Female aging is characterized by hormonal imbalances and metabolic shifts, which significantly impact overall health. Icariin, a bioactive flavonoid derived from the functional herb Epimedium, has a long-standing history of use in traditional medicine and functional food products. Our previous research has demonstrated that icariin can enhance cognitive and motor functions in aged male mice and modulate the intestinal microbiota to resemble that of younger mice. However, its effects on female aging have remained largely unexplored. In this study, we aimed to investigate the anti-aging mechanisms of icariin in older female mice (24 months old). We employed a comprehensive approach, including behavioral tests, 16S rRNA sequencing, and multi-organ metabolic profiling. The results revealed that oral administration of icariin led to significant improvements in motor coordination and cognitive function. Additionally, icariin effectively reduced oxidative stress markers while simultaneously enhancing the activity of antioxidant enzymes. Gut microbiota analysis showed that icariin enriched beneficial taxa, such as Akkermansia muciniphila and Dubosiella newyorkensis, and suppressed pathogenic bacteria, including Ileibacterium valens and Ruminococcus. Non-targeted metabolomics identified sphingosine 1 phosphate (S1P) as a key mediator. Icariin administration resulted in an increase in serum S1P levels, which was positively correlated with the abundance of Akkermansia. Furthermore, S1P levels were positively associated with antioxidant activities and anti-inflammatory cytokines, while negatively linked to pro-inflammatory markers. Transcriptomics analysis further supported the role of S1P in suppressing the NF-κB pathway and enhancing neuroactive signaling. Based on these findings, our study positions icariin as a novel dietary candidate for mitigating female aging by restoring gut microbiota balance and sphingolipid metabolism. These results not only bridge the gap between traditional herbal medicine and functional food innovation but also offer a microbiota-targeted strategy for the management of menopausal health.

The establishment of the early-life microbiota is profoundly shaped by microbial vertical transmission from mother to offspring. This review synthesized the current understanding of the timing, determinants, and health implications of mother-to-offspring microbial vertical transmission. We detailed the contentious evidence regarding prenatal microbial transmission and highlighted the well-established roles of intrapartum and postnatal transmission via birth and breastfeeding, respectively. Multiple factors, including delivery mode, gestational age, feeding patterns and antibiotic exposure, are critical modulators of microbial transmission, shaping the initial microbial community. Emerging intervention strategies, such as breastfeeding, probiotic supplementation, vaginal microbiota transplantation, and fecal microbiota transplantation, offer promising avenues for restoring a healthy microbial trajectory when natural transmission is disrupted. This review underscores that vertical transmission is the cornerstone of intergenerational microbiome inheritance and a potential therapeutic target for preventing early-life dysbiosis and associated diseases.

The biological mechanism underlying the association between low body mass index (BMI) and increased risk of esophageal malignancy remains uncertain. We aimed to explore the role of metabolic alterations in the effect of low BMI on esophageal malignancy. We conducted a nested case-control study using a large-scale community-based screening cohort in a high-risk region for esophageal cancer (263 cases and 263 matched controls). Metabolomic profiling was performed based on untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, using the serum samples collected at enrollment prior to cancer diagnosis. Linear regression and conditional logistic regression were used to identify BMI-related metabolites and metabolites associated with esophageal malignancy, respectively, and the shared metabolites were included in mediation analysis. Low BMI was positively associated with esophageal malignancy (odds ratio (OR) = 1.8 (95

BACKGROUND:Late-onset diarrhoea remains a poorly managed concern for clinical irinotecan therapy. Although bacterial β-glucuronidases (β-GUS) mediated SN-38 production is prevailingly thought to mediate intestinal toxicity, β-GUS inhibitors confer limited benefits in the clinic. OBJECTIVE:This study aimed to explore the role and mechanism of endogenous bacterial metabolites in susceptibility to irinotecan toxicity. DESIGN:Gut microbiota profiles and metabolites in patients with colorectal cancer (CRC) with or without diarrhoea were investigated via 16S rRNA sequencing, shotgun metagenomics and metabolomics. The role of microbial metabolites was investigated in mice by metabolic bioengineering and intestinal organoid culture. The mechanism of microbial metabolites on intestinal stem cells was investigated by transcriptional profiling and chemical intervention. RESULTS:Gut microbial configuration was differentially remodelled in diarrhoea and non-diarrhoea patients with irinotecan therapy, and the susceptibility was transmissible to recipient mice via transplantation of baseline faecal microbiome. Bacteroides intestinalis (B. intestinalis) was notably expanded in the diarrhoea-prone cohorts as well as in irinotecan-treated mice. B. intestinalis colonisation sensitised intestinal epithelia to irinotecan-induced chemical injury, partially via tryptophan metabolite indole-3-acetate (IAA). Both B. intestinalis and bioengineered bacteria that produce IAA exacerbated irinotecan-induced intestinal epithelial injury in mice. Mechanistically, IAA suppressed PI3K-Akt signalling, thereby impairing the renewal of intestinal epithelia under the insult of irinotecan. In clinical patients receiving irinotecan therapy, faecal IAA level was closely associated with the diarrhoea severity. CONCLUSION:Our study uncovers the mechanism of endogenous bacterial metabolite in shaping the individual susceptibility to irinotecan toxicity and suggests IAA as a potential predictive biomarker.

