Toxicity issues have long been a primary concern in public health, environmental protection, and pharmacology. Toxicity research is essential for ensuring environmental, food, drug, and occupational safety and developing and evaluating new drugs (Arome and Chinedu, 2013). With the advancement of science and technology and changing societal needs, toxicity research has shifted from descriptive to mechanistic, from single substances to composite materials, from animal experiments to alternative methods, and from empiricism to system science. The gastrointestinal microbiome refers to the complex community of microorganisms in the human gastrointestinal tract, including bacteria, fungi, viruses, and more (Lindon et al., 2018). There is an increasing consensus suggesting that the gastrointestinal microbiome plays a crucial role in maintaining human health (Marchesi et al., 2016). These microorganisms participate in the body’s metabolism and absorption of nutrients and are closely associated with various physiological functions, such as the immune and endocrine systems (Belkaid and Hand, 2014; Gomaa, 2020).

The past decade has witnessed a significant surge of interest in understanding the gastrointestinal microbiome and its crucial role in maintaining health and contributing to the development of diseases. This growing interest has prompted a rapid expansion of research efforts to explore the gastrointestinal microbiome’s influence on various aspects of human wellbeing, including its potential relationship with toxicity. Concurrently, there has been an increased incidence of gastrointestinal disorders that could be influenced by the gastrointestinal microbiome and toxicity. For instance, recent estimates suggest that over 70 million people in the United States suffer from gastrointestinal (GI) disorders (O’Neill et al., 2021). The global rise in GI disorders has been linked to factors such as dietary changes, elevated stress levels, and exposure to environmental toxins, all of which can impact the gastrointestinal microbiome (Mohr et al., 2020). Given the burgeoning interest in this field and its potential implications for public health, there is a pressing need for a comprehensive and systematic analysis of the current state of knowledge, which is the primary focus of our study.

In recent years, research has unveiled complex interactions between the gastrointestinal microbiome and toxicity, which can be synergistic or antagonistic. On the one hand, the gastrointestinal microbiome can metabolize certain exogenous or endogenous toxic substances (Jeong et al., 2013), such as drugs, environmental pollutants, and endocrine disruptors, altering their structure, bioavailability, activity, or toxicity (Wilson and Nicholson, 2017). On the other hand, the gastrointestinal microbiome can also produce toxic metabolites such as D-lactic acid, ammonia, endotoxins, or carcinogens, thereby increasing the toxicity experienced by the host (Van de Wiele et al., 2005). Furthermore, an imbalance or disruption of the gastrointestinal microbiome, such as a decrease in microbial populations, overgrowth, or displacement, can lead to immune dysfunction, intestinal barrier damage, inflammatory responses, or systemic toxicity within the host (Chi et al., 2019).

Therefore, comprehending the mechanisms underlying the interactions between the gastrointestinal microbiome and toxicity, and finding ways to modulate the gastrointestinal microbiome to prevent or treat diseases associated with toxicity, are subjects of great importance and complexity. Various strategies centered around the gastrointestinal microbiome have been proposed or developed, including probiotics, fecal transplantation, microbial metabolites, and synthetic biology. These approaches promise to enhance the effectiveness and safety of drugs, reduce the risk of exposure to environmental pollutants, and augment the immune response against cancer.

Bibliometric analysis is a quantitative research method widely used in scientific research globally (Bornmann and Mutz, 2015). It has become one of the most extensively employed methods for evaluating the credibility, quality, and impact of academic work (van Raan, 1996). Bibliometric analysis can help us understand the current state, development trends, and research hotspots in a particular field. However, no bibliometric studies have hitherto been conducted on the association between gastrointestinal microbiome and toxicity. Therefore, we conducted a bibliometric analysis to reveal the major achievements, key technologies, and future development directions in this field. We hope this work can serve as a guide to identify critical knowledge and research priorities, assist researchers in formulating research strategies, optimize resource allocation, and achieve more breakthrough results in gastrointestinal microbiome and toxicity.

