Pub Date : 2025-09-11DOI: 10.1016/j.gastha.2025.100798
Mercy PrabhuDas, Ryan T. Ranallo, Erin L. Boespflug, Scientific Organizing Committee, Andrew A. Bremer
{"title":"National Institutes of Health–Wide Workshop: Impact of Diet on Mucosal Immunity and Immune-Mediated Inflammatory Diseases of the Gastrointestinal Tract","authors":"Mercy PrabhuDas, Ryan T. Ranallo, Erin L. Boespflug, Scientific Organizing Committee, Andrew A. Bremer","doi":"10.1016/j.gastha.2025.100798","DOIUrl":"10.1016/j.gastha.2025.100798","url":null,"abstract":"","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100798"},"PeriodicalIF":0.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145466981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 10.1016/j.gastha.2025.100800
Mizuki Suzuki , Hwi Young Kim , Michael C. Reed , H. Frederik Nijhout , Allison Cruikshank , Manal Abdelmalek , Anna Mae Diehl , Paul M. Yen , Brijesh Kumar Singh , Madhulika Tripathi , Ayako Suzuki
Background and Aims
Elevated hepatic homocysteine (Hcy) contributes to hepatic inflammation and fibrogenesis in metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to evaluate the association between serum Hcy levels and the risk of MASLD and hepatic fibrosis in a large, diverse population, accounting for clinical confounders and effect modifiers such as sex and reproductive status.
Methods
We analyzed 1999–2006 National Health and Nutrition Examination Survey data for 8253 adults (≥18 years) without hepatitis B/C, excessive alcohol use, or pregnancy. MASLD was defined using the fatty liver index (≥30), and fibrosis risk was assessed using age-adjusted Fibrosis-4 and nonalcoholic fatty liver disease fibrosis score among MASLD subjects (N = 5328). Associations between serum Hcy and MASLD/fibrosis risk were evaluated using multivariable linear regression adjusting for confounders, with stratification by sex and menopausal status.
Results
Serum Hcy levels were higher among those with MASLD (fatty liver index ≥30), though the association was attenuated after covariate adjustment. Among MASLD individuals, those at higher fibrosis risk (based on Fibrosis-4 or nonalcoholic fatty liver disease fibrosis score) had significantly elevated Hcy levels. This association remained significant in men and postmenopausal women, but not in premenopausal women.
Conclusion
Elevated serum Hcy is independently associated with hepatic fibrosis risk in MASLD, particularly in men and postmenopausal women. These findings underscore the importance of accounting for sex and menopausal status in future Hcy-lowering interventions targeting MASLD.
{"title":"Elevated Homocysteine is Associated With Liver Fibrosis in Metabolic Dysfunction–Associated Steatotic Liver Disease in a Sex- and Menopause-Specific Manner","authors":"Mizuki Suzuki , Hwi Young Kim , Michael C. Reed , H. Frederik Nijhout , Allison Cruikshank , Manal Abdelmalek , Anna Mae Diehl , Paul M. Yen , Brijesh Kumar Singh , Madhulika Tripathi , Ayako Suzuki","doi":"10.1016/j.gastha.2025.100800","DOIUrl":"10.1016/j.gastha.2025.100800","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Elevated hepatic homocysteine (Hcy) contributes to hepatic inflammation and fibrogenesis in metabolic dysfunction–associated steatotic liver disease (MASLD). We aimed to evaluate the association between serum Hcy levels and the risk of MASLD and hepatic fibrosis in a large, diverse population, accounting for clinical confounders and effect modifiers such as sex and reproductive status.</div></div><div><h3>Methods</h3><div>We analyzed 1999–2006 National Health and Nutrition Examination Survey data for 8253 adults (≥18 years) without hepatitis B/C, excessive alcohol use, or pregnancy. MASLD was defined using the fatty liver index (≥30), and fibrosis risk was assessed using age-adjusted Fibrosis-4 and nonalcoholic fatty liver disease fibrosis score among MASLD subjects (N = 5328). Associations between serum Hcy and MASLD/fibrosis risk were evaluated using multivariable linear regression adjusting for confounders, with stratification by sex and menopausal status.