In this study, we analyzed the main knowledge domain and emerging trends in research linking the MGBA to depression using bibliometric analysis. Some landmark articles were also identified using this analysis (Fig. 10). We analyzed a total of 829 publications found in WoSCC, and we present a comprehensive overview of the worldwide hotspots and trends in research linking the MGBA with depression over the past three decades. The retrieval years were from 1994 to 2022, but the first relevant literature appeared in 2009.
Our analysis revealed the rapid growth in the number of publications since 2014 and the close international scientific cooperation in this field. The People's Republic of China, University College Cork, and John F. Cryan were the most influential country, institute, and scholar, respectively. China was the most productive country (192 published articles, cited 4,267 times), with Chongqing Medical University being the main representative institute. The team of Peng Xie from this institution contributed the most publications, with the latest research focus being on proteomics research of the gut-brain axis in a gut microbiota-dysbiosis model of depression, which found that protein changes of the gut-brain axis were involved in energy metabolism and inflammatory responses. Ireland is the most cited country, with 4 of the top 5 co-cited authors coming from this country, with the University College Cork being the main representative (64 published articles, cited 7,334 times). John F. Cryan is a leader at this institution, who has devoted his work to the study of the links between the MGBA and depression for nearly 20 years. His latest research supported the development of lifestyle-oriented adjunct therapies for depression, including physical activity and special diets. Modulation of the composition of the immune system and gut microbiota in combination with traditional antidepressants is a promising treatment option[22, 23].
Journal analysis and co-cited journal analysis can identify the most popular journals for scholars in the field and help researchers select appropriate journals for article submission. BRAIN BEHAV IMMUN and NUTRIENTS were the most productive and co-cited journals. Most leading-edge results and major breakthroughs in the research field of MGBA-depression connections have been published in these 2 journals. The BRAIN BEHAV IMMUN journal focuses mostly on psychobehavioral research, such as neuroimmunity, depression, and anxiety, and in recent years, on the vagus nerve, the pathway through which neuro-immune signals travel from the gut to the brain[24, 25]. Work published there also poses new questions and suggests new research directions, such as the idea that the normal gut microflora is important for maintaining a normal immune response, as well as a balanced intestinal mucosa, by inducing the natural immune defense of the host and inhibiting pathogen adhesion to mucosal cells. FMT can improve depression-like behaviors induced by chronic unpredictable mild stress. Such anti-depression effects were associated with the suppressed activation of glial cells and the NLRP3 inflammasome in the brain. Although a clinical study  has reported that FMT intervention improved depressive symptoms, the possibility of symptom recurrence following FMT may be very high, and afterwards, the FMT microflora may affect the activity of the vagus nerve, causing nerve inflammation, and resulting in worse nervous and mental symptoms. To date, no studies have examined the effects of post-FMT vagus blocking in human patients to investigate the combined efficacy of FMT and vagus blocking; therefore, it may be interesting to explore this new treatment for depression. On the other hand, the journal NUTRIENTS focuses mainly on the effect of diet on anxiety and depression. An article published in NUTRIENTS found that dietary regulation of the gut microbiota is a new method to relieve mood disorders. The widespread use of magnetic resonance imaging (MRI) provides an ideal way to study gut-brain interactions in vivo. The gut microbiota is involved in myelin formation of prefrontal cortex neurons and participates in the development of the amygdala and the hippocampus. Eating patterns that have positive effects on mental health facilitate the growth of beneficial bacteria, while limiting the growth of the pathogenic flora, and they affect the permeability and inflammatory status of the intestinal barrier. Thus, diet is an important variable in the relationship between the bowel and neurological disease.
The results of our analysis on keyword co-occurrence indicated frontier topics or emerging trends, including depression, the gut-brain axis, and anxiety. Furthermore, many keywords associated with areas of research related to MGBA-depression connections have appeared in recent years, including IBS, Parkinson’s disease, and anorexia nervosa. We found that the keyword “gut-brain axis” appeared in 2009 and the keyword “IBS” had the highest burst strength. The study of the effects of the gut microbiome on behavior and neurobiology, known as the MGBA, began with observations on patients with IBS. IBS is characterized by abdominal pain and changes in bowel habits. Although the exact etiology of IBS remains unknown, multiple pieces of evidence suggest that inflammation and cytokine imbalance may be a potential etiology of IBS. Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, characterized by tremors and bradykinesia , and its main pathological features are the loss of substantia nigra dopaminergic neurons and the formation of Lewy bodies . Stolzenberg et al. found that the expression of α-synuclein in the enteric nerves of the upper gastrointestinal tract in PD patients was positively correlated with the degree of intestinal wall inflammation . α-Synuclein is transferred to the CNS via the vagus nerve, leading to the development of PD. Approximately 80% and 75% of patients with anorexia nervosa suffer from major depression and anxiety, respectively, and anorexia nervosa patients with psychiatric comorbidities have a higher mortality rate than patients without such comorbidities[35, 36]. The HPA axis plays an important role in the pathogenesis of anorexia nervosa. Matsuwaki T et al. intraperitoneally injected lipopolysaccharide (LPS), an Escherichia coli metabolite, into IL-1 receptor-knockout mice, and observed that the HPA axis was activated and the mice exhibited anorexia.
