Introduction Our previous research demonstrated that a high-fat diet (HFD) induced jejunal inflammation and hepatic steatosis, suggesting that small bowel microbiota contribute to these pathologies. This study investigated age- and sex-specific alterations in jejunal microbiota following a high-fructose, high-fat diet (HFHFD) in F344 rats.Methods Six-week-old and two-year-old rats of both sexes were fed an HFHFD for 8 weeks, after which jejunal contents were collected for metagenomic analysis. Taxonomic profiling and linear discriminant analysis were performed, and Spearman's rank correlation analysis was used to evaluate associations with jejunal inflammation and hepatic steatosis. Beta-diversity analysis was conducted to assess group separation. In vitro, HIEC-6 human intestinal epithelial cells were used to test the protective effect of Lactobacillus intestinalis under palmitic acid-induced lipotoxic stress.Results HFHFD reduced the Firmicutes/Bacteroidetes ratio in young females and in aged rats of both sexes. Notably, Lactobacillus intestinalis-which supports barrier function-decreased in young males and aged females. In contrast, Akkermansia muciniphila increased across all HFHFD groups, particularly in young females and aged rats. Bacteroides vulgatus increased in aged HFHFD-fed rats of both sexes, while Bacteroides caccae was elevated in females across both age groups. Furthermore, the Lactobacillus reuteri group decreased only in young HFHFD rats. L. intestinalis and L. reuteri groups negatively correlated with jejunal inflammation and hepatic steatosis, whereas B. caccae and A. muciniphila showed positive correlations with both pathogenic phenotypes. Beta-diversity revealed a pronounced diet- and sex-dependent separation in young rats, which was attenuated in aged groups. In HIEC-6 cells, L. intestinalis significantly restored viability under palmitic acid-induced lipotoxic stress, though its conditioned medium did not.Discussion Collectively, HFHFD induces age- and sex-dependent dysbiosis in the jejunum, and L. intestinalis may serve as a potential probiotic for metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE:Opioid use in Asian patients with inflammatory bowel disease (IBD) remains poorly understood. This study aimed to investigate the trends in chronic opioid use, associated clinical factors, and effects of advanced therapy (AT) on opioid use in Korean patients with IBD. METHODS:This nationwide cohort study used administrative claims data from the Korean National Health Insurance Service (2010-2022). Chronic opioid use was defined as opioid use for ≥90 days or ≥3 prescriptions within a calendar year. Logistic regression was used to identify clinical factors associated with chronic opioid use. The impact of AT on opioid use was analyzed through pre- and post-initiation comparisons using McNemar's tests, generalized estimating equations (GEE), and a linear mixed model. RESULTS:Chronic opioid use increased over the study period, with a higher prevalence in Crohn's disease (CD) than in ulcerative colitis (UC) (CD: 1.38%, UC: 0.53% in 2010; CD: 5.38%, UC: 1.98% in 2020). Among 49 548 newly diagnosed IBD patients, female sex, steroid and immunomodulator treatments, hospitalizations, emergency room visits, and mental disorders were positively associated with chronic opioid use in CD and UC. AT was positively associated with chronic opioid use in UC (odds ratio [OR] 1.627, P < .0001) but negatively associated with CD (OR 0.786, P = .0013). In CD, AT significantly reduced opioid users (McNemar's test: P < .0001; GEE: OR 0.478, P < .0001) and average daily doses (mean difference -15.8 morphine milligram equivalents, P = .0073). CONCLUSION:Chronic opioid use has increased over the past decade among Korean patients with IBD, particularly among those with CD. AT is crucial for reducing opioid use in patients with CD.