OBJECTIVE:To identify real-world physical activity patterns in older adults using objective measurements from wearable devices, and to analyze the associations between these patterns and gut microbiota composition. METHODS:Based on data collected from a real-world health management project, a total of 743 participants from Eastern, Central, and Northern China were enrolled between January 2018 and June 2025. A 180-day objective physical activity dataset prior to fecal sampling was collected via smart wearable devices to extract features including mean daily steps, coefficient of variation of steps, and the proportion of active days. Fecal samples underwent 16S ribosomal RNA (rRNA) gene (V3-V4 region) amplicon sequencing to obtain genus-level relative abundance matrices. Covariates, including demographics, lifestyle, and chronic disease history, were collected via questionnaires and physical examinations. The discriminative dimensionality reduction via learning a tree (DDRTree) algorithm combined with K-means clustering was applied to identify physical activity phenotypes. Alpha diversity was evaluated using the Shannon index (Kruskal-Wallis test), and beta diversity was assessed using covariate-adjusted permutational multivariate analysis of variance (PERMANOVA) based on Bray-Curtis distance. Multivariable linear regression with false discovery rate (FDR) correction was used to screen differential taxa. A microbial risk score (MRS) was constructed based on taxa with a raw P < 0.05, defined as the difference between the standardized abundance of beneficial and harmful taxa. Co-occurrence networks were constructed to evaluate micro-ecological topological structures. RESULTS:The cohort comprised 381 (51.3%) individuals aged 60-74 years and 362 (48. 7%) aged ≥75 years. Compared with the 60-74 group, the ≥75 group had higher prevalences of hypertension (45.9% vs. 36.7%, P=0.045) and heart disease (34.0% vs. 25.2%, P=0.032), higher systolic blood pressure (median 130 mmHg vs. 120 mmHg, P < 0.001), and fewer mean daily steps (median 6 200 steps vs. 7 000 steps, P < 0.001). Clustering identified three activity patterns: active group (n=143, 19.2%; high steps, low variation, high adherence), moderate group (n=429, 57.7%), and irregular group (n=171, 23.0%; low steps, high variation, low adherence). The active group exhibited the lowest prevalences of hypertension (35.0%) and heart disease (21.7%), and the lowest systolic blood pressure (mean 124.4 mmHg), whereas the irregular group showed the highest values (51.5%, 40.4%, and 127.6 mmHg, respectively). Alpha diversity showed no significant differences among the groups. After adjusting for covariates, physical activity patterns showed no statistically significant effect on beta diversity (R2=0.003 7, P=0.115). Compared with the irregular group, two genera in the active group showed significant differences (P < 0.05). Specifically, the relative abundance of Roseburia in the active group was significantly lower than that in the irregular group (P < 0.05), and the relative abundance of Butyricimonas was also significantly lower than that in the moderate group (P < 0.01). However, these differences did not remain statistically significant after FDR correction. The MRS exhibited a significant gradient distribution across the groups, with the active group scoring the highest (P < 0.001). Co-occurrence network analysis revealed that the active group had the highest network density and proportion of positive correlations (84.5%), whereas the irregular group had the lowest (60.3%). CONCLUSION:Physical activity patterns identified from wearable device data are associated with gut microbiota composition and ecological network characteristics in older adults. Active and regular physical activity patterns indicate a higher MRS and more stable microbial co-occurrence networks, suggesting potential associations between activity regularity and gut microbial ecology, though causal inference requires longitudinal confirmation.

