Claudio Bernardazzi, Tultul Saha, Michael A Gurney, Daniel Laubitz, Pujarini Dutta Dey, Tarek Masannat, Irshad Ali Sheikh, Monica T Midura-Kiela, Fayez K Ghishan, Pawel R Kiela
{"title":"NHE3 Controls Proliferation and Migration of Colonic Epithelial Cells.","authors":"Claudio Bernardazzi, Tultul Saha, Michael A Gurney, Daniel Laubitz, Pujarini Dutta Dey, Tarek Masannat, Irshad Ali Sheikh, Monica T Midura-Kiela, Fayez K Ghishan, Pawel R Kiela","doi":"10.1093/ibd/izaf024","DOIUrl":"10.1093/ibd/izaf024","url":null,"abstract":"<p><strong>Background: </strong>In the gut, Na+/H+ exchanger 3 (NHE3; SLC9A3) plays important roles in pH regulation, absorption of Na+, and indirectly of other nutrients. NHE3-deficient mice develop inflammatory bowel disease (IBD)-like dysbiosis and spontaneous colitis, and rare mutations in the SLC9A3 gene may confer a risk factor for very early-onset IBD. However, the roles of NHE3 in the epithelial cell functions beyond the canonical ion transport, especially in the face of injury, remain poorly understood. Thus, we aimed to investigate the role of NHE3 in colonic epithelial cell proliferation and migration during wound healing.</p><p><strong>Methods: </strong>Colonic organoids from NHE3+/+ and NHE3-/- mice and SK-CO-15 cells with shRNA-mediated NHE3 knockdown (NHE3KD) were used to assess the intrinsic role of NHE3 in cellular proliferation, migration, wound healing, adhesion to the extracellular matrix (ECM), activation status of focal adhesion kinase (pFAKY397), and in gene transcription.</p><p><strong>Results: </strong>NHE3-/- colonoids showed increased cell proliferation and reduced ECM adhesion. NHE3-/- colonoids and NHE3KD cells showed increased spontaneous motility, enhanced migration in serum gradient, and in 2 models of wound healing. This was associated with FAK and Src activation and modulation of genes associated with cell-cell interactions, cell-ECM interactions, and the formation of focal adhesions. Inhibition of FAK autophosphorylation eliminated the effect of NHE3 deficiency on cell migration.</p><p><strong>Conclusions: </strong>Inhibition of NHE3, unconfounded by chronic inflammatory or microbial pressure, may represent a permissible mechanism beneficial to the host by modulating cellular plasticity and promoting epithelial wound healing. These unexpected results provide a novel insight into the pleiotropic roles of NHE3 in mucosal homeostasis.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"1966-1979"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prabhdeep Kaur, Thangaraj Karuppuchamy, Amruth Chilukuri, Margaret Kim, Josef Urrete, Zining Shen, Leo Saxon, Luke R Lundborg, Zbigniew Mikulski, Paul Jedlicka, Jesús Rivera-Nieves
{"title":"S1P Lyase Inhibition Increased Intestinal S1P, Disrupted the Intestinal Barrier and Aggravated DSS-Induced Colitis.","authors":"Prabhdeep Kaur, Thangaraj Karuppuchamy, Amruth Chilukuri, Margaret Kim, Josef Urrete, Zining Shen, Leo Saxon, Luke R Lundborg, Zbigniew Mikulski, Paul Jedlicka, Jesús Rivera-Nieves","doi":"10.1093/ibd/izaf030","DOIUrl":"10.1093/ibd/izaf030","url":null,"abstract":"<p><strong>Background: </strong>Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity.</p><p><strong>Methods: </strong>We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability.</p><p><strong>Results: </strong>Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise.</p><p><strong>Conclusion: </strong>Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"1994-2006"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Efficacy of Mirikizumab in Patients with Prior Ustekinumab Exposure: A Case Series.","authors":"Tsunaki Sawada, Masanao Nakamura, Takeshi Yamamura, Keiko Maeda, Eri Ishikawa, Kentaro Murate, Hiroki Kawashima","doi":"10.1093/ibd/izaf018","DOIUrl":"10.1093/ibd/izaf018","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"2040-2041"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ariel A Jordan, Shubha Bhat, Tauseef Ali, Sarah R Brunskill, Nancy A Clusen, Ross M Maltz, Ced Moise, Xiaofan Sun, Harry J Thomas, Cassie Ray, Mary Harkins-Schwarz, Orna G Ehrlich
