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Neurotransmitter-mediated gut-brain axis: a bibliometric analysis of research trends and knowledge structure.
INTRODUCTION: The gut-brain axis constitutes a bidirectional network linking the gastrointestinal tract and central nervous system through neural, endocrine, metabolic, and immune pathways. Neurotransmitters play a central role in mediating this crosstalk, serving as intermediates through which the gut microbiota influences brain function. Although important mechanistic advances have been made, research on the neurotransmitter-mediated gut-brain axis remains fragmented across disciplines. This study aimed to provide a comprehensive bibliometric overview of this field. METHODS: We conducted a bibliometric analysis of 788 publications retrieved from Web of Science, Scopus, and PubMed between 2005 and 2025. Using VOSviewer, CiteSpace, and Pajek, we analyzed publication trends, geographic distribution, institutional and author contributions, journal co-citations, and keyword evolution to characterize the knowledge structure and emerging themes of the field. RESULTS: The results revealed three developmental phases: an exploratory phase (2005-2016) with limited output, a developmental phase (2017-2019) with moderate growth, and a rapid expansion phase (2020-2025) marked by exponential increases in publications driven by advances in microbiome and neurotransmitter research. China led in publication volume, while the United States and Ireland served as major hubs of collaboration. University College Cork showed the highest citation impact, with 10,935 citations from 28 publications (average citations per document = 390.54). John F. Cryan, Timothy G. Dinan, and Gerard Clarke were among the leading contributors, with Cryan ranking first in both publication output and citation count. Keyword and thematic analyses identified gut microbiota, serotonin, short-chain fatty acids, depression, and inflammatory bowel disease as core topics, reflecting a shift from mechanistic studies to disease-specific and neurotransmitter-targeted research. Highly cited studies focused on microbial regulation of neurotransmitters, neuroimmune signaling, and their implications for neurodevelopmental and neurodegenerative disorders. DISCUSSION: This study provides the first comprehensive bibliometric overview of neurotransmitter-mediated gut-brain axis research, offering a macroscopic perspective on its evolution, core knowledge base, and emerging frontiers. Future research should integrate multidisciplinary approaches, apply omics technologies, and develop precision interventions targeting neurotransmitter pathways while considering individual microbial profiles, in order to translate mechanistic insights into therapeutic strategies for neuropsychiatric disorders.
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Lanzhou Lily (Lilium davidii var. unicolor) Extract Alleviates Chronic Stress-Induced Mood Disturbances by Suppressing Neuroinflammation and Modulating the Gut-Brain Axis in Mice.
Chronic stress is a major contributor to mood disturbances through dysregulation of the gut-brain axis and neuroinflammatory responses. Lilium davidii var. unicolor (Lanzhou lily), a traditional medicinal and edible plant, contains bioactive compounds with anti-inflammatory potential. This study investigated the effects of Lanzhou lily extract (LLE) on chronic restraint stress (CRS)-induced behavioral and physiological changes in mice. LLE improved CRS-induced anxiety- and depression-like behaviors, reduced microglial activation in the hippocampus, and suppressed TLR4/MyD88/NF-κB signaling and downstream cytokine release (TNF-α, IL-6, IL-1β). LLE also restored intestinal barrier integrity, decreased serum LPS levels, and modulated gut microbiota composition by enriching Ligilactobacillus murinus and Muribaculum intestinale while reducing Prevotella abundance. Correlation analysis linked microbial restoration with barrier protection and reduced neuroinflammation. UHPLC-Q-Exactive Orbitrap-MS/MS analysis tentatively identified multiple constituents of LLE, including dioscin, matrine, timosaponin AIII, and catechin. Previous studies have suggested that some of these compounds may possess neuroprotective or antidepressant-related activities. These findings suggest that Lanzhou lily extract may modulate the gut-brain axis and exert antidepressant-like effects in a preclinical stress model, warranting further investigation in clinical studies.
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Epigenetic and microbiome responses to greens supplementation in obese older adults: results from a randomized crossover-controlled trial.