This bibliometric analysis investigated research development in the gastrointestinal microbiome and toxicity from 1980 to 2022. The advancement of scientific systems is closely intertwined with the progress of human civilization, and the field of toxicology is no exception. The late 20th century witnessed a golden era of development, attributable to factors such as rapid global economic growth, ecological degradation, increased exposure to human health issues, and accelerated advancements in computer science and medicine (Watson and Wexler, 2009). During this period, molecular research techniques played a crucial role in the study of gastrointestinal microbiome, resulting in significant breakthroughs in the analysis of gastrointestinal microbiome polymorphism and conducting qualitative and quantitative studies. On the other hand, the development of model organisms and genetically engineered animals has been paralleled by increased research on the physiological functions of gastrointestinal microbiome based on animal models (Stappenbeck et al., 2002; Bäckhed et al., 2004; Rakoff-Nahoum et al., 2004). In the late 20th and early 21st centuries, researchers increasingly focused on understanding the contribution of the gastrointestinal microbiome to overall health and disease states (Cho and Blaser, 2012). These early studies provided the groundwork for more complex explorations into the relationships between the gastrointestinal microbiome, disease progression, and responses to toxins.

With the official launch of the Human Microbiome Project in 2007 [ Integrative HMP (iHMP) Research Network Consortium, 2019] and the thriving development of high-throughput sequencing technologies (Caporaso et al., 2010), the scientific community’s enthusiasm for gastrointestinal microbiome research reached unprecedented heights. A review by Sekirov et al. (2010) examined the gastrointestinal microbiome’s influence on host physiology and its role in health and disease. They explored how changes in the microbiome can lead to disorders like inflammatory bowel disease and obesity, setting a foundation for further research into the microbiome’s role in disease development (Sekirov et al., 2010). In the first half of 2012, Science published a special issue on “The Gut Microbiota” and Nature followed suit in the second half of the same year with a special issue on “Gut microbes and health” (Lupp et al., 2012; Mueller et al., 2012). Since 2010, there has been a growing focus on the gastrointestinal microbiome’s role in influencing the efficacy of various treatments, including cancer therapies (Moayyedi et al., 2010; Simrén et al., 2013; Perez-Chanona and Jobin, 2014; Rajagopala et al., 2017). The results of these studies have expanded our understanding of how the gastrointestinal microbiome can modulate treatment responses, including potential toxicities. Since 2013, research on the relationship between toxicology and the gastrointestinal microbiome has gained momentum, driven by contemporary demands. Amidst this research boom, the field has amassed considerable findings and data. A comprehensive summary and analysis of its developmental trends, disciplinary frontiers, and research hotspots are important for facilitating further in-depth investigations.

China and the United States emerged as the leading countries in terms of the number of publications in the field of gastrointestinal microbiome and toxicity research, along with the highest frequency of collaboration. The substantial volume of articles from China can be attributed to increased research investment, particularly in the biomedical field, by the Chinese government in recent years (Xie and Freeman, 2019). China’s rapid economic development has also led to a heightened focus on ecological and public health issues. In terms of total link strength, the United States ranked first, primarily due to its high reputation in scientific research and innovation and numerous world-renowned research institutions and universities that attract researchers and scholars from around the world (Adams, 2012). This contributes to collaboration and development in this field (Ioannidis et al., 2018). As barriers to international exchange are eliminated, it is highly conceivable that influential countries and regions will experience complementary advantages, which will significantly impact the long-term development of this field.

Although China, India, and Japan are major countries in the gastrointestinal microbiome and toxicity research, the publishers of the ten most active journals in this field are all from Western Europe and the United States, without representation from Asia. This observation highlights the importance of developing internationally influential journals in Asia. Furthermore, we found that the majority of the top 10 journals in terms of article quantity are environmental science journals, including Science of the Total Environment, Environmental Pollution, Ecotoxicology and Environmental Safety, and others. This finding indicates that gastrointestinal microbiome and toxicity research has become a significant topic in environmental science.

