The term 'gut health' is increasingly used as a catch-all phrase by many stakeholders, including scientists, health-care professionals, industry and the general public, to describe a wide range of health-related concepts. Despite its widespread use, particularly in relation to studies on diet, fermented foods, biotics and the gut microbiome, it remains unclear what the term gut health means. Therefore, an expert panel was convened by the International Scientific Association for Probiotics and Prebiotics to address the current state of scientific and clinical knowledge on the physiology, manifestation, application and measurement of the concept of gut health. The panel evaluated the term in the context of the central role of the gastrointestinal tract in health and overall well-being and proposed a definition of gut health as "a state of normal gastrointestinal function without active gastrointestinal disease and gut-related symptoms that affect quality of life". The definition was developed mindful of the functional, subjective and extrinsic domains that contribute to gut health. In this Consensus Statement, clinically relevant and accessible metrics to assess these domains are reviewed and a comprehensive approach to gut health is proposed that is relevant to clinical practice as well as to studies of dietary and biotic interventions.

INTRODUCTION:LUCENT-URGE (NCT05767021) was a Phase 3b, multicenter, open-label, single-arm study investigating bowel urgency (BU) in patients with moderately-to-severely active ulcerative colitis (UC) and BU at baseline, treated with mirikizumab. METHODS:Patients without prior mirikizumab exposure received intravenous mirikizumab 300 mg at weeks (W)0, 4, and 8, followed by subcutaneous mirikizumab 200 mg at W12, 16, 20, and 24. The primary objective was improvement in the validated BU severity measure (Urgency Numeric Rating Scale [UNRS]) at W12. Secondary objectives included improvement in BU at W28, novel measures of stool deferral time (SDT), bowel urgency frequency (BUF), and associations between BU measures. UNRS, BUF, and SDT were collected using a daily diary; the shortest weekly SDT was used for analysis. Baseline observation carried forward was used as the response for the corresponding visit for all missing observations. Missing continuous data were treated as having no change from baseline. RESULTS:All three BU measures at W12 were sustained or improved through W28. With mirikizumab treatment, 52.2% improved BU severity, 55.1% improved BUF, and 40.7% improved shortest weekly SDT. Patients with shortest weekly SDT ≥ 15 min or no urgency increased from 4.1% at baseline to 29.7% at W28. At W12, 36 (20.9%) achieved clinical remission and 54 (31.4%) achieved endoscopic remission, improving to 62 (36.1%) and 76 (44.2%) at W28, respectively. The safety profile was generally consistent with the known profile. CONCLUSION:In the first comprehensive approach assessing complex BU symptoms in UC, mirikizumab was associated with improvements in several BU and clinically related measures through W28. CLINICAL TRIALS REGISTRATION:ClinicalTrials.gov, NCT05767021.

Background:There is limited real-word data comparing efficacy of low dose upadacitinib (UPA) to high dose UPA as maintenance therapy for ulcerative colitis (UC). Methods:This was a retrospective cohort study utilizing the U.S. Collaborative Network in adults ≥18 years old with UC who initiated UPA 15 mg compared to 30 mg for maintenance therapy between April 2022 and December 2023. The primary outcome was a composite of intravenous steroid use, oral steroid use, or colectomy from 12 to 60 weeks from the index UPA prescription. Propensity score matching (PSM) was performed for demographics, co-morbid conditions, laboratory, and IBD medication history. Cox proportional hazard model was used to identify predictors of failure. Results:Among 1110 patients on UPA maintenance therapy, 361 (32.5%) were on 15 mg and 749 (67.5%) were on 30 mg. After PSM, there was no difference in the composite outcome of steroid use or colectomy between the 15-mg UPA cohort versus 30 mg cohort (35.3% vs 35.6%; aHR 0.95, 0.71-1.24, P = .8). There was no difference in IV steroid use, oral steroid use or change in therapy between the two cohorts. There was no difference in the proportion of patients who achieved a fecal calprotectin of <250 μg/g (55.8% vs 63.5%, P = .33). Recent oral or IV steroid use and rheumatoid arthritis were associated with failure of both 15 mg and 30 mg UPA. Conclusion:Our study indicates that 15 mg UPA shows similar efficacy as 30 mg UPA for maintenance treatment in a subset of patients with UC.

