Background/Objectives: Accumulating evidence and clinical observations suggest that the gut microbiome plays a crucial role in functional dyspepsia (FD). However, the precise characterization of this relationship is unclear. This systematic review and meta-analysis aimed to elucidate the potential role of the gut microbiome in FD based on evidence from published clinical studies. Methods: A comprehensive search of three databases (PubMed, Google Scholar, and Web of Science) was conducted, and 17 relevant clinical studies, including 8 observational studies and 9 interventional studies, published up to September 2025, were identified. Data on the gut microbiome and FD were extracted and subjected to meta-analysis. Results: Meta-analysis revealed no significant differences in gut microbiota α- or β-diversity between patients with FD and healthy controls (Shannon index: standardized mean difference [SMD] = -0.12, 95% confidence interval [CI] -0.90 to 0.67, I2 = 88%). In contrast, effective interventions induced notable shifts in the microbial community structure (pooled SMD = 0.27, 95% CI -0.28 to -0.83, I2 = 58%). These shifts were accompanied by increased short-chain fatty acid (SCFA) production and intestinal tight-junction protein levels, which coincided with improved FD symptoms. Conclusions: Although no significant differences in the gut microbiota were detected between patients with FD and healthy controls, interventions in patients with FD induced marked changes in the microbial community. Modulation of gut microbiota-related metabolites, such as SCFAs, may represent a promising therapeutic strategy for the management of FD.

Galgeun-tang (GGT) is a traditional multi-component botanical formulation widely consumed in East Asia. However, its preventive effects against diet-induced metabolic dysfunction remain incompletely understood. This study evaluated the preventive potential of GGT on high-fat diet (HFD)-induced metabolic dysfunction model, with a focus on the liver-gut-microbiome axis. Male C57BL/6J mice were pretreated with GGT for two weeks and subsequently challenged with an HFD for eight weeks. GGT supplementation attenuated body weight gain, visceral adiposity, and hepatic steatosis without affecting energy intake. These metabolic changes were accompanied by altered expression of hepatic lipogenic gene expressions and differences in pathways associated with beta-oxidation, antioxidant defense, and xenobiotic metabolism. In parallel, GGT treatment was associated with changes in intestinal barrier-related markers and shifts in gut microbiota composition, including changes in the Firmicutes/Bacteroidota ratio and relative abundance of specific taxa. Integrated multi-omics analysis revealed coordinated associations among hepatic transcriptomic changes, gut microbial profiles, and host metabolic parameters. Overall, these findings demonstrate that GGT administration was associated with attenuation of HFD-induced metabolic alterations in this preclinical model. The results support further investigation of GGT, subjected to marker-based quality control, as a potential food-derived botanical approach in the context of diet-induced metabolic stress.

Frailty, a clinical syndrome of multisystem decline and homeostatic vulnerability, is a critical public health priority. While the gut microbiome regulates immune and metabolic signaling, current evidence remains fragmented. We performed a metagenomic meta-analysis of 955 individuals from 28 independent cohorts across 24 countries to identify universal microbial signatures and develop a generalizable discriminative model. Frailty was determined using a Proxy Frailty Index based on the deficit accumulation model. Following refinement to isolate signatures from disease-specific dysbiosis, we used Firth's penalized regression for biomarker discovery and validated a Random Forest (RF) model via leave-one-study-out cross-validation. Shannon diversity exhibited a significant and sharp decline during the transition from robust to pre-frail states (p = 0.0006), manifesting at the earliest stages of physiological decline. We identified 16 microbial biomarkers characterized by the progressive attrition of core symbionts, such as Coprococcus eutactus, and the opportunistic expansion of pathobionts, including Enterococcus gallinarum. Sensitivity analysis in a healthy sub-cohort (n = 499) confirmed that these shifts occur independently of chronic clinical diagnoses and their associated confounding effects (p = 0.036). The 16-species RF model, predominantly driven by Collinsella massiliensis, achieved a corrected mean area under the receiver operating characteristic curve of 0.7572 across 5 eligible cohorts. Gut microbial restructuring is a sentinel biological hallmark of frailty that occurs independently of aging-related diseases. This study establishes a microbial signature broadly applicable across European and East Asian populations that serves as a high-fidelity, non-invasive metric for precision geriatric assessment.

