Introduction

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) represent chronic and occasionally disabling conditions, necessitating innovative treatment strategies. Covering 14% of Ireland's landscape, bogland ecosystems house unique plant biodiversity, yielding biologically active secondary metabolites. Informed by traditional medicinal knowledge and in vitro screening for immunomodulatory potential, three plant extracts (NTP0226A, NTP0127B, NTP0206EA) were selected for exploration of their potential to treat IBD and IBS within the "Unlocking Nature’s Pharmacy from Bogland Species" project.

Aims & Methods

Patients undergoing colonoscopy were prospectively recruited in three cohorts: healthy controls, IBS, and ulcerative colitis (UC). Recto-sigmoid biopsies were collected. Ex-vivo colonic tissue explants were generated and cultured for 24 hours with treatments (Infliximab, NTP0226A, NTP01227B, NTP0206EA). Real-time energy metabolism profiles and secretion of 10 inflammatory mediators were assessed using Seahorse Xfe24 analyser and multiplex ELISA, respectively. Levels of macrophage polarisation following exposure to treated explants were analysed by flow cytometry. Total protein content allowed result normalization, with significance set at P < 0.05.

Results

Twenty-seven patients were recruited (6 healthy controls, 6 IBS, and 15 UC). UC patient explants exhibited elevated glycolytic metabolism and increased IL-4, IL-6, and IL-12p70 secretion compared to non-UC patients. No differences were observed between healthy controls and IBS patients. Linear regression did not show difference between age and mitochondrial bioenergetics. There was no change in metabolism profiles of any cohort following treatment with Infliximab or the 3 novel extracts. In the UC tissue, treatment with Infliximab reduced IL-12p70 secretion (p=0.0098), this reduction was not seen in the other 2 cohorts. NTP0206EA reduced IL-10 secretion in the UC cohort (p=0.0255). In the IBS cohort; NTP01227B reduced IL-10 secretion (p=0.0048) and NTP0226A reduced IL-4 (p=0.004) and IL-6 (p=0.0219) secretion. Macrophages exposed to UC explants treated with infliximab showed a reduction in HLA-DR, CD54 and CD163 and an increase in TIM-3 and CD206 expression (p<0.05). Macrophages exposed to UC explants treated with NTP0206EA showed reduced CD163/CD206 expression (p<0.05). NTP0226A and NTP01227B did not alter macrophage polarisation. Principal components analysis demonstrated reduced separation between the immune-metabolic profiles of UC patients and healthy controls following treatment with NTP0226A.

Conclusion

Using an explant model, we have shown that UC patients have a distinct immune-metabolic profile modifiable by a standard IBD therapy and novel plant extracts. Blockade of IL-6 trans-signalling has recently shown promise as an effective treatment target in IBD. Our natural extract NTP0226A reduced IL-6 secretion in IBS patients and is a promising candidate for therapeutic exploration. These findings contribute to our understanding of the complex interplay in the colonic microenvironment and highlight potential avenues for novel therapeutic interventions.

References

https://www.cso.ie/en/csolatestnews/pressreleases/2021pressreleases/pressstatementecosystemaccounts-peatlandsandheathlands2018/

Introduction

The pathogenicity of Blastocystis spp. is still debated. Guidelines for donor feces screening differ in their advice to screen for Blastocystis spp., but when tested, its presence is a common reason for exclusion.¹Blastocystis spp. are correlated to increased bacterial alpha-diversity² and distinct bacterial groups³ and therefore its presence may indicate favorable efficacy of fecal microbiota transplantation (FMT). The latest European consensus report no longer advices to reject feces donors that test positive for Blastocystis spp.⁴ Only one paper has been published on human transmission of Blastocystis spp. via frozen FMT.⁵

Aims & Methods

We aimed to investigate the long-term effects of the application of Blastocystis-positive FMT, prepared with fresh feces.
In a FMT trial on FMT with refractory Irritable Bowel Syndrome (IBS) adolescents (age 16 – 20 years) received two administrations (at baseline and after 6 weeks) of fresh allogeneic FMT via nasoduodenal tube prepared with fecal samples from a Blastocystis spp. positive feces donor (NCT03074227). Blastocystis spp. presence and subtyping were determined using microscopy, PCR and Sanger sequencing.

Results

Three recipients received FMT from one donor colonized with Blastocystis subtype 3 (ST3). Two recipients were negative for Blastocystis spp. and one recipient carried ST2 at baseline prior to FMT. After FMT, the two prior-negative recipients tested positive for identical ST3 as the donor after FMT at 12 weeks, but lost carriership of this subtype at week 24 and week 48. The ST2 colonized recipient remained colonized with ST2 and did not acquire ST3 after FMT. Transient adverse events did occur, but did not differ from patients treated with Blastocystis spp.-negative FMT. No FMT-related serious adverse events occurred.