ABSTRACT Living organisms must adequately respond to stress to survive and proliferate. Bacterial pathogens face multiple stressors during infections, including oxidative stress from host innate immune cells and antibiotic treatment from clinical therapy. The pathogenic bacterium Acinetobacter baumannii is considered the most critical threat to public health due to its broad antibiotic resistance. However, it is poorly known how A. baumannii properly responds to antibiotics and stress molecules during infection. Here, we investigate the mechanisms by which A. baumannii regulates its morphology to reduce the uptake of stress molecules under oxidative stress and antibiotic exposure, thereby conferring virulence and survival during infection. The transcriptional regulator IscR responds to oxidative stress by upregulating pbp1a , which encodes an enzyme involved in peptidoglycan biosynthesis. Under oxidative stress, bacteria undergo a morphological shift from a rod to a coccoid form, reducing their surface area and thus decreasing their absorption of reactive oxygen species. Inactivation of either iscR or pbp1a results in an elongated morphology characterized by an elevated surface area, thereby reducing A. baumannii survival under oxidative stress. Furthermore, IscR-mediated morphological control is essential for survival under antibiotic treatment. Moreover, IscR-mediated morphology regulation is required for A. baumannii survival in macrophage and mouse models. These findings elucidate a strategy by which A. baumannii uses IscR to adapt to stress through morphological control, facilitating its survival during infections against both immune response and antibiotic therapy. IMPORTNACE Acinetobacter baumannii is a major cause of nosocomial infections. It poses a critical threat due to its extensive antibiotic resistance. This study reveals that the pathogen can change its cellular shape to survive immune system attacks and antibiotic treatment. This change represents a previously unknown survival strategy. A. baumannii transitions to a coccoid morphology under oxidative stress and antibiotic treatment. It does so by activating the peptidoglycan synthesis gene pbp1a through the IscR transcriptional regulator. This rapid morphological adaptation helps A. baumannii evade host defenses and resist antibiotic treatment by reducing uptake of stress molecules. Our findings advance understanding of how pathogens adapt to hostile environments and identify new therapeutic targets. By blocking this shape remodeling ability, it may be possible to render pathogenic bacteria more vulnerable to immune responses and antimicrobial treatments. This offers a promising strategy for combating this multidrug-resistant pathogen.

The specific roles of single-nucleotide polymorphisms and structural variants (SVs) in Korean patients with inflammatory bowel disease (IBD) susceptibility remain unclear; hence this study aimed to evaluate polygenic risk scores (PRS) for IBD and identify IBD-associated SVs in a Korean IBD cohort. Whole genome sequencing data from 75 Korean patients with IBD were analyzed, and compared with individuals from the general Korean population cohort. The PRS models significantly distinguished patients with IBD from the general Korean population, confirming the predictive power of PRS in Korean patients with IBD. SV analysis revealed IBD-associated deletions, with candidate loci including PLA2R1, PTPN2, LINC00484, CCND3, COMMD7, and ERAP2. Of these, DEL5948 in ERAP2 overlapped multiple IBD-associated SNP loci and disrupted key regulatory and coding regions, potentially influencing immune regulation. This study provides a comprehensive genome-wide analysis of PRS and SVs in Korean patients with IBD, highlighting novel genetic factors in IBD pathogenesis.

There is sex difference of obesity and it might be related with sex hormones. For instance, estrogen regulates adipose tissue function and fat deposition by activation of the sympathetic nervous system, which leads to more adiposity in subcutaneous fat instead of visceral fat. There are strong evidences for the association between obesity and cancer, predominantly cancers of digestive organs including cardia gastric cancer (GC) and cancers of hormone sensitive organs in females. The main pathways linking obesity and cancer are hyperinsulinemia/insulin resistance and abnormalities of the insulin-like growth factor (IGF)-I system, sex hormone biosynthesis and pathway, and subclinical chronic low-grade inflammation and oxidative stress. There have been several reports regarding the effect of obesity on the development of cardia GC, especially in males. The body mass index (BMI) changes from underweight or normal to overweight (23.0-24.9 kg/m²) decrease the development of non-cardia GC in males but not in females. The prognosis of GC is the better as the BMI is higher, especially in males. Estrogen can explain for the sex difference of non-cardia cancer (mainly intestinal type) regarding obesity. The peripheral adipose tissue is responsible for the process of steroid aromatization to produce sex hormones including estrogen which can explain why the obese males have better survival or less development of non-cardia GC. In terms of cardia GC, the main cause is related with frequent gastroesophageal reflux in obese males. In addition, metabolic factors such as cholesterol, glucose and IGFs are related with GC similar to other obesity related cancers.

