Introduction

Glepaglutide is a long-acting glucagon-like peptide 2 (GLP-2) analogue (Larsen B et al 2024) under development for the treatment of short bowel syndrome (SBS). Glepaglutide enhances intestinal absorption (Jeppesen P et al 2025), which may hypothetically lead to changes in the intestinal microbiota, mainly by slowing gastrointestinal transit time. This study evaluated whether the intestinal pro-absorptive effects of glepaglutide were related to changes in microbiota.

Aims & Methods

In this single-center, open-label, EASE SBS-4 phase 3b study, 10 patients with SBS (8 of the 10 with intestinal failure and 8 of the 10 without colon-in-continuity) were treated with glepaglutide 10 mg subcutaneous once weekly for 24 weeks. While the primary study finding demonstrated increased intestinal absorption assessed by metabolic balance studies, this study investigated whether treatment with glepaglutide was associated with changes in bacterial load and composition. Samples were obtained from either stool or ostomy effluent at baseline and after 24 weeks of treatment with glepaglutide. Bacterial load was quantified using a spike-in approach and composition was assessed by V3V4 16S rRNA gene sequencing.

Results

24 weeks of glepaglutide treatment did not significantly alter bacterial load nor composition of the intestinal microbiota of the patients. Bacterial load showed distinct differences between patients with and without a colon-in-continuity. In patients without a colon, most samples had values below 10⁹ cells per gram, whereas those with a colon-in-continuity had bacterial loads within the physiological range observed in healthy individuals, ranging from 10¹⁰ to 10¹¹ cells per gram feces (Vandeputte D et al 2017).
Microbiota composition also differed markedly by intestinal anatomy: patients without a colon-in-continuity had higher abundances of genera mainly associated with the upper gastrointestinal tract, such as Streptococcus, while those with a colon-in-continuity exhibited greater abundance of genera more commonly found in the lower gastrointestinal tract, including Bifidobacterium.

Conclusion

Treatment with the GLP-2 analogue glepaglutide increased intestinal wet weight and energy absorption without altering the intestinal bacterial microbiota in the patients with SBS participating in this study.
Bacterial load and composition were strongly influenced by intestinal anatomy.
In summary, this study indicated that changes in glepaglutide-induced intestinal absorption were not driven by the microbiota.

References

1. Larsen BD, Villadsen JS, Skarbaliene J, Melander C, Russell W, Petersen YM, Møller EH. Creating Glepaglutide, the first long-acting GLP-2 analogue to enable a ready-to-use injection. J Med Chem. 2025. 68 (3), 3134-3145.
2. Jeppesen PB, Vanuytsel T, Subramanian S, Joly F, Wanten G, Lamprecht G, Kunecki M, Rahman F, Nielsen TSS, Berner-Hansen M, Paper UF, Mercer DF. Glepaglutide, a long-acting glucagon-like peptide-2 analogue, reduces parenteral support in patients with short bowel syndrome: A phase 3 randomized controlled trial. Gastroenterology, 2025. 168(4):701-713.e6.
3. Vandeputte D et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature. 2017. 551(7681):507-511.

Disclosure

This study was funded by Zealand Pharma A/S

Introduction

Secondary loss of response to Infliximab(IFX) occurs in approximately half of patients with Inflammatory Bowel Disease(IBD), due to drug levels falling below the therapeutic range. This study evaluated IFX levels and related clinical and laboratory parameters and their impact on clinical outcomes.

Aims & Methods

Pre-infusion drug levels, associated laboratory data, and clinical parameters were evaluated in IBD patients receiving maintenance doses of IFX(5–15 mg/kg every 4–8 weeks) between Nov2021-Apr2025. Drug levels were measured using a bedside kit capable of quantitatively detecting values between 0.4–20µg/mL.