	Recipient	Baseline	Before FMT 1	Donor FMT 1	Before FMT 2	Donor FMT 2
		Week -2	Week 0	Week 0	Week 6	Week 6	Week 12	Week 24	Week 48
1	Woman, 18 y	negative	negative	ST3	ST 3	+, no seq	ST3	negative	negative
2	Woman, 20 y	negative	negative	ST3	+, no seq	ST3	ST 3	ST3	ST3
3	Woman, 16 y	ST2	ST2	ST3	+, no seq	ST3	ST2	ST2	ST2

Table 1: Sanger PCR sequencing results of frozen feces samples from three adolescents with IBS and one healthy donor. Samples were collected before, during and after the FMT treatment schedule with follow-up unto week 48. Light blue cells indicate a different sequence order of Blastocystis ST3 than the Blastocystis ST3 indicated in the dark blue cells. Grey cells indicate columns representing donor samples.
Abbreviations: FMT; fecal microbiota transplantation, ST; subtype, seq; sequence, y; years.

Conclusion

We present the first long-term results of Blastocystis spp. transmission by fresh FMT in three cases. Transient colonization with Blastocystis spp. did occur without the occurrence of FMT-related serious adverse events.

References

1. Benard MV, de Bruijn CMA, Fenneman AC, Wortelboer K, Zeevenhoven J, Rethans B, et al. Challenges and costs of donor screening for fecal microbiota transplantations. PLoS One. 2022;17(10):e0276323.
2. Tito RY, Chaffron S, Caenepeel C, Lima-Mendez G, Wang J, Vieira-Silva S, et al. Population-level analysis of Blastocystis subtype prevalence and variation in the human gut microbiota. Gut. 2019;68(7):1180-9.
3. Nieves-Ramirez ME, Partida-Rodriguez O, Laforest-Lapointe I, Reynolds LA, Brown EM, Valdez-Salazar A, et al. Asymptomatic Intestinal Colonization with Protist Blastocystis Is Strongly Associated with Distinct Microbiome Ecological Patterns. mSystems. 2018;3(3).
4. Keller JJ, Ooijevaar RE, Hvas CL, Terveer EM, Lieberknecht SC, Hogenauer C, et al. A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group. United European Gastroenterol J. 2021;9(2):229-47.
5. Terveer EM, van Gool T, Ooijevaar RE, Sanders I, Boeije-Koppenol E, Keller JJ, et al. Human Transmission of Blastocystis by Fecal Microbiota Transplantation Without Development of Gastrointestinal Symptoms in Recipients. Clin Infect Dis. 2020;71(10):2630-6.

Disclosure

CYP has received research grants from Gilead and Perspectum, consultancy fee from Chemomab and NGM, and speaker’s fee from Tillotts. The other authors disclose no conflicts.

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 describes etrasimod efficacy and safety in patients stratified according to baseline disease activity. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo.¹ ELEVATE UC 52 had a treat-through design comprising a 12-week (wk) induction period followed by a 40-wk maintenance period. ELEVATE UC 12 comprised a 12-wk induction period. In this analysis, data were pooled from both trials and patients’ baseline UC activity was stratified as moderately or severely active based on a Modified Mayo score (MMS) of 5–7 or 8–9, respectively. Efficacy endpoints were measured at Wk 12 and included mean percentage change from baseline in MMS and clinical response/remission according to MMS category. Efficacy data were analysed descriptively, and 95% confidence intervals (CIs) were calculated for all means or proportions using normal approximation or simultaneous estimation method, respectively. Safety was assessed up to Wk 52 in the pooled safety analysis set.

Results

Of the 743 patients in this analysis, 525 (70.7%) had a baseline MMS 5–7 and 218 (29.3%) had a baseline MMS 8–9. Baseline characteristics were broadly similar between subgroups, with the exception of lower rates of proctitis in patients with MMS 8–9 vs 5–7 (3.3% and 3.0% vs 9.3% and 9.4% in etrasimod and placebo groups, respectively). At Wk 12, patients treated with etrasimod showed larger mean percentage reductions (95% CI) in MMS, vs placebo, regardless of baseline disease activity (48.4% [52.3, 44.4] vs 27.0% [32.2, 21.7] for baseline MMS 5–7, and 46.4% [51.2, 41.5] vs 29.8% [37.2, 22.3] for baseline MMS 8–9). At Wk 12, more patients treated with etrasimod achieved clinical response, vs placebo, regardless of baseline disease activity, with an overall reduction from baseline disease activity as measured by MMS categorisation in both baseline MMS subgroups (Table). Generally, rates of treatment-emergent adverse events (TEAEs) were similar across treatment and baseline disease activity subgroups (proportion of patients with any TEAE: 59.0% vs 50.8% and 65.1% vs 56.1% for etrasimod vs placebo, in baseline MMS 5–7 and 8–9 groups, respectively).

