Michael Schultz

Background and Aims: Type I interferons (IFN-Is) are central regulators of intestinal epithelial homeostasis, yet their role in driving epithelial dysfunction and therapeutic non-response in Crohn’s disease (CD) remains poorly defined. Here, we investigated epithelial tumor necrosis factor (TNF)–IFN-I crosstalk as a previously unrecognized contributor to anti-TNF non-response in CD. Methods: We analyzed human intestinal biopsies, single-cell RNA sequencing data from CD donors, and used murine TNFR1-deficient and patient-derived organoids exposed to inflammatory cytokines and clinically relevant treatments. Results: Colonic epithelia from anti-TNF non-responders (NR-CD) showed enrichment of IFN-I genes associated with epithelial stress, impaired regeneration, and inflammatory cytokine production. Using patient-derived and murine TNFR1-deficient organoids, we demonstrated that TNF signaling sustains epithelial IFN-I responses linked to immune regulation and antiviral pathways, establishing a mechanistic connection between chronic TNF signaling and epithelial barrier failure. Low-dose butyrate (0.1 mM) suppressed cytokine-induced IFN-I genes and enhanced epithelial turnover in non-IBD and responder CD (R-CD) organoids but did not rescue the apoptosis and defective repair characteristic of NR-CD organoids. Notably, anti-IFN-I antibody treatment selectively attenuated IFN-I signaling and restored epithelial integrity in NR-CD organoids, identifying epithelial IFN-I blockade as a novel therapeutic rescue strategy for anti-TNF refractory disease. Conclusions: TNF–IFN-I crosstalk drives epithelial dysfunction in CD. Elevated epithelial IFN-I genes distinguish anti-TNF non-responders and underlie differential therapeutic responses. Together, this work supports integration of epithelial IFN-I gene expression and patient-derived ex vivo functional testing into treatment decisions for CD patients.

Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed “regenerative inflammation,” in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF–IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions.

Background: This study aimed to develop predictive models for acute severe ulcerative colitis (ASUC) using data from East Asian (EA) patients and to validate their performance in an Australia/New Zealand (ANZ) cohort. Methods: A retrospective international study was conducted across 23 referral hospitals in EA and ANZ, enrolling consecutive ASUC patients between January 2015 and December 2022. Logistic regression analyses were used to construct predictive models for 1-year colectomy and non-response to corticosteroid therapy (NRS). Results: Overall, 826 patients with ASUC were included (411 EA and 415 ANZ). Among EA patients, independent predictors of 1-year colectomy included female sex, prior exposure to tumor necrosis factor inhibitors, and admission albumin ≤3 g/dL. Independent predictors of NRS in the EA cohort were age at diagnosis ≤37 years, baseline steroid use, admission albumin ≤2.5 g/dL, and the presence of extraintestinal manifestations. The EA-derived scoring systems demonstrated strong predictive performance within the EA cohort (1-year colectomy: P < .0001; NRS: P = .001) but showed limited utility in the ANZ cohort (P = .106 and P = .012). In contrast, European-developed models—including the French 1-year colectomy score and the ADMIT-ASC index for NRS—accurately predicted outcomes in the ANZ cohort (P = .007 and P < .0001) but had reduced predictive capacity in the EA cohort (P = .106 and P = .026). These findings were consistent in both cohorts following propensity score matching. Conclusions: Predictive factors for ASUC differ substantially between EA and ANZ patients, highlighting the need for population-specific predictive tools.