Background/Aims:Peptic ulcer disease (PUD) exhibits sex-based differences in epidemiology and treatment that shift across the lifespan; however, there are no sex-specific recommendations in the current guidelines. For this scoping review, sex and gender differences in PUD were mapped to inform guideline development. Methods:Following the PRISMA-ScR guidelines, we searched PubMed, Embase, the Cochrane Library, and KoreaMed through October 2025. Two reviewers independently screened articles and extracted data on epidemiology, hormonal factors, treatment responses, and outcomes. Results:Of the 940 identified records (895 from databases and 45 from manual searching), 68 studies met the inclusion criteria. Key findings were organized into three thematic domains-Epidemiology: the male-to-female PUD ratio has narrowed from 2:1 to near parity, with elderly females (≥70 years) demonstrating elevated bleeding and mortality risk, particularly with concurrent nonsteroidal anti-inflammatory drug or aspirin use; Hormonal factors: both natural and surgical menopause were consistently associated with increased PUD risk, with a stronger association for surgical menopause. Postmenopausal females had higher perforation and mortality rates; and Treatment response and pharmacology: females experienced twice as many adverse events during Helicobacter pylori therapy despite similar eradication rates and had higher H. pylori recurrence rates. Females showed approximately 30% higher plasma proton pump inhibitor (PPI) concentrations, suggesting pharmacokinetic differences. An exploratory quantitative synthesis suggested a sex-specific benefit of PPI gastroprotection in anticoagulated females, requiring confirmation. Conclusions:Substantial sex-based differences in PUD epidemiology, hormonal factors, and treatment response remain unaddressed in current guidelines. In the future, those developing guidelines should consider incorporating postmenopausal status into risk stratification, gastroprotection measures for elderly females on antithrombotic therapy, and sex-specific pharmacokinetic differences in PPI dosing.

PURPOSE:Male sex is a recognized risk factor for colorectal adenoma, yet whether the associations of Helicobacter pylori, atrophic gastritis (AG), and intestinal metaplasia (IM) with colorectal adenoma differ by sex remains unclear. This study evaluated the sex-stratified and combined associations of anti-H. pylori IgG seropositivity, AG, and IM with conventional colorectal adenoma. MATERIALS AND METHODS:This multicenter cross-sectional study included 806 participants from a Korean health-screening cohort who underwent gastroscopy with H. pylori testing and colonoscopy within 3 years. Anti-H. pylori IgG seropositivity was determined by enzyme-linked immunosorbent assay, AG and IM were assessed endoscopically. Multivariable logistic regression models were adjusted for age, sex, body mass index, smoking, and alcohol consumption. RESULTS:Colorectal adenoma was identified in 209 participants (25.6%). Anti-H. pylori IgG seropositivity was independently associated with colorectal adenoma (adjusted odds ratio [aOR], 1.848; 95% confidence interval [CI], 1.323 to 2.581; p<0.001). AG was not significant after adjustment. IM was independently associated in a separate model (aOR, 1.648; 95% CI, 1.125 to 2.415; p=0.010), but showed only borderline significance in the combined model when including H. pylori seropositivity (aOR, 1.440; 95% CI, 0.973 to 2.131; p=0.068), whereas anti-H. pylori IgG seropositivity remained significant. Participants with both H. pylori seropositivity and IM showed the highest odds of colorectal adenoma. In sex-stratified analyses, anti-H. pylori IgG seropositivity was independently associated in males (aOR, 1.811; 95% CI, 1.147 to 2.860; p=0.011) but not in females, whereas IM was independently associated in females (aOR, 2.086; 95% CI, 1.129 to 3.856; p=0.019) but not in males. Formal interaction tests were not statistically significant. CONCLUSIONS:Anti-H. pylori IgG seropositivity and IM were associated with conventional colorectal adenoma, whereas AG was not significant after adjustment. Sex-stratified analyses suggested potential sex-related patterns, with H. pylori seropositivity appearing more prominent in males and IM appearing more prominent in females.