Table. Proportion of patients achieving clinical response and each MMS category at Wk 12 stratified according to baseline disease activity (pooled data from ELEVATE UC 52 and ELEVATE UC 12)
	Baseline MMS 5–7 (moderate)		Baseline MMS 8–9 (severe)
	Placebo QD (N=181)	Etrasimod 2 mg QD (N=344)	Placebo QD (N=66)	Etrasimod 2 mg QD (N=152)
Clinical response,a % (95% CI)b	39.8 (32.6, 46.9)	61.3 (56.2, 66.5)	30.3 (19.2, 41.4)	64.5 (56.9, 72.1)
MMS category, % (95% CI)c
Remission (MMS 0–2) Mild (MMS 3–4) Moderate (MMS 5–7) Severe (MMS 8–9) MMS not availabled	17.1 (11.1, 25.5) 26.0 (18.5, 35.1) 35.4 (26.9, 44.9) 8.3 (4.4, 15.2) 13.3 (8.1, 21.1)	38.4 (31.9, 45.3) 24.4 (19.0, 30.8) 23.0 (17.7, 29.3) 2.6 (1.1, 5.9) 11.6 (7.9, 16.8)	10.6 (4.2, 24.2) 15.2 (7.0, 29.6) 37.9 (24.3, 53.7) 24.2 (13.4, 39.8) 12.1 (5.1, 26.0)	21.7 (14.4, 31.4) 25.7 (17.7, 35.7) 30.3 (21.7, 40.5) 13.2 (7.6, 21.8) 9.2 (4.8, 17.1)
aClinical response was defined as a ≥2-point and ≥30% decrease from baseline in MMS, and a ≥1-point decrease from baseline in RBS or an absolute RBS ≤1. b95% CI is based on normal approximation to binomial proportion. c95% CI was calculated using the Goodman method of simultaneous CI estimation. dMMS was not available for some patients at Wk 12 for various reasons, including discontinuation prior to Wk 12. CI, confidence interval; MMS, Modified Mayo score; N, number of patients in the baseline disease activity subgroup by treatment; QD, once daily; RBS, rectal bleeding subscore; UC, ulcerative colitis.

Conclusion

Etrasimod showed greater reductions in disease severity and higher rates of clinical response, vs placebo, regardless of baseline disease activity. The safety profile of etrasimod was consistent with the overall trial population¹ and was not impacted by baseline disease activity.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171

Disclosure

BES has received consulting fees from AbbVie, Abivax, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, Ventyx Biosciences; speaker fees from Abivax, Bristol Myers Squibb, Janssen, Lilly, Pfizer, Takeda; research grants from Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma; stock options from Ventyx Biopharma; and other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda. MCD is a consultant for AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer Inc, Prometheus Labs, Spyre and Takeda. PGK has received consulting and speaker fees from AbbVie, Janssen, Pfizer Inc, and Takeda and has received scientific grants from Pfizer Inc and Takeda. SV has received speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; and grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. RP has received consulting fees from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, UCB; speaker fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda; an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, Ventyx; and received research support from AbbVie, Janssen, Takeda and Pfizer. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, BMS, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr, Theravance; and has received research support from Pfizer Inc and Takeda. JCW, JW and EB are employees and shareholders of Pfizer Inc. AM is an employee of Pfizer Ltd and shareholder of Pfizer Inc. MG is an employee and shareholder of Pfizer AG. AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda, Bristol Myers Squibb; and speaker fees from Bristol Myers Squibb.

Introduction

Active inflammatory bowel disease in pregnancy is associated with an increased risk of adverse maternal and neonatal outcomes. Understanding patterns of disease activity may inform strategies for improving outcomes.

Aims & Methods

A retrospective cohort study was conducted of pregnancies managed through an IBD–antenatal clinic between August 2020 and January 2025. Patients were stratified into 2 groups based on disease activity during pregnancy. Active disease was defined using the Physician Global Assessment, symptoms, and biomarkers (CRP and/or FCP). Disease flare was defined by an increase in symptoms and/or biomarkers from their baseline. Disease activity was assessed pre-conception (within 6 months before pregnancy) during pregnancy and post-partum (up to 6 months post birth).