Background: Adults with inflammatory bowel disease (IBD) have a high prevalence of modifiable cardiometabolic risk factors. This study investigates the impact of a personalised diet and physical activity intervention versus usual care on the risk factors. Methods: A 6-month randomised controlled trial was conducted at three hospitals in New Zealand (NZ) from 2023 to 2024. Adults with IBD in remission, a body mass index > 25 kg/m², and a low fibre intake < 25 g/day were recruited. Participants were randomised to receive either generic healthy eating and physical activity education or personalised heart-healthy eating education based on the NZ Heart Foundation and a self-led physical activity program. The primary outcome was change in body fat, and secondary outcomes included disease activity, biomarkers, quality of life, physical activity, and dietary intake. Between-group differences were analysed using multivariable regression. Results: Sixty-four participants were randomised, and 51 (80%) completed the intervention. The median age was 47 years (LQ, UQ: 37, 55), 59% participants were female, 61% had Crohn’s disease, and 85% had faecal calprotectin < 150 µg/g. Common cardiometabolic risks were high waist circumference (88%) and abnormal lipid profile (56%). There were no significant differences in primary or secondary outcomes except for dietary intakes: increased fruit (0.5 serves/day; 95% CI: 0.1, 1.0) and dietary fibre (3.1 g/1000 kcal/day; 95% CI: 1.1, 5.1); reduced discretionary food and drink (−1.7 serves/day; 95% CI: −3.0, −0.3), and sodium (−911 mg/day; 95% CI: −1783, −40). Conclusions: Personalised dietitian advice led to meaningful dietary changes without exacerbating disease activity. More intensive activity modalities can be recommended to support body composition improvements.

Introduction: Epidemiological measures of inflammatory bowel disease (IBD) evaluate the current and future burden of IBD on the health system. Long‐run incidence studies can identify changes in disease patterns and potentially give clues about aetiology if environmental risk factors have also changed. Methods: Clinic records and databases were retrospectively searched for adults and children diagnosed with IBD in the Otago region, southern New Zealand to the end of 2024. Medical chart review confirmed cases using standard IBD diagnostic criteria, and the Montreal phenotype, diagnostic delay, medical and surgical treatments were extracted. Previous data from Otago were included to compare incidence over time. Results: Between 2014 and 2024, there were 438 patients diagnosed with IBD in Otago, giving an average annual incidence rate of 19.7 per 100,000 (95% CI 17.9–21.6). The rates of Crohn's disease (CD) and ulcerative colitis (UC) were 8.5 (95% CI 7.4–9.8) and 10.6 (9.3–12.0) per 100,000, respectively. Most (87%) patients were of NZ European ethnicity. Individuals with CD had a lower median age (years) at diagnosis: 25.5, compared to those with UC: 40, ( p < 0.001). The median diagnostic delay was 6 months (IQR 3–9). Comparing the most recent decade (2014–2024) with previous data (1996–2013), the incidence of IBD rose from 14.2 to 19.7 per 100,000, ( p < 0.001). Over that period, the CD increase did not reach statistical significance, whereas the UC increase did. Conclusion: This long‐run incidence study observed the incidence of IBD in Otago continues to increase, representing a growing burden to patients and the health system.

In recent years, nutrition and dietetics have evolved from playing a supporting role in inflammatory bowel disease care to becoming an integral part of the treatment approach. Nutrition and dietary treatments address malnutrition, which is known to be highly prevalent in inflammatory bowel disease patients, reduce active inflammation, provide symptom relief, and enhance quality of life. Patients believe that nutrition‐based strategies are an important part of their disease management but generally have difficulty accessing specialist nutrition advice. Best practice inflammatory bowel disease management guidelines recommend coordinated multidisciplinary care models, but many multidisciplinary teams do not currently include dietitians. Research has shown that inflammatory bowel disease multidisciplinary teams that do include dietitians have improved patient disease outcomes and cost efficiencies. As the only health professional with extensive training in medical nutrition therapy and dietary counseling, dietitians are the most appropriate health professional to carry out detailed nutritional assessments and advise patients on individualized diet and nutrition treatments for inflammatory bowel disease. The growing emphasis on dietary therapy in inflammatory bowel disease and the complexity of evidence‐based dietary recommendations highlight the need for dietitians to be an integral part of the multidisciplinary team caring for inflammatory bowel disease patients.