</div></div><div><h3>Results</h3><div>Serum Hcy levels were higher among those with MASLD (fatty liver index ≥30), though the association was attenuated after covariate adjustment. Among MASLD individuals, those at higher fibrosis risk (based on Fibrosis-4 or nonalcoholic fatty liver disease fibrosis score) had significantly elevated Hcy levels. This association remained significant in men and postmenopausal women, but not in premenopausal women.</div></div><div><h3>Conclusion</h3><div>Elevated serum Hcy is independently associated with hepatic fibrosis risk in MASLD, particularly in men and postmenopausal women. These findings underscore the importance of accounting for sex and menopausal status in future Hcy-lowering interventions targeting MASLD.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100800"},"PeriodicalIF":0.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145364338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1016/j.gastha.2025.100792
Mohamed H. Eldesouki , Ashlynn Black , Karimar Amador-Martínez , Mohamed Yaser Elnaggar , Khaled Elfert , Nikki Duong
{"title":"Metabolic and Alcohol-Associated Liver Disease in Hispanics: Disparities in Outcomes Using Real-World Data From a National Sample","authors":"Mohamed H. Eldesouki , Ashlynn Black , Karimar Amador-Martínez , Mohamed Yaser Elnaggar , Khaled Elfert , Nikki Duong","doi":"10.1016/j.gastha.2025.100792","DOIUrl":"10.1016/j.gastha.2025.100792","url":null,"abstract":"","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100792"},"PeriodicalIF":0.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-02DOI: 10.1016/j.gastha.2025.100772
Jeong Yun Yang , Josephine Soddano , Sophie Wagner , Ji Yoon Yoon , Jennifer S. Ferris , Chin Hur
{"title":"Upper Endoscopy Is Associated With Reduced Gastric Cancer-Specific and Overall Mortality in Patients Undergoing Colonoscopy or Sigmoidoscopy","authors":"Jeong Yun Yang , Josephine Soddano , Sophie Wagner , Ji Yoon Yoon , Jennifer S. Ferris , Chin Hur","doi":"10.1016/j.gastha.2025.100772","DOIUrl":"10.1016/j.gastha.2025.100772","url":null,"abstract":"","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100772"},"PeriodicalIF":0.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Combination therapy with the anti–programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab and the anti–vascular endothelial growth factor-A (anti-VEGF-A) antibody bevacizumab (Atezolizumab/Bevacizumab) has commonly been used as first-line treatment for advanced hepatocellular carcinoma (HCC). However, effective second-line treatment options remain under debate. The anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab has shown promise in unresectable HCC with high serum alpha-fetoprotein (AFP) levels, but its efficacy after Atezolizumab/Bevacizumab is unclear. This study investigated the effects of VEGFR2 inhibition on the tumor microenvironment and cancer stem cells (CSCs) in HCC after anti-PD-L1/anti-VEGF-A treatment.
Methods
AFP-positive human and mouse HCC cell lines were used to evaluate the effects of the antimouse VEGFR2 antibody DC101. Syngeneic mouse models were employed to analyze the impact of DC101 as a secondary treatment following anti-PD-L1/anti-VEGF-A treatment. Various molecular biological analyses were conducted to assess tumor growth, gene expression, cellular localization, cell–cell interactions, and alterations in the tumor microenvironment.
Results
DC101 significantly inhibited tumor growth and disrupted cell–cell interactions between AFP-positive HCC cells and VEGFR2-positive endothelial cells (ECs) in human HCC xenograft models. DC101 treatment following anti-PD-L1/anti-VEGF-A treatment showed notable antitumor effects in a syngeneic mouse model, with reduced expression of CSC and EC markers. Comprehensive gene expression analysis revealed that DC101 downregulates pathways associated with cancer stemness. Furthermore, single-cell analysis demonstrated that DC101 suppresses CSCs by disrupting their interaction with ECs and induces alterations in the tumor immune microenvironment.