Aging is influenced by genetic, environmental, and lifestyle factors. Preliminary studies suggest that fruit and vegetable-based dietary supplements may reduce inflammation and oxidative stress, key factors in aging. Greens-based supplements typically contain concentrated extracts of leafy greens, fruits, vegetables, and bioactive phytochemicals, providing micronutrients and polyphenols that may influence aging-related pathways. This exploratory study evaluated the effects of a 30-day greens-based supplement on epigenetic markers of aging and metabolic health in adults aged 50-65 years with body mass index (BMI) >30 kg/m2, using a 60-day randomized crossover design. Participants were randomized to immediate or delayed supplementation. During the 30-day intervention period, participants consumed a daily greens supplement. Primary outcomes included peripheral blood mononuclear cell DNA methylation and epigenetic age (Horvath, PCGrimAge, AdaptAge, and DamAge). Secondary measures included clinical metabolic biomarkers, microbiome diversity, breath hydrogen and methane, body composition, actigraphy, dietary intake, and quality of life questionnaires [RAND 12 item short form questionnaire (SF-12), and 21-item Depression, Anxiety, and Stress Scale (DASS-21)]. Twenty-one participants began the protocol (65% female, mean age 58.4 ± 5.3 years, mean BMI 38.1 ± 8 kg/m2). Nineteen participants completed the study. Horvath clock data indicated that biological age paradoxically increased during the supplementation period, whereas newer-generation clocks (AdaptAge, DamAge) demonstrated trends toward improved outcomes. Gut microbiome alpha diversity remained stable; taxa of interest, including Bilophila (p = 0.037) and Desulfobacterota (p = 0.031) changed with supplementation. Body composition, metabolic biomarkers, dietary intake, breath gases, sleep, and psychosocial measures were unchanged during the study. Exploratory pre-to-post supplementation change score correlations found no significant associations between epigenetic clocks and secondary outcomes, except for an inverse relationship between Faith's phylogenetic diversity and fasting blood glucose (r s = -0.81, p < 0.001). In summary, 30 days of greens-based supplementation led to selective changes in epigenetic aging markers and individual gut microbial taxa, without significant effects on overall microbiome diversity, metabolic health markers, or body composition. Additionally, exploratory correlations suggest potential links between changes in microbial diversity and glycemic control following greens supplementation.
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Tuina for chronic fatigue syndrome: study protocol for a randomized controlled trial integrating tryptophan metabolism, gut microbiota, and brain network alterations.
BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling multisystem disorder characterized by persistent fatigue, post-exertional malaise, unrefreshing sleep, and neurocognitive and gastrointestinal symptoms. Effective non-pharmacological treatments remain limited. Increasing evidence suggests that CFS involves not only peripheral metabolic and gastrointestinal abnormalities but also central nervous system dysfunction. Altered tryptophan metabolism and gut-brain axis dysfunction may contribute to its pathophysiology. Tuina, a manual therapy used in traditional Chinese medicine, has been hypothesized to influence somatosensory, autonomic, stress-related, and gastrointestinal pathways. However, randomized controlled trials evaluating its clinical effects and exploratory gut-brain correlates in CFS remain scarce. METHODS: This multicenter, parallel-group, randomized controlled trial will enroll 166 participants with CFS, who will be allocated in a 1:1 ratio to a Tuina group or a standardized usual care group. The Tuina group will receive treatment twice weekly for 8 weeks, whereas the control group will receive standardized usual care consisting of health education and symptom-oriented management. The primary objective is to evaluate the effectiveness of Tuina on fatigue severity, assessed by the change in Fatigue Scale-14 (FS-14) score from baseline to week 8. Secondary outcomes include quality of life, sleep, pain, anxiety, depression, gastrointestinal symptoms, bowel function, and handgrip strength. Exploratory mechanistic outcomes include plasma tryptophan-pathway metabolites, gut microbiota profiling, resting-state functional magnetic resonance imaging, and magnetic resonance spectroscopy. Assessments will be conducted at baseline, weeks 4 and 8, and at 12 and 24 weeks after completion of treatment. DISCUSSION: This study is designed to evaluate the clinical effects of Tuina in CFS while exploring a biologically informed gut-brain framework involving tryptophan metabolism, gut microbiota, and brain network alterations. To our knowledge, few randomized trials in CFS have prospectively integrated clinical, metabolomic, microbiome, and multimodal neuroimaging measures within a single protocol. The findings may help clarify whether a non-pharmacological intervention can modulate interconnected peripheral and central pathways relevant to fatigue and related symptoms. CLINICAL TRIAL REGISTRATION: https://itmctr.ccebtcm.org.cn/mgt/project/view/1990257056896122880, Identifier ITMCTR2025002204.
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Lactobacillus paragasseri OLL2809 Improves Depression-Like Behavior and Increases Beneficial Gut Microbes in Mice.
Lactobacillus paragasseri OLL2809 is a probiotic bacterial strain isolated from healthy human feces. While OLL2809 has been studied for its immunomodulatory activities, its effect on depressive-like behaviors remains unclear. In this study, we used a mouse model of social defeat stress (SDS) to investigate whether oral administration of OLL2809 ameliorates depressive-like behavior. C57BL6 male mice were administered OLL2809 for 2 weeks following a 4-week period of SDS. Although OLL2809 did not affect serum corticosterone levels, it ameliorated depression-like behaviors, and it induced neurite outgrowth in the hippocampal dentate gyrus. The 16S rRNA amplicon sequence analyses revealed that family level gut microbiota composition was affected by stress and OLL2809 administration. Additionally, Akkermansia muciniphila, Bifidobacterium, and Lactobacillus were significantly increased by OLL2809 treatment. LEfSe analysis suggested that the antidepressive effect of OLL2809 may be mediated by increases in other microorganisms, such as Erysipelotrichaceae uncultured. Our findings suggest that L. paragasseri OLL2809 may have potential in microbiome therapeutics.
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The microbiota-gut-brain axis in stress and depression.