With the development of research on the links between the gut-brain axis and depression, some emerging research topics are gradually attracting the attention of researchers, such as "neuroinflammation", "cytokines", "corticotropin-releasing factor", and "central nervous system". Research has revolved around the role of the MGBA in the development and progression of depression. Li et al.  transplanted the microbiota of chronic unpredictable mild stress (CUMS) mice into GF mice and found that the levels of interferon -γ (IFN-γ) and tumor necrosis factor -α (TNF-α) in the hippocampus of mice were significantly increased, accompanied by an upregulation of indoleamine 2, 3-dioxygenase 1 (IDO1). Studies have shown that the gut microbiome regulates the levels of proinflammatory cytokines in the hippocampus and exacerbates depression-like behavior through a dysfunctional MGBA. More than 50% of depressed patients have dysregulated negative feedback control of the HPA axis, resulting in increased levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) . Under stress, the impaired function of the HPA axis in GF rats can be improved by transplantation of a normal gut microbiome . Probiotics have a positive effect on depression-like behavior by changing the activity of the HPA axis. Mice treated with Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 not only showed improvement of depression-like behaviors, but also had significantly reduced plasma CORT levels . Neurotransmitters such as GABA, norepinephrine, and dopamine, and metabolites of intestinal microorganisms may directly affect CNS function by activating the stress circuit through down-down signals such as the vagus nerve pathway.
According to reference co-citation network analysis, interesting research themes included “gut-brain axis”, “maternal separation”, “post-genomics diagnositics”, “vagus”, and “psychobiotics”, which formed an important basis for studies in this field. Maternal separation (MS) has been developed as a model for inducing stress and depression in studies using rodents. Probiotic bacteria have antidepressive effects, and are presently considered as psychobiotics with preventive and therapeutic potential for the treatment of neurological and neurophysiological disorders. Lactobacillus casei, Lactobacillus acidophilus, and Bifidobacteria are known as the "three healthy beneficial bacteria". Liao J. E. et al. found that Lactobacillus paracasei PS23 reduced early-life stress abnormalities in a maternal separation mouse model. Lacticaseibacillus paracasei NK112 mitigated Escherichia coli-induced depression and cognitive impairment in mice by regulating IL-6 expression and the BDNF-TrkB signal pathway. Tian P. J. et al. proposed that Bifidobacterium brevis CCFM1025 regulated the gut microbiome and tryptophan metabolism, having antidepressant effects[50, 51]. The vagus nerve plays an important role in the gut-brain axis interaction. Bravo J. A. et al. found that after the administration of Lactobacillus rhamnosus in healthy mice, anxiety- and depression-like behaviors were reduced in the mice, and the expression of GABA receptors in the brain changed. However, these effects of Lactobacillus rhamnosus were significantly reduced after vagus nerve resection.
In recent years, increasing attention is paid to some emerging research fields. Many studies have shown that traditional Chinese medicine can improve depression symptoms by regulating the gut microbiota. Xiaoyaosan improves depressive symptoms by modulating the gut microbiota and inhibiting the overactivation of the NLRP3 inflammasome in the colon. Kaixinsan alleviated depressive symptoms by modulating the gut-brain axis, improving the intestinal microenvironment and inhibiting neuroinflammation and activation of the HPA axis in the brain of CUMS model mice. Baihe Jizihuang Decoction attenuated CUMS-induced depression-like behavior by regulating BDNF and intestinal flora disorder through the gut-brain axis. In addition, Yu et al. found that paeoniflorin can be converted into benzoic acid by the intestinal flora and enter the brain through the blood-brain barrier, where it exerts an antidepressant effect. Sun et al. found that schisandrin could alleviate the disturbance of the intestinal flora in depressed mice, change SCFA, and reduce the level of pro-inflammatory factors. It is worth mentioning that the VNS is a non-drug treatment, which constitutes an FDA-approved somatic treatment for treatment-resistant depression (TRD), and can produce clinically significant antidepressant effects (12). Anatomical studies suggest that the ear is the only place on the surface of the human body where there is afferent vagus nerve distribution. A non-invasive transcutaneous vagus nerve stimulation (taVNS) method has been developed. In 2013, HEI conducted the first taVNS clinical trial for depression, which was found to have antidepressant effects and could be used as an alternative treatment. Subsequent studies have found that taVNS can regulate the gastrointestinal, immune, and endocrine systems through the MGBA, rendering it an effective depression treatment. Subsequently, Rong P. et al. observed that this therapeutic mechanism may be related to the modulation of brain default mode network (DMN). The reward and salience networks seem to be closely related[59, 60].
Although we do not fully understand the interaction between the MGBA and depression, a number of tools and animal models can help narrow the gap in our understanding of the MGBA. Numerous studies over the past decade have demonstrated that targeting the gut microbiome improves depressive symptoms, and as research continues, the field is shifting to the biological basis for such neurobiological effects. FMT is a technique establishing a donor-like microbiome in the recipient's gastrointestinal tract, and can generate strong inferences about the causal relationship between the gut microbiome and host outcomes. The GF animal model can further help us understand the relationship between microbes and the host. In addition, the flexibility and relevance of antibiotics make them a very valuable tool for studying the MGBA. The emergence of brain imaging techniques has provided conclusive evidence of a link between the gut and the activation of key brain networks. Metabolic models of the microbiome use experimental data, and their ability to generate big data can provide valuable insights into MGBA interactions.
Our research has some limitations. First, publications were retrieved only from the WoSCC database, and although we enriched the search strategy as much as possible, we cannot guarantee that all relevant articles were identified. Second, in some cases, different keywords may have the same meaning, for example, "brain-gut axis” and “gut-brain axis” or "intestinal flora” and “gut microbiota”. Thus, bias may still exist despite our normalization. Third, the conclusions obtained in this study using visualization and analysis software such as citespace and VOSviewer require further analysis in the future.