The early-life microbiome plays a pivotal role in host development and lifelong health. Maternal factors are increasingly recognized as crucial in shaping offspring microbiome. However, how maternal preconception perturbations affects offspring health remain unclear. Thus, we combined animal and clinical data to elucidate whether preconception microbial perturbations disrupt microbial succession and increase offspring susceptibility to colitis. In animals, preconception antibiotic exposure induced long-lasting disruptions in offspring microbial ecology, through enhanced maternal-offspring microbial transmission, altered microbial developmental trajectories, and increased selective pressures during microbial community assembly. Ultimately, these alterations resulted in persistent gut mucosal immaturity and heightened susceptibility to colitis in adulthood. Complementary clinical studies revealed concordant alterations in gut microbiome and metabolome of children with inflammatory bowel disease (IBD) and their seemingly healthy mothers, characterized by pro-inflammatory taxa and metabolites. Notably, mothers of IBD children reported significantly higher antibiotic exposure than controls, which was also associated with enhanced maternal-offspring microbial transmission and increased selective pressures during microbial community assembly. Our findings reveal a potential intergenerational mechanism in which preconception perturbations are associated with disrupted microbial succession, transgenerational propagation of gut mucosal immaturity, and susceptibility to colitis. These results underscore the importance of judicious antibiotic use during the often-overlooked preconception period.

Background/Aims:: The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated. This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients. Methods:: In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%), DGERD (54.4%), or non-GERD (13.1%). Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients. Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD. Results:: The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group. Regarding reflux profiles, RGERD patients without HH (RGERDHH- group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERDHH- group). Mechanistically, the RGERDHH- group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005). Notably, following a wet-swallow, the RGERDHH- group experienced the significant elevation in gastric pressure and TPG. Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure. Conclusions:: Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure. This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.

Background and Objective The association between irritable bowel syndrome (IBS) and brain function remains unclear. We conducted Mendelian randomization (MR) analysis to investigate the possible causal relationships between them.Methods We performed bidirectional MR analysis using genome-wide association study data from IBS and 191 brain resting-state functional magnetic resonance imaging (rsfMRI) traits. Odds ratio (OR) with 95% confidence intervals was used to estimate the causal effects. Enrichment analyses were further conducted on genes corresponding to involved single nucleotide polymorphisms.Results In forward analysis, IBS potentially increased the connectivity between postcentral/ precentral gyrus and cerebellum (OR = 1.15, P = 0.014), and decreased the connectivity between occipital/precuneus and superior frontal lobe (OR = 0.87, P = 0.037), as well as the connectivity between cerebellum and subcortical region (OR = 0.86, P = 0.017). In reverse analysis, increased neural activity in parietal/postcentral/precuneus region was potentially negatively associated with IBS (OR = 0.93, P = 0.036); the connectivity between cerebellum and subcortical region (OR = 1.16, P = 0.042) was potentially positively associated with IBS; the connectivity between cerebellum and precentral/frontal/superior motor area (OR = 0.85, P = 0.032), calcarine/lingual and paracentral gyrus (OR = 0.88, P = 0.031), postcentral/precentral and subcortical region (OR = 0.89, P = 0.019) were potentially negatively associated with IBS. The abnormally connected brain networks mainly included subcortical-cerebellum, motor, default mode and attention networks. Enrichment analyses demonstrated that the genes were mainly enriched in cell junctions and long-term potentiation pathways.Conclusions Our findings provided suggestive evidence for several causal relationship between IBS and rsfMRI phenotypes, in which, cerebellum, subcortical regions, postcentral and precentral gyrus played important roles. These putative causal relationships warrant further validation in independent, ideally larger-scale datasets.

The benefit of endoscopy for non-cardia gastric cancer (GC) prevention lacks evidence from randomized controlled trials (RCTs). This study aimed to evaluate the effect of endoscopic screening for non-cardia GC through an RCT. We conducted a cluster RCT in rural Hua County, northern China (ClinicalTrials.gov, NCT01688908). A total of 668 villages were randomly selected and assigned to either undergo upper gastrointestinal endoscopic screening (screening group) or no screening (control group). Permanent residents aged 45-69 years were enrolled from January 2012 to September 2016. Non-cardia GC mortality between the two groups was compared in intention-to-treat, per-protocol, and subgroup analyses. Poisson regression fitted with generalized estimating equations was used, adjusting for baseline characteristics and accounting for village clustering. The study enrolled 17,104 participants in the screening group, of whom 15,165 (88.7