Humans and animals are evolved to have instinctive physiological responses to threats. The perception of threat by the brain triggers a multitude of changes across the brain and body. A large body of research have demonstrated that our hardwired survival instinct, the stress response, can become maladaptive and promote major depressive disorders and other neuropsychiatric impairments. However, gaps in our understanding of how chronic stress contributes to depression and mental disorders suggest that we also need to consider factors beyond the biology of the host. The unravelling of the structure and function of microorganisms that humans and animals are host to have driven a paradigm shift in understanding the individual as a collective network composed of the host plus microbes. Well over 90% of bacteria in the body reside in the large intestines, and these microbes in the lower gut function almost like an organ in the body in the way it interacts with the host. Importantly, bidirectional interactions between the gut microbiota and the brain (i.e., the two-way microbiota-gut-brain axis) have been implicated in the pathophysiology of mental disorders including depression. Here, in summarizing the emerging literature, we envisage that further research particularly on the efferent brain-gut-microbiota axis will uncover transformative links in the biology of stress and depression.
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Mental health and periodontal and peri-implant diseases.
Mental health disorders, particularly depression and anxiety, affect a significant number of the global population. Several pathophysiological pathways for these disorders have been identified, including the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and the immune system. In addition, life events, environmental factors, and lifestyle affect the onset, progression, and recurrence of mental health disorders. These may all overlap with periodontal and/or peri-implant disease. Mental health disorders are associated with more severe periodontal disease and, in some cases, poorer healing outcomes to nonsurgical periodontal therapy. They can result in behavior modification, such as poor oral hygiene practices, tobacco smoking, and alcohol abuse, which are also risk factors for periodontal disease and, therefore, may have a contributory effect. Stress has immunomodulatory effects regulating immune cell numbers and function, as well as proinflammatory cytokine production. Stress markers such as cortisol and catecholamines may modulate periodontal bacterial growth and the expression of virulence factors. Stress and some mental health disorders are accompanied by a low-grade chronic inflammation that may be involved in their relationship with periodontal disease and vice versa. Although the gut microbiome interacting with the central nervous system (gut-brain axis) is thought to play a significant role in mental illness, less is understood about the role of the oral microbiome. The evidence for mental health disorders on implant outcomes is lacking, but may mainly be through behaviourial changes. Through lack of compliance withoral hygiene and maintenance visits, peri-implant health can be affected. Increased smoking and risk of periodontal disease may also affect implant outcomes. Selective serotonin reuptake inhibitors have been linked with higher implant failure. They have an anabolic effect on bone, reducing turnover, which could account for the increased loss.
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The Influence of Probiotic Supplementation on the Severity of Anxiety and Depressive Symptoms; Function and Composition of Gut Microbiota; and Metabolic, Inflammation, and Oxidative Stress Markers in Patients with Depression-A Study Protocol.
This article aims to present the theoretical basis, methodology, and design of a clinical trial we will conduct. The study will be prospective, randomized, placebo-controlled, and double-blind. Each intervention period will last 8 weeks and the trial will be conducted on 100 patients in total, who will be randomly divided into two groups consisting of 50 patients each. We plan to investigate the impact of Lactobacillus helveticus Rosell and Bifidobacterium longum Rosell on the depressive, anxiety, and stress levels in patients with depressive disorders with possible comorbid anxiety. In addition to assessing the influence of probiotics on the clinical condition, we also plan to study the clinical and biochemical parameters of metabolic syndrome, which often coexists with depression. Both depressive and metabolic issues may have part of their etiopathology in common, e.g., inflammation, oxidative stress, and dysbiosis. This is why we will additionally investigate the parameters related to gut microbiota, inflammatory, and oxidative statuses. Thus, the primary endpoint of the study will be the change in depression score measured with the Montgomery-Åsberg Depression Rating Scale. The secondary endpoints will include changes in anxiety and stress levels, as well as metabolic, inflammation, and oxidative stress parameters.
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Current state of nutritional psychiatry: A scoping review of randomized controlled trials.
BACKGROUND: Nutritional psychiatry is a rapidly expanding field of research, with mounting evidence suggesting that nutritional factors may play a role in the development of psychiatric disorders. AIM: To examine the level of evidence for nutritional psychiatry. METHODS: A scoping review was conducted to assess the current state of nutritional psychiatry, including a search for randomized controlled trials (RCTs). RESULTS: The review identified a total of seven papers, with many concentrating on the relationship between depression and the gut microbiome. A salient issue that emerged from this review was the paucity of sample size in many studies. The inherent complexity of nutritional studies, characterized by a multitude of potential factors and exposures that often act as confounders, poses significant challenges to the development of effective RCT designs. The analysis revealed that probiotics, though demonstrating efficacy, exhibited a modest effect size. CONCLUSION: Conducting RCTs with effective markers is imperative from these studies. The implementation of Mendelian randomization and the investigation of mechanisms in basic research are essential complementary approaches.
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Lactobacillus maintains IFNγ homeostasis to promote behavioral stress resilience.
The gut microbiome consists of the trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea , has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, for the first time, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea . Using this novel microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFNγ levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and give novel methods to study potential therapies developed to treat mood disorders.