Results

Of 209 pregnancies (Table 1), 76.3% (n=158) were in remission and 23.7% (n=49) had active disease pre-conception. Among those with active disease, 81.6% (n=40) remained active into pregnancy, while 18.4% (n=9) achieved remission. Of those in remission at pre-conception, 73.4% (n=116) stayed in remission during pregnancy, and 24.7% (n=39) flared. 2 patients with no pre-conception data were active in pregnancy.
Of 125 patients in remission during pregnancy, 73.6% (n=92) stayed in remission post-partum and 12.0% (n=15) flared. Among 81 patients with active disease in pregnancy, 39.5% (n=32) remained active, and 53.0% (n=43) achieved remission post-partum.
Patients in remission through pregnancy had a higher mean BMI (24.5 vs 23.0 kg/m², p=0.027), were more likely to be of white ethnicity compared to minority ethnic groups (61.0% vs 38.4% p=0.0026), have a diagnosis of Crohn’s disease (58.6% vs 37.0%, p=0.0088), and be nulliparous (51.2% vs 35.0%, p=0.0414).
At conception, approximately 30% of patients in both groups were not receiving any treatment. During pregnancy, this proportion fell to 8.6% in the active group, reflecting therapy escalation. Use of biologics increased from 22.2% to 38.2% in the active group and remained stable at 36.0% in the remission group. Corticosteroid use was exclusive to the active disease cohort (6.2% at conception; 23.5% during pregnancy).
Active disease in pregnancy was associated with higher rates of adverse outcomes: gestational diabetes (12.3% vs 8.0%, p=0.001), fetal growth restriction (4.9% vs 0%, p=0.044), and low birth weight (<2500g: 14.6% vs 2.4%, p=0.015). While rates of small for gestational age infants were higher in the active group (9.9% vs 4.0%), this was not statistically significant.
Emergency c-sections were more common in the active group (29.9% vs 15.0%, p=0.03), while elective c-sections were more frequent in the remission group (27.5% vs 13.4%, p = 0.03). Women in remission more often had an intact perineum (63.6% vs 54.7%), while episiotomy was more frequent in those with active disease (18.8% vs 11.7%); both did not reach statistical significance.

	Pre-conception % of available data (n)	Pregnancy % of available data (n)	Post-partum % of available data (n)
Active disease	23.7% (49)	39.3% (81)	25.2% (47)
Remission	76.3% (158)	60.7% (125)	74.2% (135)
Excluded (pregnancy loss)	0	3	3
Missing data points	2	0	24

Conclusion

This study underscores the impact of active IBD on maternal and neonatal outcomes.
Nearly 1 in 4 women in remission at preconception flared during pregnancy. This highlights the need for effective pre-conception counselling, access to disease monitoring tools, multidisciplinary management and timely treatment optimisation to sustain remission during pregnancy.

Disclosure

No disclosures

Introduction

Iron deficiency anaemia (IDA) is a common comorbidity in inflammatory bowel diseases (IBD). Previous studies have already showed the predictive value of anaemia on hospitalization and mortality rates, however, these studies did not focus on the effect of IDA on patients with clinical and biochemical remission, however, due to the ethiopathology, certain effects are hypothesized.

Aims & Methods

This was a multicenter retrospective real-life cohort study assessing the effect of IDA on clinically and biochemically inactive IBD patients. We included patients from the outpatient setting who has been followed-up for a year. Patients with need of blood transfusion at baseline were excluded. IDA was defined as no clinical and biochemical activity, ferritin <30 μg/mL and transferrin saturation <20% with the presence of anemia. Primary outcome was disease aggravation, defined as need of change in the current treatment/hospitalization/abdominal surgery. Secondary outcome was proportion of major complications, defined as need of hospitalization/abdominal surgery. Pearson’s chi squared sample size calculation (n=720) was performed on our pilot results based on 200 IBD patients.

Results

In total, 711 patients (median age: 43.1 years [IQR: 32.3 - 49.6]; male/female ratio: 332/379; CD: 397, UC: 311; IDA/non-IDA 85/623) were enrolled. Mean follow-up period was 1.1±0.28 years. The presence of IDA increased the risk of disease aggravation (OR: 1.7) and major complications (OR: 2.8). Furthermore, male sex (OR: 0.6) and older age (OR: 0.8) were protective, and ileocoecal resection (OR: 2.0) and higher C-reactive protein levels (OR: 1.5) increased the disease aggravation.

Conclusion

IDA predicts the risk of relapse at some degree in patients with clinical and biochemical remission in the outpatient setting. IDA may help to identify underlying disease activity in patients with clinical and biochemical remission in time, therefore, we recommend to be implemented in the treat-to-target approach.