Background

The human gastrointestinal flora is an essential organ that plays an important role in gastrointestinal and overall health. Understanding of this organ has evolved significantly over the past decades due to the large quantity of impactful research on the gastrointestinal microbiome.

Since the 1990s, the development of culture independent molecular methods, including 16S ribosomal RNA (16S rRNA) gene sequencing and metagenomic sequencing methods, has allowed for quantitative analysis of the composites of gut microbiome and provided a better understanding of its variation and function. 16S rRNA genes are bacteria’s small subunit molecules that include both conserved and variable regions that allow designing probes or primers to detect and identify bacteria, and specify a phylum, a group, a genus, or even a species [1]. This technique has increased previous culture-based estimates of 200–300 colonic species to 15,000–36,000 individual species [2]. Metagenomic sequencing represents a powerful alternative to rRNA sequencing, it utilizes taxonomically informative gene tags to target and amplify genomes of interest, analysis of this data allows researchers to determine the composite and function of different microbiomes, it is widely used for global characterization of the genetic potential of ecologically complex environments [3, 6]. The majority of the colonizing microbes reside in the gut. Previous study revealed that there is a functional core conserved in each individual, which represents the full minimal human gut metagenome that is required for the proper functioning of the gut ecosystem. The human gut ecosystem includes important beneficial functions, such as: fermentation of dietary fibers into short-chain fatty acid (SCFA) which counts up to 10% of the human energy source, degradation of complex polysaccharides, and synthesis of indispensable vitamins and amino acids [6,7,8]. The gut flora also produce multiple metabolites that function in protecting epithelial lining integrity, stimulating intestinal angiogenesis, and regulating immune response [9,10,11]. These reflect that gut flora are not just commensal with human hosts, there is mutualism in the relationship between them.

Sampling is a key step for studies on gut microbiome. A significant number of studies are human based, while most others are mice based. Fewer studies were performed on gut microbiota from tissue samples, while most others were performed on fecal microbiota. In different regions of the gastrointestinal tract, the composition and luminal concentrations of dominant microbial species vary; the distal ileum, cecum, and colon are the most common sites for tissue sample harvesting due to high quantity and variety of gut flora in these regions [3, 12, 13]. Fecal samples are often used to investigate mucosa-associated microbiota because they are easy to collect, noninvasive, are approved to be a reproducible and relevant source of biomarkers [1]. But there is still concern that the fecal microbiota may represent a combination of shed mucosal bacteria and a separate nonadherent luminal population, thus making the result less reliable [13].

Over 98% of the gut microbiota is composed of four phyla of bacteria: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. The dominant majority are from either Firmicutes or Bacteroidetes [2, 13]. Gut microbiota composition varies based on sampling region. Research has revealed that the Bacillus subgroup of Firmicutes and Actinobacteria are more prevalent in the small intestine, while Bacteroidetes and Lachnospiraceae are more prevalent in the colon [2]. Human gut microbiome is more similar among family members than unrelated individuals; intra-personal differences are minor compared to inter-personal differences in gut microbiota, indicating short term environmental change does not play a major part in microbiota composition [14].

The proper interaction between host gut mucosa and gut microbiota is important in maintaining mucosal homeostasis. The gut microbiota is proposed to shape host immunity and host immunity functions via secreting molecules that protect the mucosal barrier integrity, proper secretion of luminal antimicrobial peptides and immunoglobulins, down-regulation of innate and adaptive immune responses to commensal bacteria, and elimination of translocated bacteria across epithelial barrier [8, 11, 15]. Mucosal homeostasis is key to both host and gut flora and can be disrupted in dysbiosis causing chronic intestinal inflammation.

CiteSpace is an application designed to generate and analyze networks of co-cited references based on bibliographic database [16]. We employed this method to analyze trends and hotspots of global publications on gastrointestinal microbiome between 1998 and 2018.

Methods

We obtained a record of 2891 manuscripts published between 1998 and 2018 from the Web of Science Core Collection (WoSCC) of Thomson Reuters; this record was obtained on June 23, 2018. The WoSCC is the most frequently used source of scientific information. We used the term “Gastrointestinal Microbiomes” and all of its hyponyms to retrieve the record, and restricted the subjects to gastroenterology and hepatology. We then derived a clustered network from 70,169 references that were cited by the 2891 manuscripts, and identified 676 top co-cited articles. Next, we used the bibliometric method, CiteSpace V, and VOSviewer 1.6.8 to identify top authors, journals, institutions, countries, keywords, co-cited articles, and trends.

Results

Distribution of articles by publication years

Between 1998 and 2018, 2891 original research articles were published. There was an increasing trend for quantity of research publications on gastrointestinal microbiome (Fig. 1). The number of published articles on gastrointestinal microbiome steadily increased from 1998 through 2009, and then the number of publications significantly increased from 2010 onwards, with the number of publications almost doubled in 2014 compared to 2010. During 2016 through 2017, the activity in gut microbiome research reached a peak.