Background:Galgeun-tang (GGT) is a traditional Korean multi-component formulation composed of several botanical drugs and has long been prescribed for febrile and musculoskeletal disorders. With the global rise in obesity and obesity-related metabolic diseases, there is increasing demand for safer and multi-targeted therapeutic strategies. However, the systemic metabolic effects and anti-obesity potential of GGT remain incompletely understood. Methods:The anti-obesity effects of GGT were evaluated using a tiered experimental approach comprising C2C12 myotubes, high-fat diet (HFD)-induced obese C57BL/6J mice, and Caenorhabditis elegans (C. elegans) exposed to high-glucose conditions. In vitro analyses assessed glucose uptake, gene expression, and protein signaling pathways. In mice, body weight, glucose tolerance, serum biochemical parameters, histological changes, and hepatic and adipose gene expression were examined. In C. elegans, lifespan, lipid and glucose accumulation, and insulin signaling-related gene expression were analyzed following treatment with GGT or metformin (MET). Results:GGT enhanced glucose uptake and increased the expression of insulin-responsive and mitochondrial regulatory genes in C2C12 myotubes. In HFD-fed mice, GGT attenuated body weight gain, improved glucose tolerance and insulin sensitivity, and alleviated hepatic steatosis and adipose hypertrophy, accompanied by suppression of lipogenic genes and induction of β-oxidation markers. In C. elegans, GGT reduced lipid and glucose accumulation, prolonged lifespan, and modulated the expression of insulin signaling-related genes, including daf-16 and daf-2. Across models, GGT exerted metabolic benefits in a dose- and context-dependent manner, with effects comparable to those of MET. Conclusion:GGT improves obesity-related metabolic dysfunction by coordinately regulating glucose homeostasis, lipid metabolism, and energy expenditure across cellular, nematode, and murine models. These findings provide preclinical evidence supporting GGT as a multi-targeted herbal intervention for obesity and metabolic disorders and warrant further targeted mechanistic studies and clinical investigations.

Background:The purpose of this study is to evaluate the predictive accuracy of a machine learning-based herbal medicine response prediction algorithm in patients with functional dyspepsia (FD). In a preliminary clinical study, the algorithm was developed using the XGBoost regressor framework to predict the relative effect sizes of three commonly prescribed herbal formulations-Yijung-tang (Lizhong-tang), Pyeongwi-san (Pingwei-san), and Shihosogan-tang (Chaihu Shugan-tang). The prediction system recommends the formulation expected to yield the greatest therapeutic benefit for each individual. Methods:This study is a randomized, assessor-blinded, parallel-group, open-label, multicenter clinical trial. A total of 100 patients with FD will be recruited from two Korean medical hospitals and randomly assigned to either the ACCORD group (n = 50), which will receive treatment guided by the machine learning algorithm, or the DISCORD group (n = 50), which will receive one of the two treatments not recommended by the algorithm. Patients will take the assigned herbal medicine for 8 weeks, three times daily, between meals. Outcomes:The primary outcome will be gastrointestinal symptom score. Secondary outcomes will include total dyspepsia symptom score, adequate relief of dyspepsia, overall treatment effect, visual analog scale score, functional dyspepsia-related quality of life, and pattern identification questionnaire results. Exploratory outcomes will include blood and fecal metabolome analysis, fecal and salivary microbiota profiling, and measurements obtained using Korean medicine diagnostic devices (heart rate variability, tongue, pulse, and abdominal diagnosis). Conclusion:Integrating a machine learning-based prediction system into treatment strategies for FD may enhance clinical practice and support the broader adoption of artificial intelligence-driven approaches in personalized medicine. Clinical trial registration:Clinical Research information Service (registration number: KCT0010587) and Open Science Framework (https://osf.io/2ecz8).