Background:The Crohn's disease (CD) exclusion diet (CDED) is an emerging dietary therapy for inducing remission in CD. However, data on its effects on gut microbiome in adults remain limited. This study investigated microbial responses to CDED in adults with mild-to-moderate CD and compared them with pediatric patients and healthy pediatric controls. Methods:Microbiome data were analyzed from a randomized controlled trial (RCT) in adults (baseline, weeks 6, 12, 24) and a pediatric RCT (baseline, weeks 6, 12). Baseline microbial composition, diversity, and functional potential were compared between patients who achieved sustained clinical remission (SCR) at both weeks 12 and 24 and those who did-not. Functional profiling was performed using gene ortholog annotations, linear discriminant analysis, and metabolite inference. Results:Baseline microbial and functional profiles differed between patients with and without SCR. SCR was associated with lower alpha diversity, higher relative abundances of Alistipes and Faecalibacterium, and increased flagellin gene expression. SCR was associated with enrichment of genes for redox balance, fatty acid metabolism, and DNA repair, while non-SCR showed elevated NAD biosynthesis, bacterial adhesion, and pro-inflammatory pathways. Haemophilus and Prevotella were negatively linked to SCR. Compositional and functional microbiome analyses revealed a microbiome shift during CDED-induced remission toward a profile more similar to healthy pediatric controls. Conclusions:Before and during CDED, distinct baseline microbial and functional profiles were associated with SCR. These highlight the potential of the gut microbiome as a biomarker for identifying patients most likely to benefit from sustained effects of dietary therapy, supporting a more personalized approach to CD management.

BACKGROUND AND AIMS: Epidemiologic research in eosinophilic esophagitis (EoE) is limited by the accuracy and efficiency of case identification algorithms. We aimed to evaluate rule-based natural language processing (RB-NLP) and large language model-based natural language processing (LLM-NLP) pipelines for identifying EoE diagnoses and features from unstructured text. METHODS: We identified gastrointestinal pathology reports with any mention of "eosinophil" paired with gastroenterology clinic notes. Three hundred randomly selected patients were divided into training (n = 200, 56 with EoE) and testing (n = 100, 36 with EoE) sets. Manual chart review was the reference standard. RB-NLP used spaCy with medspaCy's clinical components; LLM-NLP prompts were developed through iterative human-in-the-loop refinement. In the validation set, we compared International Classification of Diseases (ICD) codes, RB-NLP, and LLM-NLP against the reference standard using sensitivity (recall), positive predictive value (precision), and F1 score. RESULTS: In the validation set, ICD codes alone had a sensitivity 0.86 (95% confidence interval [CI]: 0.75-0.97), a positive predictive value of 0.97 (95% CI: 0.91-1.0), and an F1 value of 0.91 (95% CI: 0.84-1.0). Combining ICD and LLMassigned diagnosis yielded a 3-point improvement in F1 score (95% CI:-0.01 to 0.07; P = .2) compared to ICD alone. In a larger cohort (n = 580), the LLM + ICD approach identified the most EoE cases (n = 203) and captured 15% of cases missed by ICD codes. Clinical characteristics varied depending on the case identification strategy used. CONCLUSION: Combining LLM-NLP with a single ICD code reduced false negatives and modestly improved the F1 score compared to either method alone. This may represent a scalable approach to enhance EoE case identification in real-world data.

SUMMARY 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.

Background and Aims:Bowel urgency is a distressing and disruptive symptom in adults with ulcerative colitis (UC). We hypothesized that bowel urgency is associated with disease-related disability and influenced by psychosocial factors. Methods:Hierarchical multiple linear regression assessed baseline disease symptoms (severity of bowel urgency, stool frequency, and rectal bleeding) and psychosocial factors' association with disability, using cross-sectional data from the ADEPT (Addressing Disability Effectively with Psychosocial Telemedicine) trial. Results:Among 241 adults with UC, 48% (116/241) had moderate-to-severe bowel urgency, and 75% (89/119) of participants without diarrhea or rectal bleeding experienced bowel urgency. Bowel urgency was strongly correlated with disability (ρ = 0.597; P < .0001), with mediation from negative illness perceptions, lower self-efficacy, and more health-related social needs (all P < .001). Gastrointestinal symptoms explained 40% of the variance in disability, and psychosocial factors accounted for an additional 19% (both P < .001). Conclusion:Bowel urgency occurs in 75% of patients with UC without diarrhea or rectal bleeding and is strongly associated with disability. Illness perceptions, self-efficacy, and health-related social needs mediate bowel urgency and disability.