Conclusion
VEGFR2-targeted therapy not only suppressed tumor angiogenesis but also inhibited CSCs and enhanced antitumor immune activity, suggesting its potential utility as a second-line treatment following Atezolizumab/Bevacizumab.
{"title":"Vascular Endothelial Growth Factor Receptor 2-Targeted Therapy Suppresses the Progression of Alpha-Fetoprotein-Positive Hepatocellular Carcinoma After Combination Therapy With Anti–Programmed Death-Ligand 1 and Anti–Vascular Endothelial Growth Factor-A Antibodies","authors":"Gen Sugiyama , Kouki Nio , Hikari Okada , Akihiko Kida , Keisuke Sako , Yasunori Iwata , Hideo Takayama , Yutaro Kawakami , Tomoyoshi Chiba , Kazuki Nagai , Saiho Sugimoto , Masaki Nishitani , Tomoyuki Hayashi , Hajime Takatori , Tetsuro Shimakami , Masao Honda , Taro Yamashita","doi":"10.1016/j.gastha.2025.100778","DOIUrl":"10.1016/j.gastha.2025.100778","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Combination therapy with the anti–programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab and the anti–vascular endothelial growth factor-A (anti-VEGF-A) antibody bevacizumab (Atezolizumab/Bevacizumab) has commonly been used as first-line treatment for advanced hepatocellular carcinoma (HCC). However, effective second-line treatment options remain under debate. The anti–vascular endothelial growth factor receptor 2 (VEGFR2) antibody ramucirumab has shown promise in unresectable HCC with high serum alpha-fetoprotein (AFP) levels, but its efficacy after Atezolizumab/Bevacizumab is unclear. This study investigated the effects of VEGFR2 inhibition on the tumor microenvironment and cancer stem cells (CSCs) in HCC after anti-PD-L1/anti-VEGF-A treatment.</div></div><div><h3>Methods</h3><div>AFP-positive human and mouse HCC cell lines were used to evaluate the effects of the antimouse VEGFR2 antibody DC101. Syngeneic mouse models were employed to analyze the impact of DC101 as a secondary treatment following anti-PD-L1/anti-VEGF-A treatment. Various molecular biological analyses were conducted to assess tumor growth, gene expression, cellular localization, cell–cell interactions, and alterations in the tumor microenvironment.</div></div><div><h3>Results</h3><div>DC101 significantly inhibited tumor growth and disrupted cell–cell interactions between AFP-positive HCC cells and VEGFR2-positive endothelial cells (ECs) in human HCC xenograft models. DC101 treatment following anti-PD-L1/anti-VEGF-A treatment showed notable antitumor effects in a syngeneic mouse model, with reduced expression of CSC and EC markers. Comprehensive gene expression analysis revealed that DC101 downregulates pathways associated with cancer stemness. Furthermore, single-cell analysis demonstrated that DC101 suppresses CSCs by disrupting their interaction with ECs and induces alterations in the tumor immune microenvironment.</div></div><div><h3>Conclusion</h3><div>VEGFR2-targeted therapy not only suppressed tumor angiogenesis but also inhibited CSCs and enhanced antitumor immune activity, suggesting its potential utility as a second-line treatment following Atezolizumab/Bevacizumab.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100778"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-30DOI: 10.1016/j.gastha.2025.100786
Kalee Moore , Colby Adamson , Alexander Grieme , Suparna Nanua , Erik Rahimi
{"title":"The Impact, Characteristics, and Demographics of Choledochal Cysts From a Local Population in Texas","authors":"Kalee Moore , Colby Adamson , Alexander Grieme , Suparna Nanua , Erik Rahimi","doi":"10.1016/j.gastha.2025.100786","DOIUrl":"10.1016/j.gastha.2025.100786","url":null,"abstract":"","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100786"},"PeriodicalIF":0.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To date, neoadjuvant chemotherapy (NAC) is a well-accepted therapeutic strategy for patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). We previously reported that the relative abundance of Bifidobacterium in the gut microbiota is associated with a more favorable pathological response to NAC in R/BR-PDAC. In the current study, we evaluated the association between pretreatment gut microbiota and postoperative prognosis in patients with R/BR-PDAC who underwent pancreatectomy after NAC.