Objective: The aim of this study was to evaluate the effects of Bacillus subtilis -fermented Cynanchum atratum (BSCA) on excessive lipid accumulation using a mouse model. Methods: The anti-fatty liver and anti-hyperlipidemic potentials of BSCA were evaluated in mice fed a high-fat, high-fructose diet (HFHFD) for 10 weeks. Results: In long-term HFHFD-fed mice, BSCA treatment resulted in notable decreases in body, liver, and fat masses compared to those in the HFHFD control group. Additionally, BSCA lowered the serum levels of aspartate transaminase, alanine transaminase, triglycerides, and total cholesterol, with no significant changes observed in HDL or LDL levels. BSCA also restored the gut microbiota diversity and increased peripheral serotonin levels, which were reduced by the HFHFD. Conclusions: BSCA exhibits anti-fatty liver and anti-hyperlipidemic activities by inhibiting lipogenesis, a process associated with alterations in gut microbiota composition and increased serotonin levels. These findings suggest that fermented C. atratum holds promise as an herbal medicine for treating chronic metabolic disorders, including metabolic dysfunction-associated fatty liver disease, metabolic syndrome, and obesity.

BACKGROUND:Recent studies have highlighted the intricate relationship between gut microbiome (GM) and osteoporosis (OP), particularly in postmenopausal females. However, the precise mechanisms underlying this association remain unclear. MATERIALS AND METHODS:This retrospective review and meta-analysis aimed to elucidate the role of GM in postmenopausal OP (PMO) by synthesizing clinical findings from recent literature. A systematic search of four databases (PubMed, Google Scholar, Cochrane Library, and Web of Science) identified 16 relevant clinical studies published between January 2000 and July 2025. RESULTS:A total of 1520 postmenopausal females (mean age: 59.25 ± 6.63 years) were included, comprising 656 patients with PMO and 864 healthy controls (HC). A meta-analysis of gut microbial α diversity revealed a significant reduction (p = 0.04) in the abundance-based coverage estimator (ACE) index in patients with PMO, indicating a loss of microbial richness. At the same time, β-diversity findings were inconsistent across studies. Taxonomic analysis confirmed differences between patients and HC at the phylum and genus levels. PMO is characterized by a significant increase in primary bile acids and a reduction in tryptophan and daidzein metabolism at the metabolic level. Additionally, Patients with PMO exhibited markedly lower serum estradiol levels, higher levels of lipopolysaccharide and tumor necrosis factor-α, a higher proportion of Th17 cells, and a lower Treg cell population, indicating a pro-inflammatory state. CONCLUSION:Overall, this review provides a comprehensive synthesis of current clinical evidence on the role of GM in PMO, emphasizing its potential impact on bone metabolism. Given these findings, targeting the composition of gut microbiota and its metabolites may offer a promising therapeutic strategy for mitigating OP in postmenopausal females.

Background/Objectives: Esomeprazole, a proton pump inhibitor (PPI), is commonly prescribed for gastric-acid-related disorders but has been associated with impaired gastrointestinal (GI) motility with long-term use. However, the effect of concurrent antibiotic administration on this dysfunction remains unclear. Therefore, this study aimed to investigate the effects of antibiotics on esomeprazole-induced GI motility dysfunction and explore the underlying mechanisms in a mouse model. Methods: Male C57BL/6 mice were orally administered esomeprazole (160 mg/kg) five times per week for 4 weeks. Three days before initiating esomeprazole treatment, a broad-spectrum antibiotic cocktail (ABX) consisting of ampicillin (1 g/kg), neomycin (1 g/kg), metronidazole (1 g/kg), and vancomycin (0.5 g/kg) was provided in drinking water and maintained throughout the experimental period. Mosapride (3 mg/kg), a prokinetic agent, was used as a positive control. Results: Neither esomeprazole alone nor in combination with ABX affected body weight or food intake. Compared to normal controls, esomeprazole treatment significantly delayed both intestinal transit and gastric emptying. However, ABX co-administration further pronounced intestinal transit time and improved gastric motility. The potential mechanisms may involve interactions among gastric H+/K+-ATPase, CYP3A11, gastrointestinal hormones (secretin and motilin), and the gut microbiome. Conclusions: Long-term esomeprazole use can impair both gastric and intestinal motility, and ABX co-treatment further exacerbates intestinal transit delay while paradoxically enhancing gastric emptying. These findings highlight the critical role of the gut microbiota in esomeprazole-induced GI motility dysfunction and suggest that antibiotic use should be approached with caution, particularly when combined with PPI therapy.