BACKGROUND AND AIMS:Real-world data are needed to better understand the burden and outcomes of patients hospitalized with severe ulcerative colitis (UC). METHODS:This retrospective cohort study analyzed US electronic health record (EHR) data with linked insurance claims to identify adults hospitalized for UC who received intravenous corticosteroids during an inpatient admission (index hospitalization) between January 1, 2014, and December 31, 2022, with ≥180 days of prior EHR activity. Results were analyzed for the overall cohort, in three subgroups: (1) no prior UC diagnosis in the EHR, (2) prior UC diagnosis without prior advanced therapy, and (3) prior UC with prior advanced therapy, and in a nested cohort of patients discharged without colectomy. Multivariable analyses assessed factors associated with colectomy before discharge. RESULTS:Overall, we identified 9716 patients (mean [SD] age, 46.3 [17.4] years); 83.3% had a previous diagnosis of UC and 23.8% had prior biologic use for UC. During hospitalization, 13.1% received advanced therapy; 12.2% underwent colectomy. The rate of colectomy was 12.6% in subgroup 1, 9.2% in subgroup 2, and 19.6% in subgroup 3 (P < .0001). Prior UC diagnosis with prior advanced therapy use and abnormal/missing albumin labs were associated with higher risk of colectomy. The cumulative risk of colectomy <1 year after index hospitalization was 20.4% overall and 18.5%, 16.1%, and 32.7% in subgroups 1, 2, and 3, respectively. In the nested cohort (n = 4383), one-third received advanced therapy within 90 days; 38.4% experienced a UC-related hospitalization <1 year after index hospitalization. CONCLUSION:These data from a large contemporary cohort elucidate the burden and outcomes for patients hospitalized with severe UC.

Using over 100 intestinal tissue sections from non-diseased controls and patients with ulcerative colitis or Crohn's disease across multiple inflammatory bowel disease consortia, we construct a spatially resolved atlas containing over three million cells and systematically evaluate two imaging-based spatial transcriptomics platforms. Here we show that CosMx tends to achieve higher detection efficiency than Xenium across commercially available panels in both ulcerative colitis and Crohn's disease, whereas Xenium shows reduced performance associated with tissue type, block quality, and panel size. CosMx identifies regulatory T cell associated biology in both disease subtypes, which we validate using independent laboratory experiments and multi-plex spatial multi-omics. CosMx's data quality remains stable across variation in fixation time and sectioning procedures, supporting its operational feasibility for multi-center studies. This study establishes a technical and biological benchmark for the application of single-cell-resolved spatial transcriptomics in gastrointestinal tissue, enabling more reliable application of spatial technologies in translational inflammatory bowel disease research.

Glucuronidation is an important detoxification pathway that operates in balance with gastrointestinal microbial β-glucuronidase (GUS) activity, which can regenerate bioactive metabolites from their glucuronidated forms. How this host-microbe interaction shapes the distribution and pool of glucuronidated metabolites (i.e., the glucuronidome) remains poorly understood. In this study, we employed pattern-filtering data science approaches in conjunction with untargeted LC-MS/MS metabolomics to map the glucuronidome in urine, serum, and colon/fecal samples from gnotobiotic and conventional mice, and in humans. We find that microbial colonization and GUS activity compress the colonic glucuronidome and expand urinary glucuronidome diversity, revealing a compartmental redistribution of glucuronidated metabolites. Reverse metabolomics of known glucuronidated chemicals and glucuronidation pattern filtering searches in public metabolomics datasets exposed the diversity of glucuronidated metabolites in human and mouse ecosystems. In summary, we present a glucuronidation fingerprint resource that provides broader access to and analysis of the glucuronidome. Together, this work establishes a scalable analytical framework and provides mechanistic insight into how microbial activity reshapes systemic glucuronidation, with implications for drug metabolism, diet-microbe interactions, and biomarker discovery.