Introduction:Helicobacter pylori (H. pylori) is a major cause of gastric cancer (GC); however, GC also develops in H. pylori-negative patients, and the characteristics of non-H. pylori microbial communities remain unclear. Methods:We characterized gastric microbiota in patients with GC according to H. pylori status, sex, GC subtype, and longitudinal changes following H. pylori eradication therapy. Gastric corpus mucosal samples were collected from 35 patients with GC who underwent endoscopic therapy and longitudinal follow-up. Some patients were followed for more than 10 years, and gastric microbiota were analyzed using 16S rRNA gene sequencing. Results:H. pylori-negative samples exhibited significantly higher microbial diversity and distinct community structures compared with H. pylori-positive samples, which was consistent across sex and GC subtypes. Multiple non-H. pylori taxa were enriched in H. pylori-negative samples, including organisms with reported urease and nitrate-reducing activities. Longitudinal analyses demonstrated that successful eradication induced significant but non-uniform microbial shifts, whereas persistent infection maintained stable H. pylori-dominated profiles. Notably, species-level analyses revealed selective and H. pylori eradication-specific microbial changes, with Actinomyces naeslundii consistently enriched only in the H. pylori eradicated group across longitudinal modeling and differential abundance analyses. Functional prediction analyses revealed a reduced representation of host-pathogen interaction-related pathways in H. pylori-negative samples. Discussion:These findings suggest that H. pylori-negative gastric microbiota harbor functionally distinct microbial communities that may contribute to gastric carcinogenesis through alternative microbial and ecological pathways. In addition, H. pylori eradication revealed a longitudinal remodeling of gastric microbiota.

Purpose:Fecal immunochemical tests (FIT) are widely used for colorectal cancer (CRC) screening. This systematic review and meta-analysis evaluated the diagnostic accuracy of quantitative FIT for CRC and advanced neoplasm (AN), and examined variations in performance by sex, geographic region, study design, FIT platform, and positivity threshold. Materials and Methods:A comprehensive search of MEDLINE, Embase, Cochrane Library, and KoreaMed was conducted. Studies evaluating the accuracy of quantitative FIT for CRC or AN using colonoscopy as a reference standard were included. The pooled sensitivity and specificity were estimated using a bivariate random-effects model. Meta-regression analysis was performed to analyze the diagnostic differences between sexes. Results:Thirty-three studies were included. FIT showed higher sensitivity for CRC than for AN (78.6% vs. 32.3%), with high specificity for both outcomes (93.7% and 95.2%, respectively). Case-control studies yielded a significantly higher AN sensitivity than cohort studies (50.7% vs. 29.7%; p<0.05). Western studies showed significantly higher AN sensitivity and lower specificity than Eastern studies (31.6% vs. 24.2%, p<0.05; and 95.0% vs. 96.5%, p<0.05, respectively). In the sex-stratified analyses, males showed higher AN sensitivity than females (34.1% vs. 30.8%) and significantly lower CRC specificity (90.1% vs. 93.1%; p<0.05); however, the meta-regression showed no significant sex effect on the overall diagnostic accuracy for CRC or AN. Conclusion:Quantitative FIT demonstrated strong performance for CRC detection but limited sensitivity for AN. Variations in the study design, FIT platform, threshold, region, and sex should be considered when interpreting FIT accuracy.

Objectives:Successful eradication of Helicobacter pylori is essential for improving patient outcomes and preventing gastric cancer; however, evidence regarding sex-specific differences in treatment success and adverse event profiles remain limited. This study investigated sex-based differences in eradication efficacy and treatment tolerability. Methods:We retrospectively reviewed patients who underwent diagnostic testing, received eradication therapy, and completed post-treatment confirmation testing between 2003 and 2024 at Seoul National University Bundang Hospital. First-line therapy consisted of 10-day sequential therapy, while second-line treatment included 14-day bismuth-based quadruple therapy or 14-day moxifloxacin-based triple therapy. Treatment success and adverse events were evaluated by sex and treatment regimen. Results:Females had lower eradication rates in the overall cohort. The intention-to-treat analysis showed significantly higher success rates in males compared to females in the total population (71.1% vs. 65.1%, p<0.001) and in sequential therapy (70.5% vs. 62.1%, p<0.001), although this pattern was not replicated in the per-protocol results. Adverse events were reported nearly twice as often in females, regardless of the regimen, which may partly explain the reduced rates of successful eradication and increased discontinuation. Conclusions:Sex-based differences influence H. pylori eradication outcomes, with females showing lower treatment success rates and substantially more adverse events. Higher therapy intolerance and dropout rates in females may partially account for reduced effectiveness of eradication therapy, highlighting the need for sex-specific strategies and improved supportive care.

