuan has the largest number of articles and great influence in the field of intestinal I / R. Chiu, Cj was most co-cited by the intestinal I / R field researchers for the important role of Chiu's Score in the evaluation of intestinal injury.Journal of Surgery Research is the most important journal to intestinal I/R as the hugest size both in Publications and Citations. Specifically, the mechanisms of tissue-bacteria interactions, the association between modes of death, and the role of enteric exosomes or clinical anesthetic drugs will significantly determine the results of these studies in intestinal I/R. In summary, our results showed a comprehensive bibliometric analysis of research in intestinal I/R from a global perspective and may provide helpful clues for future research directions and scientific decisionmaking in this domain.

Data availability statement
The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author/s.

Author contributions
XYZ and KL: study conception. YW, PD, and XBZ: study design. YW, PD, XBZ, YL, and JS: study conduct. YW: data analysis. YW, PD, and XBZ: full access to all the data in the study, take responsibility for the integrity of the data and the accuracy of the data analysis, data interpretation, and drafting of the manuscript. YW, PD, XBZ, YL, JS, WL, KL, and XYZ: critical revision of the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version.