BACKGROUND & AIMS:Elevated fecal calprotectin (FC), a biomarker of intestinal inflammation, can be detected 3 months before symptomatic flare in patients with ulcerative colitis (UC). We hypothesized that proactive home-based FC monitoring would prevent symptomatic flares in patients with UC in remission. METHODS:This prospective, multicenter clinical trial randomized adults with a modified partial Mayo score ≤2 and no rectal bleeding to standard care or FC testing every 2 months for 18 months or until symptomatic flare. Confirmatory FC testing was performed within 2 weeks for FC ≥250 μg/g; change in therapy was at physician discretion. Primary end point was time to symptomatic flare. Secondary end points included health care use, medication use, and quality of life. RESULTS:The trial enrolled 716 patients; 308 in the control arm and 303 in the intervention arm were analyzed. Mean age was 42 years, and 47% were men. Distribution of disease extent was similar in both arms, and 45% were on advanced therapy. Symptomatic flare occurred in 32% in both arms; median time to flare was not reached. There was no difference in risk for symptomatic flare overall (hazard ratio, 1.05; 95% confidence interval, 0.79-1.40), by disease extent, or advanced therapy use. Flare frequency was lower among the 88 who changed therapy after confirmatory elevated FC (49% vs 55%), but flare risk was not different. There were no differences in secondary end points. CONCLUSIONS:Our results suggest that proactive home-based FC monitoring without protocolized escalation does not prevent symptomatic flares. Additional studies are needed to define the optimal use of FC monitoring and the benefit of early intervention. CLINICALTRIALS:gov number: NCT03549988.