BACKGROUND:Transcutaneous auricular vagus nerve stimulation (taVNS) is a potential noninvasive treatment for functional dyspepsia (FD). We aimed to systematically analyze the clinical evidence of taVNS for FD. METHODS:Eight databases were searched to identify randomized controlled trials (RCTs) using taVNS in patients with FD published by June 27, 2024. The primary outcome was dyspepsia symptoms, whereas the secondary outcomes were the total effective rate (TER), quality of life, anxiety, depression, and incidence of adverse events. The certainty of the evidence was assessed using the GRADE methodology. Detailed information on the taVNS parameters and the suggested underlying mechanism were also extracted. RESULTS:Six RCTs with 716 participants were included. Compared to the sham intervention, taVNS significantly improved dyspepsia symptoms, quality of life, and clinician-rated anxiety and depression with moderate certainty of evidence. The TER based on dyspepsia symptoms was also significantly higher with high certainty of evidence. When taVNS was used as an add-on therapy, dyspepsia symptoms were significantly improved with moderate certainty of evidence. No serious adverse events related to taVNS were reported. The stimulation sites for taVNS were concha and tragus, with common pulse frequencies of 25 or 20 Hz twice a day for 2-4 weeks. Gastric accommodation, electrogastrogram, heart rate variability, and functional magnetic resonance imaging were measured to explore the mechanism of taVNS. CONCLUSIONS:Considering the certainty of the evidence, taVNS can improve dyspepsia symptoms, quality of life, anxiety, and depression in patients with FD without serious adverse events. Additional high-quality studies are needed to establish optimal treatment protocols.

Neurodevelopmental disorders (NDDs) are associated with gut–brain axis dysfunction, and chloride ion channel 4 (CLCN4) has been implicated in their pathology. We investigated whether CLCN4 knockout (KO) alters gut microbiota and contributes to NDD-like phenotypes in mice. CLCN4-KO mice displayed behavioral abnormalities, microbial dysbiosis, and increased serum p-cresol levels, along with altered hippocampal signaling proteins (PSD95, AKT, ERK). Treatment with haloperidol (Halo) modified gut microbiota, reduced p-cresol, and improved behavior, effects accompanied by increased hippocampal protein activation in homozygous KO mice but abolished by antibiotic-induced dysbiosis. Prevotellaceae_UCG-001 abundance correlated positively with hippocampal protein activation and negatively with hyperactivity, and Halo treatment significantly increased this population. Fecal microbiota transplantation (FMT) from wild-type mice restored gut microbial balance, memory, and protein phosphorylation in KO mice. These findings indicate that CLCN4 deficiency contributes to NDD-like behaviors via microbiota-mediated mechanisms and highlight Halo and FMT as promising microbiota-targeted strategies.

BACKGROUND:Cold exposure has traditionally been considered a pathological factor that can easily impair gastrointestinal (GI) digestion. Shihosogan-tang (ST), Yijung-tang (YT), and Pyeongwi-san (PS) are well-known herbal formulas frequently used to treat GI disorders in East Asia. AIM:To compare the effects of these herbal formulas on GI motility and investigate their mechanisms of action using a cold stress (CS)-induced dyspepsia mouse model. METHODS:C57BL/6J mice were exposed to CS by immersion in cold water (10 ± 1 °C) while being restrained in conical tubes for 1 hour. This procedure was repeated six times over 2 weeks. Herbal formulas or mosapride (positive control) were administered orally five times per week over a 2-week period. RESULTS:The pre-test results revealed that CS, rather than restraint stress, significantly delayed gut motility in mice. However, PS and ST notably improved gastric emptying and intestinal transit, surpassing YT. Additionally, PS and ST significantly reduced gastric potential of hydrogen and increased pepsin and lipase gene expression compared to CS. The observed mechanisms likely involved increased gastric acidity and enhanced levels of digestive enzymes, such as pepsin and lipase. Furthermore, PS administration elevated GI hormone levels and metabolites related to the gut microbiota (5-hydroxytryptamine and short-chain fatty acid) more effectively than ST and YT treatments. CONCLUSION:PS more effectively alleviated CS-induced GI dysfunction than both YT and ST. These comparative findings offer valuable insights for clinical applications in the treatment of cold-related digestive disorders.