Fig. 1
figure 1

Trends in the number of scholarly publications on gastrointestinal microbiome research from 1998 to 2018

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Journal analysis

The total number of journals that published the 2891 articles on gastrointestinal microbiome was 112. The characteristics of the 10 most active journals and the main ideas of their representative articles are shown in Table 1 [1, 17,18,19,20,21,22,23,24,25]. All the publishers of the journals are located in either the United States of America or the United Kingdom. Digestive Diseases and Sciences published the greatest number of articles on gut microbiome, followed by World Journal of Gastroenterology and Gut. Regarding impact factor, Gastroenterology has the highest impact factor, followed by Gut and Alimentary Pharmacology Therapeutics.

Table 1 Top 10 journals that published articles on gastrointestinal microbiome
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Country and institution analysis

The 2891 articles on gastrointestinal microbiome research were published by research groups in 41 countries/regions. The top 10 countries (6 European countries, 2 Asian countries, and 2 North American countries) published 2692 articles, accounting for 93.12% of the total number of publications. The leading country was the United States, which took up 31.92% (923/2891) of the total, the next 2 high production countries were Italy and the People’s Republic of China, which took up 10% and 8% of the total, respectively. There were more than 370 research institutions that published articles related to gut microbiome. The leading research institution with the highest number of publications was the University of North Carolina, which had 64 articles with the strongest citation burst from 2003 to 2011, followed by Harvard University (53 articles), Mayo Clinic (41 articles), French National Institute for Agricultural Research (40 articles), and Massachusetts General Hospital (39 articles).

Keyword co-occurrence cluster analysis of research hotspots

VOSviewer keyword analysis of the 2891 articles identified 274 keywords with a minimum of 20 occurrences and divided them into 5 clusters (Gut microbiota, IBD, probiotics, double-blind, and irritable bowel syndrome) (Fig. 2).

Fig. 2
figure 2

Map of keyword clustering showed 274 keywords with a minimum of 20 occurrence and divided into 5 clusters

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Top co-cited articles analysis

The clustered network is derived from 70,169 references (including duplicates) that were cited by the 2891 articles. The clustered network of gastrointestinal microbiome is demonstrated in this part. Citation reference knowledge maps consist of references with higher centrality and citation counts. Visualization of co-cited articles showed a total of 676 nodes and 1427 links (Fig. 3a). Each node represents a cited article. The area of each node is proportional to the total co-citation frequency of the associated article.

Fig. 3
figure 3

a Co-citation map of authors on clustered network of gut microbiome; b clustered network of co-cited articles on gut microbiome and their sub-networks

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The top 10 co-cited articles, their cited frequency, and cited half-year life are shown in Table 2. Sokol [12] in PNAS had the highest number of citations (168 citations), followed by Caporaso [17] in Nature Methods (163 citations), and Qin [6], and expression of antibacterial peptide; causing microbiota remodeling; lower serum endotoxin; etc. [36, 37]. Studies suggested that A. muciniphila abundance is inversely correlated with obesity, metabolic syndrome, IBD, and acute appendicitis [38,39,40,41]. Recent study also suggests an association between A. muciniphila abundance and clinical response to PD-1-based immune check-point inhibitors [42]. Supplementation of A. muciniphila to mice gut has been shown to be protective against development of obesity, type 1 and type 2 diabetes, atherosclerosis, and poor response to the antitumor effects of PD-1 blockade [36, 38, 42,43,44]. Ongoing research is further investigating A. muciniphila as a therapeutic tool in the management of multiple diseases.

Intestinal microbiota-host interaction has been shown to play a role not only in gastrointestinal diseases, but also in extra-gastrointestinal diseases [45, 46]. Studies have shown correlation between intestinal microbiome and extra-gastrointestinal malignancy and its response to immunotherapy [47, 48], atherosclerotic cardiovascular disease. Wang et al. and Tang et al. [49, 50] psychiatric diseases including mood disorders, schizophrenia, and autism spectrum disorder [51,52,53,54,55], neurologic diseases including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis [56,57,58], metabolic disorders including diabetes [59, 60], allergic/immunologic diseases including asthma, systemic lupus erythematosus, autoimmune arthritis, and inflammatory skin diseases [58, 61,62,63]. Targeting the gut microbiome dysbiosis to intervene in the underlying pathogenesis might be the new therapeutic approach for diseases of multiple systems.

Compared to traditional reviews, analysis based on Citespace provides a better insight of the evolving research foci and trends, but it comes with certain limitations. Similar words need be merged together during the analysis; even though only original articles were included in the majority of analysis, all article types were included during the co-cited reference analysis.

Conclusions

There is no doubt that our understanding of gut microbiome has significantly advanced via bursts of high quality research occurring over the past 20 years. With the help of information visualization, we were able to identify research foci and overall trends in the field and offer gathered information to future researchers. We believe gut microbiota is associated with the pathogenesis of significantly more diseases than we currently know of. The emerging new therapeutic targets in gut microbiota would be the foci of future research.