Methods
In this prospective observational study, we analyzed 42 patients with R/BR-PDAC who underwent pancreatic resection following NAC with gemcitabine plus S-1 between 2020 and 2022 at Kansai Medical University Hospital. Stool samples were collected at PDAC diagnosis for microbiota analysis using 16S RNA gene sequences. In 19 genera accounting for ≥ 1% in relative abundance, the relationship between the microbiota profile and recurrence-free survival (RFS) and overall survival was examined using the Kaplan–Meier method and the Cox proportional hazards model.
Results
The median postoperative observation period was 24 months. During the observation period, 23 patients (55%) experienced recurrence, and 10 patients (24%) died of PDAC. RFS was significantly favorable in patients in the high-Bifidobacterium group (relative abundance ≥ 4%) compared to patients in the low-Bifidobacterium group (<4%). Furthermore, multivariable analysis revealed high-Bifidobacterium and pathological metastasis of lymph node were significantly associated with RFS (hazard ratio 0.37; 95% confidence interval 0.14–0.97, P = .042). Regarding overall survival, there was no significant association with gut microbiota, including Bifidobacterium genus (hazard ratio 0.23; 95% confidence interval 0.03–1.50), in the multivariable analysis.
Conclusion
The relative abundance of Bifidobacterium in the gut microbiota at diagnosis may be a predictor of postoperative recurrence in patients with R/BR-PDAC treated with NAC.
{"title":"Fecal Bifidobacterium Serves as a Predictor of Postoperative Recurrence After Neoadjuvant Chemotherapy in Pancreatic Cancer","authors":"Ayaka Takaori , Tsukasa Ikeura , Daisuke Hashimoto , Motonobu Maruo , Masatoshi Ikeda , Takashi Ito , Koh Nakamaru , Masataka Masuda , Shinji Nakayama , Hidetaka Miyazaki , Kazuki Matsumura , So Yamaki , Tomoyo Yasuda , Masashi Kanai , Shohei Akagawa , Shoji Tsuji , Koichiro Higasa , Sohei Satoi , Makoto Naganuma","doi":"10.1016/j.gastha.2025.100779","DOIUrl":"10.1016/j.gastha.2025.100779","url":null,"abstract":"<div><h3>Background and Aims</h3><div>To date, neoadjuvant chemotherapy (NAC) is a well-accepted therapeutic strategy for patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). We previously reported that the relative abundance of <em>Bifidobacterium</em> in the gut microbiota is associated with a more favorable pathological response to NAC in R/BR-PDAC. In the current study, we evaluated the association between pretreatment gut microbiota and postoperative prognosis in patients with R/BR-PDAC who underwent pancreatectomy after NAC.</div></div><div><h3>Methods</h3><div>In this prospective observational study, we analyzed 42 patients with R/BR-PDAC who underwent pancreatic resection following NAC with gemcitabine plus S-1 between 2020 and 2022 at Kansai Medical University Hospital. Stool samples were collected at PDAC diagnosis for microbiota analysis using 16S RNA gene sequences. In 19 genera accounting for ≥ 1% in relative abundance, the relationship between the microbiota profile and recurrence-free survival (RFS) and overall survival was examined using the Kaplan–Meier method and the Cox proportional hazards model.</div></div><div><h3>Results</h3><div>The median postoperative observation period was 24 months. During the observation period, 23 patients (55%) experienced recurrence, and 10 patients (24%) died of PDAC. RFS was significantly favorable in patients in the high-<em>Bifidobacterium</em> group (relative abundance ≥ 4%) compared to patients in the low-<em>Bifidobacterium</em> group (<4%). Furthermore, multivariable analysis revealed high-<em>Bifidobacterium</em> and pathological metastasis of lymph node were significantly associated with RFS (hazard ratio 0.37; 95% confidence interval 0.14–0.97, <em>P</em> = .042). Regarding overall survival, there was no significant association with gut microbiota, including <em>Bifidobacterium</em> genus (hazard ratio 0.23; 95% confidence interval 0.03–1.50), in the multivariable analysis.</div></div><div><h3>Conclusion</h3><div>The relative abundance of <em>Bifidobacterium</em> in the gut microbiota at diagnosis may be a predictor of postoperative recurrence in patients with R/BR-PDAC treated with NAC.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100779"},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transmembrane 6 superfamily member 2 (TM6SF2) p.Glu167Lys (E167K) is associated with hepatic steatosis and male-predominant type 2 diabetes (T2D) presumably due to defective secretion of very low density lipoprotein (VLDL) particles. The causal relationship between secreted VLDL density and insulin sensitivity in the context of the E167K variant remains unclear.