Background:Hashimoto's thyroiditis (HT) is the most common thyroid disease leading to hypothyroidism in developed countries. Recent studies have highlighted vitamin D as a potential risk factor or therapeutic agent for HT owing to its role in modulating immune responses, although concrete evidence has not been presented. This retrospective observational study was conducted to investigate serum vitamin D levels and dysregulation of vitamin D signaling pathways in patients with HT. Methods:Patients who underwent thyroid surgery for various thyroid neoplasm with or without HT were recruited. We analyzed serum thyroid biomarkers, including serum vitamin D, anti-thyroglobulin (TG) antibody, and anti-thyroid peroxidase (TPO) antibody for patients with HT. Using RNA-seq, the gene expression profile of thyroid tissue and the potential correlation between HT and vitamin D levels or its signaling were investigated. Results:The serum vitamin D levels were significantly lower in patients with HT. However, vitamin D receptor (VDR) expression and genes involved in vitamin D-associated biological process (BP) were significantly upregulated in the HT group. Visualization of expression profile on Wikipathways revealed multifaceted regulation of vitamin D-related pathways in the HT group. Real-time PCR and immunofluorescence staining confirmed enhanced VDR expression in thyroid tissues from the HT cohort. Conclusion:Our study presents RNA-seq data acquired from the Korean HT cohort in this study, and highlighted dysregulated vitamin D signaling in thyroid tissues from the HT cohort. Further investigations are needed to elucidate the causal role of vitamin D signaling in the pathogenesis of HT.

Dyspepsia is a prevalent refractory condition that arises from various causes and lacks definitive treatment. There is an urgent need for evidence to support the use of herbal medicines in the treatment of gastroenterological disorders. This study aimed to compare the therapeutic effects of two common herbal formulas-namely, Shihosogan-tang (SST) and Yijung-tang (YJT)-on loperamide (LOP)-induced dyspepsia and to explore their potential mechanisms. A dyspepsia model was established using Sprague-Dawley rats by intraperitoneal LOP injection at a dose of 3 mg/kg/day for one week. During this period, 30% ethanol extract of SST (1.4 g/kg/day) or YJT (2 g/kg/day) was intragastrically administered in rats. Mosapride (3 mg/kg/day) was used as the positive control. Unlike YJT, SST significantly mitigated LOP-induced reductions in intestinal length, gastrointestinal transit ratio, and serum ghrelin levels. Conversely, YJT significantly enhanced defecation, ileum villus length, and muscular thickness, outperforming SST. Expression of genes related to intestinal motility (ZO-1), inflammation (IL-6), and water absorption (SERT, AQP-3) indicated that both treatments ameliorated LOP-induced changes in the duodenum. Additionally, neuropeptides and hormones (TRH, bombesin, motilin, glucagon, neurotensin, PYY), Toll-like receptors (TLR-2 and TLR-4), and growth factors (GDNF and BMP2) were noticeably altered by SST and/or YJT treatment. While neither LOP nor the herbal formulas affected gut microbiota α-diversity, SST and YJT altered β-diversity compared to LOP alone, unlike mosapride. SST improves dyspepsia more effectively than YJT, possibly through mechanisms involving intestinal hormone regulation, inflammation inhibition, and gut microbiota modulation.

Objective: The aim of this study was to evaluate the effects of Bacillus subtilis -fermented Cynanchum atratum (BSCA) on excessive lipid accumulation using a mouse model. Methods: The anti-fatty liver and anti-hyperlipidemic potentials of BSCA were evaluated in mice fed a high-fat, high-fructose diet (HFHFD) for 10 weeks. Results: In long-term HFHFD-fed mice, BSCA treatment resulted in notable decreases in body, liver, and fat masses compared to those in the HFHFD control group. Additionally, BSCA lowered the serum levels of aspartate transaminase, alanine transaminase, triglycerides, and total cholesterol, with no significant changes observed in HDL or LDL levels. BSCA also restored the gut microbiota diversity and increased peripheral serotonin levels, which were reduced by the HFHFD. Conclusions: BSCA exhibits anti-fatty liver and anti-hyperlipidemic activities by inhibiting lipogenesis, a process associated with alterations in gut microbiota composition and increased serotonin levels. These findings suggest that fermented C. atratum holds promise as an herbal medicine for treating chronic metabolic disorders, including metabolic dysfunction-associated fatty liver disease, metabolic syndrome, and obesity.