Results

A total of 1,059 single pre-infusion measurements from 455 patients and consecutive dual measurements at weeks 4 and 8 from 64 patients were evaluated. In the single and double measurement groups, 75.4% and 84.4% of patients had Crohn’s disease(CD), respectively. The most commonly used doses were 5 mg/8 weeks and 10 mg/4 weeks(Table 1) Drug levels were below 5 µg/mL in 33% of the measurements. Antibody positivity was present in 47.5% of 120 available measurements ranging from 0.4-20 µg/mL, showing no significant correlation with drug levels or immunomodulatory(IM) use (p=0.62 and p=0.61) However, for all positive antibody measurements drug levels were ≤ 3.5 µg/mL. CRP differed significantly across drug level groups, whereas albumin did not(Table 1). A weak negative correlation was found between IFX levels and CRP(r = -0.13, p = 0.001), with no correlation for albumin(p=0.54). In UC patients, the correlation between CRP and IFX levels was slightly stronger(r= -0.280, p=0.004).No significant associations were found between IM use and IFX levels >5 µg/mL(p=0.55), >10 µg/mL(p= 0.93), or >20µg/mL(p = 0.87). Abdominal pain was more common in patients with IFX levels <5 µg/mL (p=0.032) and <10 µg/mL (p=0.044). Smoking status was not associated with achieving IFX levels >5 µg/mL( p=0.57), >10 µg/mL (p=0.89), and >20 µg/mL (p=0.633). Among CD patients, those with IFX levels >5 µg/mL had significantly lower CDAI scores (p = 0.039), and lower daily stool frequency (p=0.002).Regression analysis showed that higher BMI (p=0.045), lower CRP(p < 0.001), higher IFX dose(p < 0.001), and CD diagnosis(p =0.014) to be independently associated with achieving IFX levels >5 µg/mL. These factors also predicted levels >10 µg/mL and >20 µg/mL, except for BMI at the >20 µg/mL threshold. In the dual measurement group, the median CRP levels at weeks 4 and 8 were 2.1(5.1) and 2.5(6.3), respectively (p = 0.108). Among patients with IFX >20 µg/mL at week 4, 75% maintained levels >5 µg/mL at week 8, whereas this rate was 64% for those with levels >10 µg/mL. Only 59.6% of those with >5 µg/mL at week 4 retained >5 µg/mL at week 8(all p <0.001). Week 4 IFX levels was 7.3 times higher than at week 8 for cases within measurable range.

Conclusion

One-third of patients demonstrated sub-therapeutic drug levels, which were associated with elevated CRP levels and worse clinical outcomes. Notably, the 5mg/4 weeks group exhibited higher drug concentrations compared to the 10mg/8 weeks group, suggesting that increased infusion frequency may contribute to achieving higher levels. Moreover, maintaining sufficient drug levels at week 8 requires substantially higher levels at week 4. Measurement of anti-TNF antibodies may not be fruitful if drug level is > 3.5µg/mL. These findings support the drug monitoring and personalized dosing to reduce the risk of loss of response and improve outcomes.

Introduction

Inflammatory bowel disease (IBD) has a high incidence in young people directly impacting their reproductive years. In 2023, ECCO produced guidelines on sexuality, fertility, pregnancy & lactation to support healthcare professionals in managing patients considering, and throughout pregnancy. This audit undertaken as 3rd year medical student project.

Aims & Methods

The study aimed to evaluate the extent to which ECCO standards on are being met at a tertiary hospital and look at disease activity and adherence to advice.The IBD service was benchmarked against the ECCO guidelines. The women received antenatal care at our linked women’s Hospital. Patients are offered monthly appointments with the IBD team during pregnancy. Data was collected from electronic patient records (EPIC©) of patients under the care of the IBD team. The data were analysed in SPSS using statistical tests, including Mann-Whitney U test.

Results

The study included patients who became pregnant or gave birth between April 1, 2023 - March 31, 2024. The results included 56 women, of whom 28 had already given birth. Thirty women (53.6%) had Crohn’s Disease and 26 (46.4%) had ulcerative colitis. Ages ranged from 20 to 42 years. Forty-eight women (85%) were receiving active treatment, with 23 (41%) on advanced therapies and of these of the 23 people on biologics, 13 (56.6%) continued taking the biologic throughout pregnancy, 6 (26.1%) stopped taking the biologic before the third trimester. 71.4% of women had a documented & individualized care plan. Documentation was noted to be poor around advice re lactation (12.5%).
IBD activity improved between pre-conception and during pregnancy, as indicated by faecal calprotectin levels decreasing on average from 392.7 (SD 630) pre-conception to 104.2 (SD 142.7) during pregnancy. Women with active disease generally give birth earlier than those without active disease, and those with active disease were more likely to have a preterm birth with 25% of the active disease group giving birth prematurely, i.e. before 37 weeks, although this did not meet statistical significance. 50% had a spontaneous vaginal delivery, while 32.2% had a caesarean section. There was no significant difference in the baby’s birth weight between mothers on biologic treatment and those not on biologic treatment.

Conclusion

The audit identified areas where the ECCO standards were not fully met, such as documenting advice around medications and lactation. The IBD team has developed an action plan to address the findings of the audit. We also demonstrated reduced disease activity during pregnancy in this cohort of women and in keeping with previous studies saw that patients with active IBD were more likely to deliver before 37 weeks.

References

1. Torres, J., Chaparro, M., Julsgaard, M., Katsanos, K., Zelinkova, Z., Agrawal, M., Ardizzone, S., Campmans-Kuijpers, M., Dragoni, G., Ferrante, M., Fiorino, G., Flanagan, E., Gomes, C. F., Hart, A., Hedin, C. R., Juillerat, P., Mulders, A., Myrelid, P., O’Toole, A., … van der Woude, C. J. (2023). European Crohn’s and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. Journal of Crohn’s and Colitis, 17(1), 1–27. https://doi.org/10.1093/ecco-jcc/jjac115

Disclosure

No conflict of interest