Methods
E167K-carrying induced pluripotent stem cells were generated using a genome-editing method. Guided by targeted phospholipidomic analysis, we established an improved protocol to derive hepatocyte-like cells (HLCs) from induced pluripotent stem cells with significantly improved VLDL secretory profiles after linoleic acid, arachidonic acid and Liver X receptor agonist exposure. Furthermore, the E167K-defined steatosis and metabolic phenotype of HLCs treated with or without dihydrotestosterone were analyzed. In public database, we stratified male subjects by testosterone level and analyzed the impact of TM6SF2 on the incidence of hepatic steatosis and T2D.
Results
E167K hepatocytes showed defective VLDL secretion and an exacerbated lipid accumulation phenotype, accompanied by a decrease in arachidonic acid-containing phosphatidylcholine. Furthermore, dihydrotestosterone supplementation worsened the steatotic phenotype of E167K HLCs without altering insulin sensitivity. In the clinical data, E167K-defined hepatic steatosis was testosterone-dosage dependent unlike the other genetic variant, while T2D was not.
Conclusion
We report an improved human hepatocyte differentiation model to investigate metabolic dysfunction with functional VLDL secretory profiles influenced by TM6SF2 gene variant. Our combinatorial analysis of in vitro and human data indicates that male testosterone modifies the effect of E167K on hepatic steatosis but not insulin sensitivity. These data support the hypothesis that male-predominant T2D in E167K carriers is not causative but rather a consequence of persistent steatosis.
{"title":"Modeling Transmembrane 6 Superfamily Member 2 p.Glu167Lys-associated Steatotic Liver Disease Using Androgen-treated Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells","authors":"Asei Hirai , Yosuke Yoneyama , Ismael Assi , Sho Osonoi , Sosuke Sakai , Kanae Ohtsu , Takanori Takebe","doi":"10.1016/j.gastha.2025.100774","DOIUrl":"10.1016/j.gastha.2025.100774","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Transmembrane 6 superfamily member 2 (TM6SF2) p.Glu167Lys (E167K) is associated with hepatic steatosis and male-predominant type 2 diabetes (T2D) presumably due to defective secretion of very low density lipoprotein (VLDL) particles. The causal relationship between secreted VLDL density and insulin sensitivity in the context of the E167K variant remains unclear.</div></div><div><h3>Methods</h3><div>E167K-carrying induced pluripotent stem cells were generated using a genome-editing method. Guided by targeted phospholipidomic analysis, we established an improved protocol to derive hepatocyte-like cells (HLCs) from induced pluripotent stem cells with significantly improved VLDL secretory profiles after linoleic acid, arachidonic acid and Liver X receptor agonist exposure. Furthermore, the E167K-defined steatosis and metabolic phenotype of HLCs treated with or without dihydrotestosterone were analyzed. In public database, we stratified male subjects by testosterone level and analyzed the impact of TM6SF2 on the incidence of hepatic steatosis and T2D.