Background: People with inflammatory bowel disease (IBD) have a higher risk of developing cardiovascular diseases (CVD). This study describes modifiable CVD risk factors and their associations with diet and physical activity in New Zealand (NZ) adults with IBD. Methods: A cross-sectional study was conducted in 2021-2022. Online questionnaires collected demographics, IBD, diet (food frequency questionnaire), and physical activity data. Clinical measures included anthropometrics, blood pressure, handgrip strength, body composition (bioelectrical impedance), and biological markers. Data were compared to NZ guidelines or established population/CVD reference values. Linear regression investigated associations between diet, physical activity and CVD risk factors. Results: One hundred two adults with mostly disease remission to mildly active IBD (53% Crohn’s disease) participated. Median age was 38 (LQ, UQ: 25,51) years, 58% were female, and 92% were NZ European. A proportion of participants had low intakes of vegetables (85.3%), fruit (62.7%), and dietary fiber (45.1%), and high saturated fat (99.0%) and sodium (60.8%) intake. Approximately 28% of participants were physically inactive. Modifiable CVD risk factors were: central adiposity (64%), high body fat percentage (42%), low handgrip strength (26%), high LDL-cholesterol (22%), and elevated blood pressure (19%). Regression analyses found that high intakes of discretionary foods, red meat, poultry, and eggs; and low intakes of legumes, lentils, vegetables, dietary fiber, and seafood were associated with several CVD risk factors. Physical activity was not associated with any CVD factors. Conclusions: Adults with IBD have modifiable CVD risk factors amenable to dietary changes, while physical activity remains a valuable adjunct given its well-known cardiovascular benefits.

Background: Functional dyspepsia is a common gastrointestinal condition that reduces the quality of life and increases health care costs. The lack of well-defined causes limits effective treatments. Consumers report using mānuka honey to treat gastrointestinal symptoms, although clinical evidence supporting such use is limited. Preclinical studies suggest its unique bioactive compounds may reduce gastrointestinal inflammation. Recently, 3,6,7-trimethyllumazine (Lepteridine), a natural pteridine in mānuka honey, was shown to inhibit enzymes involved in gastrointestinal inflammation in in vitro studies. Therefore, Lepteridine-standardized mānuka honey may deliver digestive health benefits. Objective: The aim of this feasibility study is to gather the data required to estimate sample size and support study logistics to design future trials. The primary objective will be preliminary assessments of the impact of Lepteridine-standardized mānuka honey on symptom severity and the quality of life in participants with mild-to-moderate functional dyspepsia. Other feasibility objectives include assessing the biological responses to mānuka honey standardized to medium and high levels of Lepteridine and measuring mānuka honey–derived metabolites in blood and urine. Methods: This is a 3-arm, parallel, controlled, double-blind, randomized feasibility study. A total of 75 healthy adults with symptoms of functional dyspepsia (Rome IV criteria) and mild-to-moderate dyspepsia severity (Short Form Leeds Dyspepsia Questionnaire) were recruited between October 2022 and September 2023. Participants were randomized into one of three groups: (1) mānuka honey standardized to contain 10 mg/kg Lepteridine, (2) mānuka honey standardized to contain 40 mg/kg Lepteridine, or (3) honey maple flavored syrup control. After a 2-week lead-in period, participants consumed 10 g of allocated intervention twice daily for 6 weeks. Throughout the study, participants completed daily bowel movement diaries and validated weekly questionnaires about their gastrointestinal symptoms and quality of life. Stool samples and 3-day diet records were collected at baseline and the end of the intervention. Blood samples were collected at baseline, weeks 2 and 4, and at the end of the intervention. In addition, 6 healthy participants without symptoms of functional dyspepsia were recruited to undergo an acute 5-hour assessment for the appearance of Lepteridine and related metabolites in plasma and urine following consumption of Lepteridine-standardized mānuka honey. The study was approved by the Northern B Health and Disability Ethics Committee. Results: Initial analysis includes 68 participants, with laboratory and data analyses being undertaken as of March 2024. The results of the primary and secondary outcomes will be published in peer-reviewed journals. Conclusions: This study will provide essential information on the potential efficacy and suitability of Lepteridine-standardized mānuka honey for designing future clinical trials investigating its effect in treating symptoms of functional dyspepsia. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12622001140741p; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384094 International Registered Report Identifier (IRRID): DERR1-10.2196/66417