{"title":"Healthcare Access for Patients With Inflammatory Bowel Disease in the United States: A Survey by the Crohn's & Colitis Foundation.","authors":"Ariel A Jordan, Shubha Bhat, Tauseef Ali, Sarah R Brunskill, Nancy A Clusen, Ross M Maltz, Ced Moise, Xiaofan Sun, Harry J Thomas, Cassie Ray, Mary Harkins-Schwarz, Orna G Ehrlich","doi":"10.1093/ibd/izae237","DOIUrl":"10.1093/ibd/izae237","url":null,"abstract":"<p><strong>Background: </strong>A prior survey disseminated in 2017 identified that healthcare access barriers exist and significantly affect patients with inflammatory bowel disease (IBD). We sought to identify, through an updated survey, the healthcare access barriers that patients continue to face, with a focus on socioeconomic factors and patient awareness of resources to navigate existing barriers.</p><p><strong>Methods: </strong>A 52-question online survey evaluating (1) access to healthcare professionals, medications, and procedures; (2) associated financial challenges; and (3) patient awareness of education and advocacy tools to navigate IBD care barriers, was disseminated through multiple channels to IBD patients and their caregivers.</p><p><strong>Results: </strong>Of the 2281 completed responses, patients on advanced specialty medications, younger than 65 years of age, or on employer insurance experienced significantly greater issues with insurance barriers to accessing medications and coverage of medically necessary tests/treatments. Patients who live in areas of concentrated poverty were more likely to experience poor health outcomes when subjected to step therapy compared to patients who did not. Additionally, patients were more likely to experience one or more financial barriers or trade-offs if the patient used an advanced specialty medicine or lived in an area with concentrated poverty.</p><p><strong>Conclusions: </strong>While there have been significant and numerous advancements in IBD treatments, patients with IBD continue to experience barriers to healthcare access and treatment and financial struggles. Ongoing awareness and advocacy efforts focused on healthcare system reform and related policies to further minimize care disparities and barriers remain vital.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"1819-1832"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andreas Blesl, Lukas Binder, Bettina Halwachs, Franziska Baumann-Durchschein, Stefan Fürst, Patrizia Constantini-Kump, Heimo Wenzl, Gregor Gorkiewicz, Christoph Högenauer
{"title":"The Fecal Microbiome of IBD Patients Is Less Divertible by Bowel Preparation Compared to Healthy Controls: Results From a Prospective Study.","authors":"Andreas Blesl, Lukas Binder, Bettina Halwachs, Franziska Baumann-Durchschein, Stefan Fürst, Patrizia Constantini-Kump, Heimo Wenzl, Gregor Gorkiewicz, Christoph Högenauer","doi":"10.1093/ibd/izaf053","DOIUrl":"10.1093/ibd/izaf053","url":null,"abstract":"<p><strong>Background: </strong>The fecal microbiome of patients with inflammatory bowel diseases (IBD) is characterized by longitudinal variability. It remains unknown if this is caused by decreased resilience of the microbiome to external factors. We investigated the influence of osmotic diarrhea induced by bowel preparation as a disruptive factor on the fecal microbiome in IBD patients and healthy comparators.</p><p><strong>Methods: </strong>We conducted a prospective, single-center study including IBD patients and healthy controls scheduled for colonoscopy with uniform bowel preparation. Fecal samples were collected at 7 time points prior, during, and until 3 months after the intervention. 16S rRNA was isolated from stool and sequenced using the Illumina technique.</p><p><strong>Results: </strong>Twenty-two IBD patients and 17 healthy controls were included in the study. Baseline diversity was higher in healthy controls. Bowel preparation longitudinally decreased alpha diversity and altered beta diversity and taxonomic composition in both groups. Alterations were more pronounced in healthy controls, and the microbial composition converged between the 2 groups. Bowel preparation resulted in an increased relative abundance of Anaerostipes and Coprococcus in both groups and in decreased relative abundance of Bifidobacterium and Clostridium sensu stricto in IBD patients and of Eubacterium hallii group and Ruminococcus in healthy controls. Changes largely restored to baseline composition within 1 week in both groups and remained stable thereafter.</p><p><strong>Conclusions: </strong>Bowel preparation induced reversible short-term microbial perturbations which were less pronounced in IBD patients than in healthy comparators suggesting that a single external disruptive factor may have less impact on an already altered fecal microbiome.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"2007-2018"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144006815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachel Porth, Tina Deyhim, Grace Geeganage, Brenden Smith, Samantha Zullow, Loren G Rabinowitz, Laurie B Grossberg, Adam S Cheifetz, Konstantinos Papamichael