In bibliometric analysis, hotspots typically refer to the most active and widely followed research directions or topics within a specific field and the characteristics and changes of hotspots can be reflected through citation analysis, keywords, and other indicators (Wu et al., 2021). Citation analysis can demonstrate the academic influence of research (Breugelmans et al., 2015). Interestingly, among the top 10 most globally cited documents, “microplastics” and “cancer therapy” were recurring topics. The top-ranked article, a review published in Environmental Science and Technology in 2017, was cited 1,042 times (Wright and Kelly, 2017). This article suggests that exposure to microplastics may affect the intestinal microbiome by promoting the growth of certain types of bacteria and altering the balance of microbial communities, potentially leading to adverse health outcomes such as inflammation and weakened immunity. In addition, three of the top 10 explored the role of the microbiome, particularly the gastrointestinal microbiome, in cancer and cancer therapy (Chaput et al., 2017; Roy and Trinchieri, 2017; Helmink et al., 2019). The gastrointestinal microbiome can modulate the response to various forms of cancer treatment, such as chemotherapy and radiotherapy, by influencing drug metabolism, pharmacokinetics, anticancer activity, and toxicity.

Interestingly, among the top 10 most co-cited articles, the majority (70%) focused on “cancer therapy” and were published in Science from 2010 to 2018. Three of these articles, cited over 110 times, were all dedicated to studying how the gastrointestinal microbiome influences the efficacy of PD-1-based immunotherapy (Sivan et al., 2015; Gopalakrishnan et al., 2018b; Routy et al., 2018). Anti-PD-1 immunotherapy is a type of cancer treatment that blocks the interaction between programmed cell death protein 1 (PD-1) and its ligands (PD-L1 and PD-L2), thereby enhancing T-cell anti-tumor activity. However, this therapy can also cause various adverse events, such as immune-related colitis. The severity and frequency of these toxicities depend on the type and combination of PD-1 or PD-L1 inhibitors used (Naidoo et al., 2015). The gastrointestinal microbiome has been shown to modulate the efficacy of anti-PD-1 immunotherapy, with higher diversity and abundance of certain bacterial taxa (such as Bifidobacterium and Faecalibacterium) being associated with better prognosis and lower incidence of immune-related adverse events (Sivan et al., 2015). Possible mechanisms by which the gastrointestinal microbiome regulates anti-PD-1 immunotherapy include affecting the composition and function of immune cells, altering the expression of PD-L1 on tumor cells, and producing metabolites that regulate inflammation and immunity (Gopalakrishnan et al., 2018a; Miller and Carson, 2020). These findings demonstrate the significant role of cancer therapy in the field of gastrointestinal microbiome and toxicity research. Therefore, interventions targeting the gastrointestinal microbiome, such as probiotics, prebiotics, antibiotics, or fecal microbiota transplantation, represent a promising strategy to improve cancer treatment outcomes and reduce toxicity.

In addition, the analysis of citation bursts, keyword clustering, and keyword bursts provides valuable insights into the key focus areas in the gastrointestinal microbiome and toxicity research. Several notable characteristics that attract significant attention in this field were identified: (1) toxic substances: drugs, nanoparticles, microplastics, heavy metals, pesticides, and biotoxins; (2) target organs: gastrointestinal tract, liver, and brain; (3) mechanisms: oxidative stress, metabolism, inflammation, and cell apoptosis. It is essential to interpret the identified burst keywords with caution. While they can be instrumental in signaling new and fast-emerging research areas, they do not always correlate with the quality or significance of the research. Thus, while these findings provide an overview of the research trajectory, a further qualitative assessment is required to discern the impact and importance of these emerging trends.

