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Pain and Opioid-Induced Gut Microbial Dysbiosis.
Opioid-induced dysbiosis (OID) is a specific condition describing the consequences of opioid use on the bacterial composition of the gut. Opioids have been shown to affect the epithelial barrier in the gut and modulate inflammatory pathways, possibly mediating opioid tolerance or opioid-induced hyperalgesia; in combination, these allow the invasion and proliferation of non-native bacterial colonies. There is also evidence that the gut-brain axis is linked to the emotional and cognitive aspects of the brain with intestinal function, which can be a factor that affects mental health. For example, Mycobacterium, Escherichia coli and Clostridium difficile are linked to Irritable Bowel Disease; Lactobacillaceae and Enterococcacae have associations with Parkinson's disease, and Alistipes has increased prevalence in depression. However, changes to the gut microbiome can be therapeutically influenced with treatments such as faecal microbiota transplantation, targeted antibiotic therapy and probiotics. There is also evidence of emerging therapies to combat OID. This review has collated evidence that shows that there are correlations between OID and depression, Parkinson's Disease, infection, and more. Specifically, in pain management, targeting OID deserves specific investigations.
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Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut-brain communications.
Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn's disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain-gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.
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A randomized clinical trial examining the impact of LGG probiotic supplementation on psychological status in middle-aged and older adults.
Cognitive decline is common in older adults and more than 5 million Americans suffer from Alzheimer's disease (AD). A number of physiological processes including systemic inflammation, excess adiposity, and impaired glucoregulation arise from a combination of genetic and behavioral factors and increase risk for developing AD or other forms of dementia. Recent research suggests that the gut microbiome may moderate these pathological processes and possibly influence cognitive outcomes. This paper reviews the methodology for a double-blind, randomized clinical trial examining the influence of Lactobacillus GG (LGG) probiotic supplementation on mood and cognitive functioning in middle-aged and older adults. Our two primary hypotheses include: 1) Participants randomized to the probiotic group will show greater improvements in psychological status compared to participants in the placebo group; 2) Participants randomized to the probiotic group will show greater improvements in executive functioning and processing speed, as evidenced through performance on neuropsychological testing, than participants in the placebo group. We anticipate these results will inform future efforts on the feasibility of LGG probiotic supplementation as an intervention for psychological status and cognitive functioning and further elucidate the link between the gut microbiome and cognitive health.
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Protection against Neurological Symptoms by Consuming Corn Silk Water Extract in Artery-Occluded Gerbils with Reducing Oxidative Stress, Inflammation, and Post-Stroke Hyperglycemia through the Gut-Brain Axis.
Corn silk (Stigma maydis), rich in flavonoids, is traditionally used to treat edema, depression, and hyperglycemia and may alleviate ischemic stroke symptoms in Chinese medicine. This study examined whether corn silk water extract (CSW) could alleviate ischemic stroke symptoms and post-stroke hyperglycemia in Mongolian gerbils with transient cerebral ischemia and reperfusion (I/R). After being given 0.05% (I/R-LCSW) and 0.2% (I/R-HCSW), 0.02% aspirin (I/R-aspirin), and cellulose (I/R-control) in their 40 energy% fat diets for three weeks, the gerbils underwent an artery occlusion for eight minutes and reperfusion. They took the assigned diet for an additional three weeks. Sham-operated gerbils without artery occlusion had the same diet as Sham-control. CSW intake reduced neuronal cell death in gerbils with I/R and dose-dependently improved the neurological symptoms, including drooped eyes, crouched posture, flexor reflex, and walking patterns. CSW intake also alleviated the short-term memory and spontaneous alteration and grip strength compared to the I/R-control group. The protection against ischemic stroke symptoms was associated with the reduced tumor necrosis factor-α, interleukin-1β, superoxide, and lipid peroxide levels, promoting superoxide dismutase activity in the hippocampus in the CSW groups, compared to the I/R-control. The blood flow measured by Doppler was improved with CSW compared to the I/R-control. Furthermore, CSW intake prevented the post-stroke hyperglycemia related to decreasing pancreatic β-cell mass as much as the Sham-control, and it was related to protection against β-cell apoptosis, restoring the β-cell mass similar to the Sham-control. CSW intake elevated the relative abundance of Lactobacillus, Bifidobacterium, Allobaculum, and Akkermansia compared to the I/R-control. Picrust2 analysis showed that CSW increased the propionate and butyrate metabolism and the starch and glucose metabolism but reduced lipopolysaccharide biosynthesis compared to the I/R-control. In conclusion, CSW intake protects against neuronal cell death and post-hyperglycemia by reducing oxidative stress and inflammation and increasing blood flow and the β-cell mass. The alleviation was associated with promoting the gut-brain axis by changing the gut microbiome community.
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Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression- and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner.
Methamphetamine (Meth) abuse can cause serious mental disorders, including anxiety and depression. The gut microbiota is a crucial contributor to maintaining host mental health. Here, we aim to investigate if microbiota participate in Meth-induced mental disorders, and the potential mechanisms involved. Here, 15 mg/kg Meth resulted in anxiety- and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor (SIGMAR1)/BDNF/TRKB pathway in the hippocampus. Meanwhile, Meth impaired gut homeostasis by arousing the Toll-like receptor 4 (TLR4)-related colonic inflammation, disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids (SCFAs). Moreover, fecal microbiota from Meth-administrated mice mediated the colonic inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated the anti-anxiety and -depression effects of SCFAs. The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety- and depression-like behaviors. Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis, and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner. This study confirms the crucial role of microbiota in Meth-related mental disorders and provides a potential preemptive therapy.
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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.