{"title":"Proactive Therapeutic Drug Monitoring of Ustekinumab Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease.","authors":"Rachel Porth, Tina Deyhim, Grace Geeganage, Brenden Smith, Samantha Zullow, Loren G Rabinowitz, Laurie B Grossberg, Adam S Cheifetz, Konstantinos Papamichael","doi":"10.1093/ibd/izae231","DOIUrl":"10.1093/ibd/izae231","url":null,"abstract":"<p><strong>Background: </strong>There are limited data on the role of proactive therapeutic drug monitoring (TDM) of ustekinumab (UST) in patients with inflammatory bowel disease (IBD). This study investigated the efficacy and safety of proactive TDM in IBD patients treated with subcutaneous (sc) UST.</p><p><strong>Methods: </strong>This was a retrospective single-center cohort study. Consecutive patients with IBD who received maintenance subcutaneous (sc) UST therapy and underwent TDM from January 2017 to February 2023 were eligible for inclusion. Patients were followed through May 2024 or until drug discontinuation or an IBD-related surgery. Patients underwent either at least one proactive TDM or reactive TDM only. Survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event (SAE) or an IBD-related surgery, and IBD-related hospitalizations.</p><p><strong>Results: </strong>The study population consisted of 83 patients (proactive TDM, n = 46) of whom 67 (81%) had Crohn's disease. Patients who had at least one proactive TDM had higher drug persistence (Log-rank P < .001) and less IBD-related hospitalization (Log-rank P = .012) compared to patients undergoing only reactive TDM. In multivariable COX proportional hazard regression analysis, at least one proactive TDM was associated with increased drug persistence (hazard ratio [HR]: 5; 95% confidence interval [95% CI], 2-10; P < .001) and decreased IBD-related hospitalization (HR: 0.24; 95% CI, 0.07-0.83; P = .024). There was no SAE reported.</p><p><strong>Conclusions: </strong>This retrospective study showed that proactive TDM is associated with increased drug persistence and decreased IBD-related hospitalization in IBD patients treated with sc UST.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"1806-1810"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Letter to the Editor: Microscopic Colitis after Ocrelizumab for Multiple Sclerosis.","authors":"Mark Chatto, Cady Zeman-Pocrnich, Vipul Jairath","doi":"10.1093/ibd/izaf028","DOIUrl":"10.1093/ibd/izaf028","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"2045-2046"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Philip R Harvey, David McNulty, Benjamin Coupland, Polychronis Kemos, Nicholas M Croft, Nigel J Trudgill
{"title":"The Risk of Venous Thromboembolism in Children With Inflammatory Bowel Disease.","authors":"Philip R Harvey, David McNulty, Benjamin Coupland, Polychronis Kemos, Nicholas M Croft, Nigel J Trudgill","doi":"10.1093/ibd/izae249","DOIUrl":"10.1093/ibd/izae249","url":null,"abstract":"<p><strong>Background: </strong>Recent studies of children with inflammatory bowel disease (IBD) demonstrate an increased venous thromboembolism (VTE) risk. However, estimates of risk are variable and case numbers are limited. The aim of this study was to provide national estimates of the risk of VTE in children with IBD.</p><p><strong>Methods: </strong>Hospital Episode Statistics was used to identify patients diagnosed with either IBD or VTE before reaching 18 years of age between 2001 and 2019. Populations and subgroups are described, and the risks of developing VTE in the general and IBD populations were calculated.</p><p><strong>Results: </strong>Children with VTE following a diagnosis of IBD or in the previous 6 months (n = 85) and with VTE without IBD (n = 4160) were studied. The absolute risk in children with IBD was 9.42 (95% confidence interval [CI], 7.4-11.4) per 10 000 patient-years, compared with 0.18 (95% CI, 18-0.19) in children without IBD. Between 6 months prior to and 1 year following IBD diagnosis was the highest absolute risk period for VTE (18.0; 95% CI, 13.7-22.4). The relative risk of VTE in children with IBD vs children without IBD was greatest in younger patient groups: the relative risk for the age band 0 to 8 years was 96.5 (95% CI, 51.8-179.9) and for 9 to 11 years was 153.1 (95% CI, 81.2-288.8) vs 14.3 (95% CI, 10.3-20.0) for 15 to 17 years. Cerebral venous sinus thrombosis represented 17.6% of pediatric VTE events in IBD patients compared with 4.2% in children without IBD (P = .001).</p><p><strong>Conclusions: </strong>This study confirms the increased risk of VTE in children with IBD compared with children without IBD. The time of greatest VTE risk was around diagnosis. Cerebral venous sinus thrombosis was significantly more common in children with IBD than other children.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":"1861-1867"},"PeriodicalIF":4.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Novel mRNA Signature for Anti-TNF-α Therapy Primary Response in Patients With Ulcerative Colitis.","authors":"","doi":"10.1093/ibd/izaf140","DOIUrl":"https://doi.org/10.1093/ibd/izaf140","url":null,"abstract":"","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}