Probiotics have gained increasing clinical attention as adjunctive treatment for lower gastrointestinal disorders. However, evidence supporting their therapeutic efficacy remains limited, particularly with regard to sex-related differences. This expert review provides evidence-based insights and practical recommendations for the use of probiotics in patients with irritable bowel syndrome (IBS), functional constipation (FC), and Clostridioides difficile infection (CDI), considering possible sex-related differences. Evidence from randomized controlled trials and meta-analyses indicates that probiotics can modestly improve global symptoms, abdominal pain, and bloating in IBS and enhance bowel movement frequency and stool consistency in FC. However, these effects are strain-specific and heterogeneous. Although clinical studies on probiotics in IBS have not confirmed significant sex-related differences, experimental animal studies using stress-induced IBS models have demonstrated sex-dependent responses to specific probiotic strains, supporting the biological plausibility of such differences. For CDI, the efficacy of probiotics in preventing primary or recurrent infections remains inconsistent across large trials, and current guidelines usually do not recommend their routine use. However, sex and age difference of immunology supports the clinical differences of CDI. Probiotics are generally considered safe for healthy individuals, although caution is advised in patients who are immunocompromised or critically ill. Clinicians should select probiotic products based on strain-specific clinical evidence, adequate viable doses, patient's characteristics, or patient's sex. In conclusion, probiotics might play a role as adjunctive therapy for IBS and FC, with variability in responses influenced by microbial, host, and potential sex-related factors. Further research is needed to establish optimized personalized probiotic strategies.

Gastric cancer (GC) remains a significant concern worldwide, with a very high incidence in Japan, South Korea, and China. Early diagnosis of GC is important for reducing its mortality; to achieve this, screening of individuals at a high risk for developing GC should include frequent esophagogastroduodenoscopy. Currently, various population-based GC screening strategies are being implemented in South Korea, Japan, and the Matsu region of Taiwan. Many studies have suggested that serum pepsinogens (sPGs) can be used as GC biomarkers in South Korea, China, Europe, and other countries; indeed, Japan first included the sPG test in GC screening prior to 1990. However, while the role of sPGs (particularly type 1) as a marker of atrophic gastritis is well known, studies on the association between sPG levels and GC have mainly focused on the association with intestinal-type GC. Recent studies have demonstrated that sPGII is associated with severe inflammation and proliferation. Specifically, high sPGII levels and Helicobacter pylori positivity are associated with an increased risk of early diffuse-type GC, particularly in young females. In this review, the physiology of sPGs and the usefulness of sPG levels in the detection of intestinal- or diffuse-type GC are discussed in terms of sex and age.

Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent disorder that significantly impairs quality of life, yet therapeutic advances remain limited. Serotonin dysregulation, primarily driven by enterochromaffin cells in the intestinal epithelium, is central to IBS-D pathogenesis. We hypothesized that targeted modulation of enterochromaffin cell activity through microbiome-based interventions could provide a novel treatment approach. Here, we screened 128 Bifidobacterium isolates and identified B. stercoris KC84 as a promising candidate. KC84 alleviated IBS-D-like symptoms in both chemically and stress-induced models, accompanied by changes in serotonin-related markers. Transcriptomic analysis revealed activation of type I interferon (IFN)-associated pathways, consistent with ex vivo evidence of KC84-induced IFN-β secretion, predominantly from CD11b- dendritic cells. Furthermore, IFN-β treatment attenuated contractile activity in colonic smooth muscle cells. Collectively, these findings suggest that KC84 mitigates IBS-D-like symptoms, potentially through modulation of serotonin-related pathways and activation of a KC84-IFN-β-smooth muscle regulatory axis, supporting KC84 as a mechanism-guided probiotic candidate for IBS-D therapy.