Interestingly, the research hotspots in the field of gastrointestinal microbiome and toxicity have gradually shifted from drugs to environmental pollutants. Indeed, since 2018, studies on the correlation between microplastic toxicity and gastrointestinal microbiome have begun to intensify. Microplastics are a common environmental pollutant that can lead to particle toxicity, oxidative stress, and inflammatory responses in organisms (Prata et al., 2020). Jin et al. (2018) found that exposure to two sizes of polystyrene microplastics for 14 days resulted in a significantly decreased abundance of Bacteroidetes and Proteobacteria in the intestine, while Firmicutes significantly increased. Besides, the levels of inflammatory factors IL-1α, IL-1β, and IFN were increased in the gut. Moreover, several studies have confirmed that microplastics can lead to gastrointestinal microbiome dysbiosis and metabolic disorders (Jin et al., 2019; Lu et al., 2019; Qiao et al., 2019). Notably, microplastics may also induce neurobehavioral toxicity through the gut-brain axis, potentially activating neuroactive ligand-receptor interaction and serotonergic synapse-related pathways (Huang et al., 2022). Importantly, Lianguo Chen et al. (2018) found that the toxicity of titanium dioxide nanoparticles and bisphenol A exposure in zebrafish is associated with the gastrointestinal microbiome, with the combined exposure leading to oxidative stress closely related to the ratio of pathogenic Lawsonia and normal metabolic Hyphomicrobium (Chen et al., 2018). Recent research findings indicate that the ingestion of differentially charged nanoplastics leads to the development of inflammatory lesions in the gut, disruption of electron transfer processes, inhibition of energy metabolism during mitochondrial oxidative phosphorylation, oxidative stress, increased expression of pro-inflammatory factors, and disturbances in pathways related to glycolipid metabolism (Xu et al., 2023). Our findings highlight that zebrafish is the predominant model organism in environmental toxicity studies. Their appeal as a crucial animal model in environmental toxicology research stems from several advantages: low maintenance cost, high breeding rate, swift growth, and considerable genetic homology with humans.

The primary target organs in the gastrointestinal microbiome and toxicity research are the gastrointestinal tract, liver, and brain. Studies on the microbiota-target organ axis have flourished in recent years, spurring many researchers to explore toxicology in this field. Zhong et al. (2021) investigated the toxic effects of arsenic trioxide (ATO) on the intestines and liver of ducks. The results demonstrated that ATO could mediate hepatic and jejunal inflammation and pyroptosis through the gut-liver axis and LPS/TLR4/NF-κB signaling pathway (Zhong et al., 2021). Another study found that exposure to perfluorooctanoic acid (PFOA) in mice led to a decrease in intestinal probiotics (including Lactobacillus and Bifidobacterium), while Dehalobacterium and Pseudomonas genera were significantly disturbed, which are associated with liver inflammation and oxidative stress. This confirmed that the hepatotoxicity of PFOA might be related to gastrointestinal microbiome dysbiosis (Wang et al., 2021). As previously mentioned, the importance of the gut-brain axis in toxicity research is increasing. Diazinon is an organophosphorus insecticide known to cause neurotoxicity. Studies have found that diazinon disrupts the gut microbiota composition and its metabolic functions in a sex-specific manner (Gao et al., 2017). Sub-chronic and chronic exposure to glyphosate-based herbicides (GBH) induces anxiety and depression-like behaviors in mice and leads to a decrease in the abundance of Bacteroides, Firmicutes, Pseudomonas, and Lactobacillus in the mouse gastrointestinal microbiome. Researchers hypothesized that gut dysbiosis might be highly associated with the observed changes in neurobehavior (Aitbali et al., 2018). In a recent study, a correlation between the gut microbiota and two specific organs, the lungs and the brain, has been established. The study found that inhalation of zinc oxide nanoparticles by the lungs can potentially lead to cerebral cortical impairment by disrupting the intricate lung-gut-brain axis (Zhang L. et al., 2023).

Oxidative stress, metabolism, and inflammation are the most reported mechanisms involving gastrointestinal microbiome and toxicity. The gastrointestinal microbiome can induce or exacerbate oxidative stress by metabolizing drugs or environmental pollutants to produce reactive oxygen species or free radicals or influence the host’s antioxidant system. For instance, the oral antiviral brivudine can be metabolized by the host and gastrointestinal microbiome into bromovinyluracil, exhibiting hepatotoxicity. The hepatotoxicity of brivudine may be associated with oxidative stress induced by its metabolic products (Jameson and Hsiao, 2019). Moreover, the gastrointestinal microbiome can induce or modulate inflammatory responses by regulating the host’s immune system or releasing endotoxins or pro-inflammatory cytokines. For example, the gastrointestinal microbiome can indirectly influence an individual’s response to immunotherapy in cancer treatment. Some commensal bacteria in the gut can enhance the antitumor effects of immune checkpoint inhibitors (ICIs), while some pathogenic bacteria may suppress the efficacy of ICIs or increase their toxic side effects (Lu et al., 2022). Nevertheless, certain probiotics can potentially exert a beneficial effect on the toxicity of specific substances. In this respect, the efficacy of Lactobacillus fermentum HNU312 has been demonstrated in mitigating oxidative damage and behavioral abnormalities induced by chronic lead exposure during early brain development (Zhang Z. et al., 2023). The gastrointestinal microbiome can influence the metabolism of drugs and environmental pollutants in various ways, thereby altering their toxicity (Li et al., 2008; Inamura, 2021).