Cervical cancer remains a persistent and critical challenge in global health, primarily driven by chronic infections with high-risk human papillomavirus (HPV) types. This virus strategically exploits inflammatory signaling pathways, such as NF-κB, and modulates key enzymes like COX-2, promoting chronic inflammation and cellular alterations that sig nificantly elevate the risk of carcinogenesis. A precise and comprehensive understanding of these pathways, combined with insights from advanced studies, is imperative for developing effective strategies to manage inflammation and mitigate the adverse impacts of HPV on cellular health. This study follows our previous research, which established HPV genotyping and related analyses, providing a foundation for the current investigation. It confirms a strong association between high-risk HPV genotypes and significant cytological and inflammatory alterations. Among individuals infected with high-risk HPV (16, 18, 52), 90 % exhibited notable cellular changes and severe inflammatory responses, compared to 45.5% in low-risk HPV cases and 59.3% in samples containing other HPV genotypes. In the 20 -30-year age group, 100% of samples displayed endocervical/metaplastic cells, with 70% exhibiting substantial cytological abnormalities, highlighting an increased susceptibility of younger individuals to HPV-induced epithelial disruptions. These findings emphasize the critical role of NF-κB and AhR pathways in modulating cellular responses, providing a foundation for targeted therapeutic interventions. Regulating NF-κB activity and microbiota-driven AhR modulation emerge as promising therapeutic strategies for mitigating inflammation and cellular damage associated with HPV infections. By integrating cytological observations with molecular analyses, this study presents a comprehensive perspective on HPV-induced pathophysiology, reinforcing the necessity for precision-based therapeutic approaches to effectively manage HPV-driven cellular and inflammatory alterations. Author Summary In this study, we investigated how human papillomavirus (HPV) triggers inflammation and cellular changes that can lead to cervical cancer. We combined laboratory analysis of patient samples with a review of existing research to map out the molecular pathways involved. We found that infections with high-risk HPV types (like 16, 18, and 52) cause severe inflammation and cellular damage, especially in younger women aged 20-30. Specifically, 90% of samples with high-risk HPV showed significant inflammatory changes, compared to only 45.5% in low-risk cases. Our results highlight the critical role of two key pathways—NF-κB and AhR—in driving HPV-induced inflammation. Targeting these pathways with anti-inflammatory compounds (like protopine) or immune-modulating agents (like immunobiotics) could offer new strategies to prevent or treat HPV-related cervical abnormalities. This work underscores the importance of early HPV screening and personalized therapeutic interventions to reduce the risk of cervical cancer, particularly in high-risk populations. ### Competing Interest Statement The authors have declared no competing interest.

Helicobacter pylori has been implicated in various gastrointestinal disorders, including functional dyspepsia. This study aimed to compare the anti-H. pylori activity and gastroprotective effects of three typical herbal formulas used for gastrointestinal disorders in Korea: Shihosogan-tang (ST), Yijung-tang (YT), and Pyeongwi-san (PS). Firstly, we assessed the total phenolic and flavonoid contents, as well as the antioxidative capacity. Additionally, we evaluated the antibacterial effect on H. pylori using an ammonia assay, minimum inhibitory concentration (MIC) test, and the disk agar diffusion method. Furthermore, we examined alterations in the gene expression of tight junction proteins, pro-inflammatory cytokines, and cellular vacuolation using an AGS cell model infected with H. pylori. While ST exhibited a higher total phenolic content, superior free radical scavenging, and inhibition of H. pylori compared to YT and PS, YT more evidently inhibited gastric cellular morphological changes such as vacuolation. All formulations significantly ameliorated changes in inflammatory and gastric inflammation-related genes and cellular morphological alterations induced by H. pylori infection. Overall, the present in vitro study suggests that all three herbal formulas possess potential for ameliorating gastrointestinal disorders, with ST relatively excelling in inhibiting H. pylori infection and inflammation, while YT potentially shows greater efficacy in directly protecting the gastric mucosa.