Background/Aims:Colorectal cancer (CRC) shows clear sex-related differences influenced by hormonal and molecular factors, with estrogen generally exerting a protective effect through estrogen receptor beta (ERβ). The nuclear factor erythroid 2-related factor 2 (NRF2) pathway, a key regulator of oxidative stress and immune responses, may interact with estrogen signaling; however, this relationship in CRC patients remains poorly understood. Methods:A total of 300 patients with histologically confirmed CRC, 37 patients with colorectal adenomas, and 35 control subjects were prospectively enrolled. Colonic tissue samples were subjected to immunohistochemical staining for ERα, ERβ, androgen receptor, and NRF2. The associations of ER expression with clinicopathological variables, tumor stage, and survival outcomes were evaluated using chi-square tests, Pearson correlation analysis, Cox proportional hazards regression models, and Kaplan-Meier survival analysis. Results:ERβ expression was significantly lower in patients with advanced-stage, metastatic, and poorly differentiated CRC, whereas higher ERβ expression was more frequent in those with right-sided and early-stage CRC and was associated with higher body mass indices and lower metastatic rates. High ERβ expression correlated with significantly improved overall and cancer-specific survival (p=0.005 and p=0.010, respectively). A strong positive correlation was observed between ERβ and NRF2 expression (r=0.717, p<0.001), suggesting a mechanistic link between estrogen signaling and antioxidative pathways. ERα expression was low and inconsistent, whereas androgen receptor expression correlated with a favorable survival trend but lacked independent prognostic value. Conclusions:High ERβ expression was associated with favorable tumor characteristics and improved survival in CRC, supporting a tumor-suppressive role potentially mediated through interaction with the NRF2 antioxidative pathway (ClinicalTrials.gov identifier: NCT05638542).

Background/Aims:Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder influenced by stress, microbial dysbiosis, and immune activation. Microbiota-directed therapies, including fecal microbiota transplantation and probiotics, show promise, but their sex-specific effects remain unclear. We compared the therapeutic effects of lyophilized fecal microbiota (LFM) with Bifidobacterium longum BBH016 in male and female Wistar rats subjected to repeated water avoidance stress. Methods:Fecal pellet output (FPO), colonic mast cell infiltration, and fecal short-chain fatty acids were measured. Gut microbial composition and function were analyzed by 16S rRNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway prediction. Results:Both interventions significantly reduced FPO and mast cell infiltration in males but had less pronounced effects in females. Microbiota analyses revealed sex-dependent responses, with distinct microbial trajectories in each treatment group. Using linear discriminant analysis effect size, we identified seven key taxa with treatment- or sex-specific enrichment. Alistipes onderdonkii and Bacteroides uniformis consistently increased in both LFM- and B. longum-treated groups, regardless of sex. Bacteroides finegoldii and Barnesiella intestinihominis were specifically enriched in the LFM group. In males, Blautia faecis and Fusicatenibacter saccharivorans were enriched following the interventions, whereas Parabacteroides goldsteinii appeared exclusively in stressed males. Functional predictions revealed the enrichment of estrogen signaling and bile acid pathways in males and the attenuation of proinflammatory pathways in females following LFM. Correlations between microbial taxa and host outcomes were predominantly observed in male rats. Conclusions:These findings highlight sex-specific microbial and host responses to microbiota-targeted therapies in a stress-induced IBS model, emphasizing sex as a biological variable in designing personalized microbiome-based treatments.

PURPOSE:The effect of behavior changes in alcohol drinking on gastric cancer (GC) development, and the sex differences in those effects have not yet been fully elucidated. This study investigated the effect of behavior changes in alcohol drinking on the GC risk by sex. MATERIALS AND METHODS:The cohort consisted of 310,192 Koreans (≥ 40 years) from the National Health Insurance Service-Health Screening Cohort with a median follow-up period of 12 years. Subjects were classified according to alcohol consumption behavior changes (non-drinker, quitter, reducer, sustainer, and increaser). The independent effect of changes in alcohol drinking patterns or concurrent effect of alcohol on GC risk were evaluated using the Cox proportional hazard regression. RESULTS:In males, non-drinkers showed a lower risk of developing GC (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84 to 0.98), whereas increasers showed a higher risk of GC than sustainers (HR, 1.11; 95% CI, 1.02 to 1.20). Starting to drink alcohol, even at a mild level, was associated with an increased GC risk, while a decreased GC risk was induced when alcohol consumption dose decreases to a mild from a moderate level among males. However, in females, only substantial change of alcohol consumption dose from non- to heavy-drinking was associated with increased GC risk (HR, 1.97; 95% CI, 0.98 to 3.96). CONCLUSION:These results suggest that alcohol abstinence can reduce the risk of developing GC, particularly among males.