An important direction for future research in the gastrointestinal microbiome field is exploring the therapeutic potential of manipulating the microbiome to mitigate the harmful effects of toxins. Building upon the existing knowledge of how the gastrointestinal microbiome influences responses to cancer therapies and the effects of environmental pollutants, investigations can focus on interventions such as probiotics, prebiotics, antibiotics, or fecal microbiota transplantation to enhance treatment efficacy and reduce toxicity. In addition, given the complexity of the interactions between the gastrointestinal microbiome and host health, interdisciplinary research approaches will be crucial in advancing our understanding of this field. Collaborations among toxicologists, microbiologists, environmental scientists, and health professionals could significantly advance our understanding of the gastrointestinal microbiome and its role in toxicity.

Despite the insights provided by our bibliometric analysis, this study is not without limitations. This study employed bibliometric analysis to assess research progress on the gastrointestinal microbiome and toxicity. However, it is important to note that bibliometric analysis mainly provides a quantitative assessment of the literature and does not necessarily reflect the quality or impact of the research. It allows for an objective and comprehensive exploration of the literature but does not substitute for a thorough qualitative assessment. Evaluating the quality of bibliometrics should not solely depend on quantitative measures. Instead, it requires an amalgamation of different methods and standards, such as peer review, expert opinion, and societal benefits, among others, to attain a more comprehensive and equitable scientific assessment. We acknowledge that our study was limited to English publications, potentially omitting significant contributions from non-English sources. A more extensive and inclusive approach would entail translating and analyzing scientific literature published in other languages. Furthermore, our study did not include unpublished literature, such as conference presentations, thesis work, and data from ongoing studies, which could also contribute valuable insights. While this literature is an essential part of the scientific discourse, its inclusion often presents practical challenges due to accessibility and verification issues. Nonetheless, future studies should also consider these sources to capture a more comprehensive view of the research landscape. In addition, this study only analyzed publications indexed in the Web of Science Core Collection database, which may not represent the entire body of literature on this topic. Therefore, these results should be interpreted with consideration of this limitation.

In conclusion, the relationship between the gastrointestinal microbiome and toxicity has become a research hotspot, with a substantial growth in annual publications indicating the global importance of this research field. China and the United States are the core competitive countries in this field. This research has identified the major researchers and institutions involved in this field globally. Science of the Total Environment is the most productive and core journal in this research area. Gastrointestinal microbiome and their relationships with metabolism, immune systems, and cancer treatments are considered hot topics, while environmental pollution and health may be the focus of future research. While we have discussed the potential for modifications to the gastrointestinal microbiome as new directions for treating and mitigating toxicity, we acknowledge the complexity of the underlying mechanisms. These complex interactions require further rigorous investigation. In summary, bibliometric analysis can provide valuable insights into the current state of toxicity and gastrointestinal microbiome research, highlight knowledge gaps, and identify potential future developments. These insights can guide future research directions, facilitate collaboration, and ultimately lead to the development of effective gastrointestinal microbiome intervention strategies for preventing and treating toxicity.

Publicly available datasets were analyzed in this study. This data can be found here: Web of Science™ (WOS, http://www.webofknowledge.com).

JD, CL, TJ, and XB analyzed the data, carried out the literature research, and wrote the manuscript. JD, CL, and XZ contributed to interpreting and discussing the results. TJ reviewed and edited before submission. All authors read and approved the final manuscript.