</div></div><div><h3>Results</h3><div>E167K hepatocytes showed defective VLDL secretion and an exacerbated lipid accumulation phenotype, accompanied by a decrease in arachidonic acid-containing phosphatidylcholine. Furthermore, dihydrotestosterone supplementation worsened the steatotic phenotype of E167K HLCs without altering insulin sensitivity. In the clinical data, E167K-defined hepatic steatosis was testosterone-dosage dependent unlike the other genetic variant, while T2D was not.</div></div><div><h3>Conclusion</h3><div>We report an improved human hepatocyte differentiation model to investigate metabolic dysfunction with functional VLDL secretory profiles influenced by TM6SF2 gene variant. Our combinatorial analysis of <em>in vitro</em> and human data indicates that male testosterone modifies the effect of E167K on hepatic steatosis but not insulin sensitivity. These data support the hypothesis that male-predominant T2D in E167K carriers is not causative but rather a consequence of persistent steatosis.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100774"},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-28DOI: 10.1016/j.gastha.2025.100776
Gaurav Syal , Siddharth Singh , Edward L. Barnes
Background and Aims
The 8-strain probiotic formulation appears to be effective for primary and secondary prevention of pouchitis in patients with ulcerative colitis after ileal pouch anal anastomosis. We aimed to study its cost-effectiveness compared to no prophylaxis in these settings.
Methods
We constructed decision trees with Markov models for primary prevention of pouchitis and secondary prevention of relapsing pouchitis in patients with ulcerative colitis after ileal pouch anal anastomosis. All patients were followed for 2 years. In the primary prophylaxis model, Markov cycle length was 2 weeks and the pouchitis treatment sequence was ciprofloxacin, metronidazole and a combination of ciprofloxacin and tinidazole. In the secondary prophylaxis models, the Markov cycle length was 4 weeks and the pouchitis treatment sequence was ciprofloxacin, metronidazole, ciprofloxacin/tinidazole, vedolizumab and infliximab. Third-party payers’ perspective with a willingness-to-pay threshold of $100,000/quality-adjusted life years (QALYs) was used. Frequent relapsing pouchitis was defined as ≥2 pouchitis episodes/year.
Results
For primary prevention of pouchitis, no prophylaxis was more cost effective compared with the probiotic prophylaxis on base-case analysis (incremental cost effectiveness ratio $236,661/QALY). On base-case analysis for secondary prevention of pouchitis relapse in infrequent pouchitis, no prophylaxis was more cost effective compared to the probiotic prophylaxis (incremental cost effectiveness ratio $153,011/QALY). One-way sensitivity analysis showed that the probiotic prophylaxis would be the dominant strategy in patients with frequent relapsing pouchitis.
Conclusion
Compared to no prophylaxis, the 8-strain probiotic is not cost-effective for primary prevention of pouchitis. It is cost-effective for secondary prophylaxis of frequent pouchitis but not for secondary prophylaxis of infrequent pouchitis.