Mirikizumab (MIRI), an anti-IL-23p19 IgG4 monoclonal antibody, has demonstrated efficacy in treating patients with moderately to severely active ulcerative colitis (UC) and is effective in reducing colonic inflammation, as assessed by histologic and histologic-endoscopic outcomes. LUCENT-URGE (NCT05767021) was a Phase 3b, multicenter, open-label, single-arm study investigating bowel urgency (BU) and histologic features in patients with moderately-to-severely active ulcerative colitis (UC). LUCENT-URGE enrolled 172 adult patients with a baseline Modified Mayo Score of 4-9 and with current bowel urgency (defined by Urgency Numeric Rating Scale (UNRS) ≥3). Patients received MIRI 300mg intravenously at Week (W)0, 4, and 8, followed by MIRI 200mg subcutaneously at W12, W16, W20, and W24. Up to 10 biopsy samples (5 from the colon and 5 from the rectum) were collected per endoscopy procedure. Histologic improvement was defined as a Geboes score ≤3.1: neutrophil infiltration in < 5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue. Histologic remission was defined as Geboes score ≤2B.0: no mucosal neutrophils, crypt destruction, erosions, ulcerations, or granulation tissue. Histologic endoscopic mucosal improvement (HEMI) was defined as Geboes score ≤3.1 and a Mayo endoscopic subscore (ES)=0 or 1​. Histologic endoscopic mucosal remission (HEMR) is defined as Geboes score ≤2B.0; ES = 0 or 1​. The percentage relative change for each element from W12 to W28 was calculated as: V (value)1 to V2 = (V2-V1) / V1 x 100. Improvements in the achievement of HEMI and HEMR were observed from W12 to W28 in both the colon and rectum, with more pronounced improvements in the rectum. Specifically, the proportion of patients achieving HEMI in the colon increased by 43.5% from W12 to W28 (26.7% to 38.4%), while achievement of HEMR in the colon increased by 40.0% (23.3% to 32.6%). In the rectum, the proportion of patients achieving HEMI increased by 56.4% (22.7% to 35.5%), and HEMR increased by 66.7% (17.4% to 29.1%). Additionally, the proportion of patients achieving histologic improvement and histologic remission was numerically higher at W28 compared to W12 for both the colon and rectum. This is the first study evaluating patients with baseline BU with standardized histology assessment from both the rectum and the colon. The proportions of patients achieving histologic and histologic-endoscopic endpoints increased from W12 to W28, with a more notable improvement in the rectum. The results support the continued and increasing efficacy of MIRI in reducing and resolving inflammation in UC. Conflict of interest: Danese, Silvio: Personal Fees: AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor Lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda Magro, Fernando: Fernando Magro served as speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor. Ponich, Terry: TP has served as a consultant for Bristol Myers Squibb, Celltrion, Eli Lilly and Pfizer recently. He currently serves as an investigator on clinical research studies for Abivax, Alimentiv, AnaptysBio, Eli Lilly, Merck, Morphic Therapeutic, Pfizer/Kanyos Bio, Spyre Therapeutics and Takeda. Walsh, Alissa: Grant: Alfasigma, Helmsley Trust, Johnson & Johnson, Pfizer, Takeda Personal Fees: AbbVie, Alfasigma, Bristol Meyers Squibb, Dr Falk, Ferring, Johnson & Johnson, Lilly, Pfizer, Takeda, Tillotts Dignass, Axel: Personal Fees: AbbVie, Alfasigma, CED Service GmbH, Celltrion, Dr. Falk Pharma, Falk Foundation, Ferring, Fresenius Kabi, Gilead, High5MD, J & J, Lilly, Materia Prima, MSD, Pfizer, Pharmacosmos, Sandoz, Stada, Streamed-Up, Takeda, Tillotts, Vifor Pharma Grant Abbvie, J & J, Takeda Non-financial support Abbvie, J & J, Takeda Other: Abivax, AbbVie, Alfasigma, Dr Falk Pharma, Fewrring, J & J, Pfizer Laharie, David: Personal Fees: Board, consulting and lecture fees from Abbvie, Alfasigma, Amgen, Biocon, Celltrion, Ferring, Fresenius-Kabi, Johnson & Johnson, Lilly, MSD, Pfizer, Sandoz and Takeda Limdi, Jimmy: Speaker and Consultancy fees: Abbvie, Arena, AlfaSigma, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Tillotts Kempinski, Radoslaw: Lecture fees from AbbVie, Aboca S.p.A. Societa Agricola, Ferring, Eli Lilly and company grant/research support from Takeda, Johnson & Johnson Innovative Medicine. Lewis, James: Dr. Lewis consulted or served on an advisory board or data monitoring committee for Amgen, Crohn’s & Colitis Foundation, Eli Lilly and Company, Galapagos, Janssen Pharmaceuticals (Johnson & Johnson), Merck, Odyssey Therapeutics, Pfizer, Protagonist Therapeutics, Sanofi, and Spyre Pharmaceuticals. He has had research funding or in kind support from Nestle Health Science, Takeda, Janssen Pharmaceuticals, AbbVie and Eli Lilly. He has had educational grants from Janssen. He has performed legal work on behalf of manufacturers of generic ranitidine and 3M. He owns stock in Dark Canyon Labs. Younes, Ziad: -Research grants: Abivax, AbbVie, Agomab, Genentech, Eli Lilly, Johnson and Jonhson, Mirador, Takeda -Consulting: AbbVie, BMS, Eli Lilly -Speaking honoraria: AbbVie, BMS, Eli Lilly, Johnson and Johnson, Pfizer Cohen, Erica: advisory board and consultant for Pfizer, Takeda, and PRIME Education speaker for AbbVie, Eli Lilly and Company, Janssen, and Takeda. Eastman, William: Employee and shareholder of Eli Lilly and Company. Fisher, Deborah: Employee and shareholder of Eli Lilly and Company. Tian, Tian: Employee and shareholder of Eli Lilly and Company. Rubin, David T.: Grant support: Takeda Pharmaceuticals Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Dubinsky, Marla C: Personal Fees: Consultant or Advisory Board: Abbvie, Abivax, Astra Zeneca, BMS, Celltrion, Gilead, Genentech, Janssen, Johnson and Johnson, Lilly, Merck, Pfizer, Prometheus Biosciences, Sanofi, Spyre, Target RWE, Takeda Other: Shareholder, Co-founder, Board of Directors of Trellus Health Co-Founder Mi Test Health

Data derived from our previously published pooled administrative claims database analysis were applied to estimate race-weighted state-specific prevalences of inflammatory bowel diseases in the United States to support public health, clinical, and research initiatives at the state and regional level.

This Viewpoint discusses why treatment should be routinely recommended in the pediatric patient with Helicobacter pylori .