This review aims to highlight the relative importance of cardiovascular disease (CVD) lifestyle-associated risk factors among individuals with inflammatory bowel disease (IBD) and examine the effectiveness of lifestyle interventions to improve these CVD risk factors. Adults with IBD are at higher risk of CVD due to systemic and gut inflammation. Besides that, tobacco smoking, dyslipidaemia, hypertension, obesity, physical inactivity and poor diet can also increase CVD risk. Typical IBD behavioural modification including food avoidance and reduced physical activity, as well as frequent corticosteroid use, can further increase CVD risk. We reviewed seven studies and found that there is insufficient evidence to conclude the effects of diet and/or physical activity interventions on CVD risk outcomes among populations with IBD. However, the limited findings suggest that people with IBD can adhere to a healthy diet or Mediterranean diet (for which there is most evidence) and safely participate in moderately intense aerobic and resistance training to potentially improve anthropometric risk factors. This review highlights the need for more robust controlled trials with larger sample sizes to assess and confirm the effects of lifestyle interventions to mitigate modifiable CVD risk factors among the IBD population.

BACKGROUND Functional dyspepsia is a common gastrointestinal condition that reduces the quality of life and increases health care costs. The lack of well-defined causes limits effective treatments. Consumers report using mānuka honey to treat gastrointestinal symptoms, although clinical evidence supporting such use is limited. Preclinical studies suggest its unique bioactive compounds may reduce gastrointestinal inflammation. Recently, 3,6,7-trimethyllumazine (Lepteridine), a natural pteridine in mānuka honey, was shown to inhibit enzymes involved in gastrointestinal inflammation in in vitro studies. Therefore, Lepteridine-standardized mānuka honey may deliver digestive health benefits. OBJECTIVE The aim of this feasibility study is to gather the data required to estimate sample size and support study logistics to design future trials. The primary objective will be preliminary assessments of the impact of Lepteridine-standardized mānuka honey on symptom severity and the quality of life in participants with mild-to-moderate functional dyspepsia. Other feasibility objectives include assessing the biological responses to mānuka honey standardized to medium and high levels of Lepteridine and measuring mānuka honey–derived metabolites in blood and urine. METHODS This is a 3-arm, parallel, controlled, double-blind, randomized feasibility study. A total of 75 healthy adults with symptoms of functional dyspepsia (Rome IV criteria) and mild-to-moderate dyspepsia severity (Short Form Leeds Dyspepsia Questionnaire) were recruited between October 2022 and September 2023. Participants were randomized into one of three groups: (1) mānuka honey standardized to contain 10 mg/kg Lepteridine, (2) mānuka honey standardized to contain 40 mg/kg Lepteridine, or (3) honey maple flavored syrup control. After a 2-week lead-in period, participants consumed 10 g of allocated intervention twice daily for 6 weeks. Throughout the study, participants completed daily bowel movement diaries and validated weekly questionnaires about their gastrointestinal symptoms and quality of life. Stool samples and 3-day diet records were collected at baseline and the end of the intervention. Blood samples were collected at baseline, weeks 2 and 4, and at the end of the intervention. In addition, 6 healthy participants without symptoms of functional dyspepsia were recruited to undergo an acute 5-hour assessment for the appearance of Lepteridine and related metabolites in plasma and urine following consumption of Lepteridine-standardized mānuka honey. The study was approved by the Northern B Health and Disability Ethics Committee. RESULTS Initial analysis includes 68 participants, with laboratory and data analyses being undertaken as of March 2024. The results of the primary and secondary outcomes will be published in peer-reviewed journals. CONCLUSIONS This study will provide essential information on the potential efficacy and suitability of Lepteridine-standardized mānuka honey for designing future clinical trials investigating its effect in treating symptoms of functional dyspepsia. CLINICALTRIAL Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12622001140741p; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384094 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/66417