{"title":"Cost Effectiveness of the 8-Strain Probiotic in Primary and Secondary Prophylaxis of Pouchitis","authors":"Gaurav Syal , Siddharth Singh , Edward L. Barnes","doi":"10.1016/j.gastha.2025.100776","DOIUrl":"10.1016/j.gastha.2025.100776","url":null,"abstract":"<div><h3>Background and Aims</h3><div>The 8-strain probiotic formulation appears to be effective for primary and secondary prevention of pouchitis in patients with ulcerative colitis after ileal pouch anal anastomosis. We aimed to study its cost-effectiveness compared to no prophylaxis in these settings.</div></div><div><h3>Methods</h3><div>We constructed decision trees with Markov models for primary prevention of pouchitis and secondary prevention of relapsing pouchitis in patients with ulcerative colitis after ileal pouch anal anastomosis. All patients were followed for 2 years. In the primary prophylaxis model, Markov cycle length was 2 weeks and the pouchitis treatment sequence was ciprofloxacin, metronidazole and a combination of ciprofloxacin and tinidazole. In the secondary prophylaxis models, the Markov cycle length was 4 weeks and the pouchitis treatment sequence was ciprofloxacin, metronidazole, ciprofloxacin/tinidazole, vedolizumab and infliximab. Third-party payers’ perspective with a willingness-to-pay threshold of $100,000/quality-adjusted life years (QALYs) was used. Frequent relapsing pouchitis was defined as ≥2 pouchitis episodes/year.</div></div><div><h3>Results</h3><div>For primary prevention of pouchitis, no prophylaxis was more cost effective compared with the probiotic prophylaxis on base-case analysis (incremental cost effectiveness ratio $236,661/QALY). On base-case analysis for secondary prevention of pouchitis relapse in infrequent pouchitis, no prophylaxis was more cost effective compared to the probiotic prophylaxis (incremental cost effectiveness ratio $153,011/QALY). One-way sensitivity analysis showed that the probiotic prophylaxis would be the dominant strategy in patients with frequent relapsing pouchitis.</div></div><div><h3>Conclusion</h3><div>Compared to no prophylaxis, the 8-strain probiotic is not cost-effective for primary prevention of pouchitis. It is cost-effective for secondary prophylaxis of frequent pouchitis but not for secondary prophylaxis of infrequent pouchitis.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100776"},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145271178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-26DOI: 10.1016/j.gastha.2025.100767
Rohan Ahuja , Malek Shatila , Jay Shah , Cristina Natha , Varun Vemulapalli MDi , Nitish Mittal , Jasmine Mikal Haydel , Irene Jeong-Ah Lee , Andres Caleb Urias Rivera , Carolina Colli Cruz , Bryan Schneider , Shilpa Grover , Aliyah Pabani , Anusha S. Thomas , Yinghong Wang
Background and Aims
Risk factors for immune checkpoint inhibitor (ICI) therapy enterocolitis (IMC) have not been greatly explored. Abdominal surgery can reduce bacterial diversity, increase the presence of pathogenic bacteria, and lead to inflammatory changes. This retrospective analysis seeks to determine if a history of recent abdominal surgery in patients who receive ICI therapy affects the severity and duration of enterocolitis.
Methods
We retrospectively reviewed patients with history of abdominal surgeries, who received ICI for cancers and then developed IMC. Clinical profiles, oncology variables, and colitis-related characteristics were reported.
Results
Seven hundred sixty-five patients met the inclusion criteria. Patients median age was 64 years, were predominantly Caucasian (78.2%), and male (58.1%). Melanoma and genitourinary cancers both had 29.5% (N = 222) patients. Programmed death-1/ligand-1 agents (50.2%) or combination therapy (44.2%) were the most common treatments. Patients with a history of abdominal surgery (N = 352) had higher rates of upper GI immune-related adverse events (24 vs 16%, P = .014) compared to patients without (N = 444). Those with abdominal surgery within 3 years of IMC (N = 111) had significantly higher rates of hospitalization (72.1 vs 59.8%), recurrence of symptoms (59.6% vs 42.2%), upper GI immune-related adverse events (25.2 vs 16.4%) and worse overall survival (P = .025). Concomitant antibiotic use (N = 31) led to even higher rates of hospitalization (80.6%), recurrence of symptoms (62.1%), and upper GI symptoms (42.9%).
Conclusion
Surgery within 3 years of IMC diagnosis confers an increased IMC severity with high rates of hospitalization, recurrence, upper gastrointestinal adverse events, and decreased overall survival. Concomitant antibiotic usage serves as an effect modifier increasing the severity of the disease course.