Background:Biologic therapy has improved care for patients with inflammatory bowel disease (IBD), but adherence is often suboptimal, and a gap in care is lack of engagement between visits. We evaluated the effect of a behaviorally-informed remote text monitoring program on outcomes and adherence among patients with IBD. Methods:Adults with IBD and receiving biologics through home health or self-injection were individually randomized 1:1 to control (usual care) or intervention (remote monitoring), stratified by medication type (home infusion vs. injection). The 4-month intervention included the following components via text message: (1) biologic dose reminders, (2) medication adherence check-ins after each dose, (3) weekly symptom check-ins with escalation to the patient's care team if above threshold, and (4) feedback to an identified support partner (when applicable). The primary outcome was change in quality of life via the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Results:150 patients were enrolled; 148 completed the study, and 144 were analyzed for the survey outcomes (73 control, 71 intervention). The mean age was 38.9, 52.7% were female, and 81.1% were White. No significant differences were found between arms for the change in median score from baseline to end of study for the SIBDQ, MARS-5, or patient satisfaction surveys. Medication adherence remained high across both arms, and there was no significant difference in the proportion of days covered for infusion or injection between arms. Conclusions:Remote monitoring was feasible with high patient satisfaction, but there was no improvement in quality of life or medication adherence. Trial Registration:clinicaltrials.gov NCT04388865.

BACKGROUND:Diltiazem is a potent inhibitor of cytochrome P450 3A4 and P-glycoprotein substrates, which can affect the metabolic pathways of factor Xa inhibitors, predisposing patients with atrial fibrillation (AF) to serious bleeding complications. OBJECTIVE:To compare the risk for bleeding among patients with AF who used apixaban or rivaroxaban in combination with diltiazem compared with metoprolol. DESIGN:Retrospective cohort active comparator study. SETTING:U.S. administrative health care database. PATIENTS:Persons with AF. INTERVENTION:Use of apixaban or rivaroxaban with diltiazem or metoprolol. MEASUREMENTS:The primary study outcome was a composite of serious bleeding events leading to hospitalization. Secondary study outcomes included composites of stroke or systemic embolism. Diltiazem was stratified by high dose (>120 mg/d) and low dose (≤120 mg/d). Propensity score matching was used to adjust for differences between diltiazem and metoprolol users. RESULTS:In the matched cohort of patients with AF, 23 000 were users of diltiazem and 23 000 were users of metoprolol. After propensity score matching, diltiazem (vs. metoprolol) was associated with a higher risk for bleeding events (rate difference [RD], 5.4 [95% CI, 1.2 to 9.6] per 1000 person-years). The risk for bleeding increased with high- versus low-dose diltiazem (high dose: RD, 9.2 [CI, 2.7 to 15.7]; low dose: RD, 2.6 [CI, 0.5 to 8.0]). The estimated 12- and 6-month risk differences between diltiazem and metoprolol were 0.48 percentage points (CI, 0.09 to 0.83 percentage points) and 0.31 percentage points (CI, 0.04 to 0.58 percentage points), respectively. LIMITATION:Residual confounding. CONCLUSION:In commercially insured patients with AF receiving apixaban or rivaroxaban, the use of diltiazem was associated with an increased risk for serious bleeding complications when compared with metoprolol. PRIMARY FUNDING SOURCE:National Heart, Lung, and Blood Institute.

γδ T cells maintain intestinal immune homeostasis, but their contributions to human ulcerative colitis (UC) are poorly understood. We characterized γδ T cells in intestinal biopsies obtained from patients with UC and healthy donors using single-cell RNA sequencing, T cell receptor profiling, and mass cytometry. UC reduced CD103 + Vγ4Vδ1 + γδ intraepithelial lymphocytes (γδ IELs) and increased γδ T cell subsets with stemlike phenotypes expressing TCF-1 (T cell factor 1) and PD-1 (programmed cell death receptor 1) or effector-like phenotypes expressing granzyme B, perforin, and T-bet in the lamina propria. γδ T cell composition changes in UC correlated with decreased expression of epithelial BTNL3 and BTNL8 and increased BTN3A1 and BTN3A3 , suggesting altered recruitment and activation. Clinical improvement recovered γδ IELs and reduced inflammation-associated subsets. Inflammation-associated changes were observed in peripheral blood γδ T cells. Thus, distinct γδ T cell subsets in different niches exert protective or pathogenic functions in UC.