BACKGROUND & AIMS:Mast cells (MCs) play a critical role in the pathogenesis of inflammatory bowel diseases (IBD), encompassing ulcerative colitis and Crohn's disease. Nevertheless, their regulatory impact on intestine stem cells (ISCs) compartment remains poorly characterized. We aim to study the effect of MCs on ISC-mediated epithelial regeneration in IBD. METHODS:The bulk RNA sequencing data of intestine tissues from patients with IBD were collected from the Mount Sinai Crohn's and Colitis Registry to explore the direct and indirect correlation of MCs with ISCs, stemness, and related pathways. Subsequently, the results were verified by experiments such as dextran sulfate sodium (DSS)-induced colitis in MC-deficient rats and C57BL/6 mice, and co-culture of bone marrow-derived mast cells and small intestinal organoids. RESULTS:Bulk RNA sequencing data analysis demonstrated significant MC activation in inflamed mucosa of patients with IBD, showing negative correlations with transcriptional signatures of ISC, stemness markers, and Wnt pathway activity. Genetic ablation of MCs in rats conferred protection against DSS-induced epithelial damage, exhibiting enhanced Lgr5 expression and Wnt/lrp6/β-catenin signaling activation compared with wild-type rats. Pharmacological stabilization of MCs with cromolyn sodium or intervention with a carboxypeptidase A inhibitor during the recovery phase of DSS-induced colitis promoted epithelial restoration in mice, evidenced by improved crypt architecture and upregulation of ISC-associated genes and proteins. In vitro co-culture experiments demonstrated MC-mediated suppression of intestinal organoid growth and Wnt/lrp6/β-catenin signaling pathway, reversible through Lrp6 activation and carboxypeptidase A3 inhibition. Mediation analysis coupled with neutrophils detection revealed an additional indirect regulatory axis involving MC-driven neutrophil recruitment to inhibit ISC-mediated epithelial repair. CONCLUSIONS:Our findings establish that MCs play a pivotal role in inhibiting ISC-mediated epithelial regeneration by suppressing Wnt/lrp6/β-catenin pathway in IBD, directly through carboxypeptidase A3 secretion and indirectly through neutrophils recruitment.

Objective: The risk factors and role of mother–child gut microbiota in pediatric inflammatory bowel disease (PIBD) remain unclear. We aimed to explore the clinical risk factors associated with PIBD, analyze the characteristics of gut microbiota of children and their mothers, and examine the correlation of the microbial composition in mother–child pairs. Methods: We conducted a case-control study including children with PIBD and their mothers as the case group, as well as healthy children and their mothers as the control group. Questionnaires were used to collect information such as family illness history and maternal and early-life events. Fecal samples were collected from the children and mothers for microbiota 16S ribosomal RNA (rRNA) sequencing to analyze the composition and its potential association with PIBD. Results: A total of 54 pairs of cases and 122 pairs of controls were recruited. A family history of autoimmune disease and antibiotic use during pregnancy were associated with an increased risk of PIBD, and a higher education level of the father was associated with a decreased risk of PIBD. Children with PIBD and mothers exhibited different gut microbiota compared to healthy children and mothers. Similarities were observed in the gut microbiota of mothers and children in the same groups. Some bacterial biomarkers of mothers discovered in this study had the power to predict PIBD in their offspring. Conclusions: PIBD is influenced by maternal risk factors and has unique gut microbiota characteristics. The mother–child gut microbiota is closely related, suggesting the transmission and influence of the gut microbiota between mothers and children. This study highlights the potential pathogenesis of PIBD and provides a basis for developing targeted interventions.

Maternal health, specifically changes in the gut microbiota, can profoundly impact offspring health; however, our understanding of how gut microbiota alterations during the preconception period influence the offspring remains limited. In this study, we investigated the impact and mechanisms of preconception maternal gut dysbiosis on the development of the enteric nervous system (ENS) in mice. We found that preconception maternal exposure to antibiotics led to the abnormal development of the ENS in offspring, increasing their susceptibility to water avoidance stress at the adult stage. Metagenomic, targeted metabolomic, and transcriptomic analyses revealed that preconception antibiotic exposure disrupted the expression of genes crucial for embryonic ENS development by altering maternal gut microbiota composition. Multi-omics analysis combined with Limosilactobacillus reuteri and propionate gestational supplementation demonstrated that the maternal gut microbiota and metabolites may influence embryonic ENS development via the GPR41-GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota before conception to support normal ENS development in offspring.