背景与目的免疫检查点抑制剂（ICI）治疗小肠结肠炎（IMC）的危险因素尚未深入研究。腹部手术可减少细菌多样性，增加致病菌的存在，并导致炎症变化。本回顾性分析旨在确定接受ICI治疗的患者近期腹部手术史是否会影响小肠结肠炎的严重程度和持续时间。方法回顾性分析有腹部手术史的患者，这些患者因癌症接受ICI后发展为IMC。报告了临床概况、肿瘤变量和结肠炎相关特征。结果765例患者符合纳入标准。患者中位年龄为64岁，主要为白种人（78.2%）和男性（58.1%）。黑色素瘤和泌尿生殖系统癌均为29.5% （N = 222）。程序性死亡-1/配体-1药物（50.2%）或联合治疗（44.2%）是最常见的治疗方法。有腹部手术史的患者（N = 352）与没有手术史的患者（N = 444）相比，上消化道免疫相关不良事件发生率更高（24 vs 16%, P = 0.014）。IMC 3年内进行腹部手术的患者（N = 111）的住院率（72.1 vs 59.8%）、症状复发率（59.6% vs 42.2%）、上消化道免疫相关不良事件发生率（25.2 vs 16.4%）和总生存率较差（P = 0.025）。同时使用抗生素（N = 31）导致更高的住院率（80.6%）、症状复发率（62.1%）和上消化道症状（42.9%）。结论IMC诊断3年内手术加重了IMC的严重程度，住院率、复发率、上胃肠道不良事件发生率高，总生存率降低。同时使用抗生素可作为一种效果调节剂，增加病程的严重程度。
{"title":"Recent Abdominal Surgery as a Risk Factor for Unfavorable Immune-Mediated Colitis Outcomes","authors":"Rohan Ahuja , Malek Shatila , Jay Shah , Cristina Natha , Varun Vemulapalli MDi , Nitish Mittal , Jasmine Mikal Haydel , Irene Jeong-Ah Lee , Andres Caleb Urias Rivera , Carolina Colli Cruz , Bryan Schneider , Shilpa Grover , Aliyah Pabani , Anusha S. Thomas , Yinghong Wang","doi":"10.1016/j.gastha.2025.100767","DOIUrl":"10.1016/j.gastha.2025.100767","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Risk factors for immune checkpoint inhibitor (ICI) therapy enterocolitis (IMC) have not been greatly explored. Abdominal surgery can reduce bacterial diversity, increase the presence of pathogenic bacteria, and lead to inflammatory changes. This retrospective analysis seeks to determine if a history of recent abdominal surgery in patients who receive ICI therapy affects the severity and duration of enterocolitis.</div></div><div><h3>Methods</h3><div>We retrospectively reviewed patients with history of abdominal surgeries, who received ICI for cancers and then developed IMC. Clinical profiles, oncology variables, and colitis-related characteristics were reported.</div></div><div><h3>Results</h3><div>Seven hundred sixty-five patients met the inclusion criteria. Patients median age was 64 years, were predominantly Caucasian (78.2%), and male (58.1%). Melanoma and genitourinary cancers both had 29.5% (N = 222) patients. Programmed death-1/ligand-1 agents (50.2%) or combination therapy (44.2%) were the most common treatments. Patients with a history of abdominal surgery (N = 352) had higher rates of upper GI immune-related adverse events (24 vs 16%, <em>P</em> = .014) compared to patients without (N = 444). Those with abdominal surgery within 3 years of IMC (N = 111) had significantly higher rates of hospitalization (72.1 vs 59.8%), recurrence of symptoms (59.6% vs 42.2%), upper GI immune-related adverse events (25.2 vs 16.4%) and worse overall survival (<em>P</em> = .025). Concomitant antibiotic use (N = 31) led to even higher rates of hospitalization (80.6%), recurrence of symptoms (62.1%), and upper GI symptoms (42.9%).</div></div><div><h3>Conclusion</h3><div>Surgery within 3 years of IMC diagnosis confers an increased IMC severity with high rates of hospitalization, recurrence, upper gastrointestinal adverse events, and decreased overall survival. Concomitant antibiotic usage serves as an effect modifier increasing the severity of the disease course.</div></div>","PeriodicalId":73130,"journal":{"name":"Gastro hep advances","volume":"5 1","pages":"Article 100767"},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145270547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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