Introduction

The presence of an aberrant clonal IEL population is the hallmark of RCDII. We have observed patients who have clinical features of RCDII but do not fit the classical immunophenotypic or molecular features of same.

Aims & Methods

Our aim was to describe the profile of RCDII patients who present with classical aberrancy in the absence of clonality or atypical aberrancy +/- clonality.
We conducted a retrospective review of flow cytometry and TCR-GR analysis of RCDII patients in University Hospital Galway over a 14 year period.

Results

We included 13 RCDII patients, 5 males and 7 females, with a median age of 62 years at RCDII diagnosis. 6 patients had classical RCDII, median 80% aberrant IELs (cytoCD3+/sCD3-/sCD8-) and had a clonal TCR-GR. Of the remaining 7 patients, 4 had classical aberrancy (median 52%) without clonality, including 1 who lost the TCR-GR clone 1 year post autologous stem cell transplant but whose aberrancy persisted (43%) 10 years later, and 1 who subsequently developed a clonal TCR-GR on follow up. 2 patients had an atypical aberrant IEL population without clonal TCR-GRs; one of whom developed lymphoma 3 years post RCDII diagnosis and the other remains under surveillance (16% classical aberrancy, 41%NK cells). The remaining patient has a mixed aberrant IEL population (71% cytoCD3+/sCD3-/sCD8+, 19% cytoCD3+/sCD3-/sCD8-) but has a clonal TCR-GR. Mortality rate for the classical RCD II was 66% compared to 14% in variant RCD II.

Conclusion

​The heterogeneity of RCDII poses many diagnostic challenges. Newer sequencing technologies will likely aid the expansion of the diagnostic criteria to include variant RCDII. While follow up is ongoing, variant RCDII maybe associated with a lower mortality.

Introduction

Celiac disease, a chronic autoimmune enteropathy caused by exposure to gluten in genetically predisposed individuals, is characterized by a broad clinical spectrum often with multisystem involvement. Symptoms related to the reproductive system include delayed menarche, early menopause, fertility disorders, miscarriages, and prematurity.

Aims & Methods

To study the impact of celiac disease on fertility in a female Greek population. A retrospective review of all patient records from the celiac disease outpatient clinic at our hospital.

Results

Medical histories of 231 female patients were reviewed (69% of the total patient population) with a mean age of 44.3 years and a mean age at diagnosis of 35.3 years. The mean age of menarche was 12.7 years. Menstrual irregularities were reported in 27% (20% instability, 7% dysmenorrhea). A total of 28% (65/231) were in menopause, with an average age of menopause onset at 50.7 years. A history of miscarriages was recorded in 15% of all women (35/231), but in 29% of women in menopause (19/65). 82% (53/65) of women in menopause had children, with 98% (52/53) having been pregnant before the diagnosis of the disease. Among all women who gave birth, only 12/113 (11%) had been diagnosed before pregnancy. 56% (63/113) and 44% (50/113) had a vaginal delivery and cesarean section, respectively. Pregnancy complications were recorded in 24 women (18 preterm births, 15 low birth weight infants, 1 intrauterine death).

Conclusion

Women with celiac disease tend to have relatively late menarche and an increased rate of miscarriages. However, the disease does not seem to significantly affect fertility.

References

1.Ehud Galron MD, Rayna Boyarsky MD,Ido Sold MD, Chen Ben David MD,and Eyal Gal MD,Interactions between celiac disease and pregnancy:A literature review, Isr Med Assoc J.2023 Dec;25(12):830-835
2.Giovanni Casella et. Al. Celiac disease and obstetrical-gynecological contribution, Gastroenterol Hepatol Bed Bench. 2016 Autumn; 9(4): 241–249.
3.Stephanie M. Moleski et. Al., Increased rates of pregnancy complications in women with celiac disease, Annals of Gastroenterology (2015) 28, 236-240
4.Nafeesa N. Dhalwani et Al., Women With Celiac Disease Present With Fertility ProblemsNo More Often Than Women in the General Population, Gastroenterology 2014;147:1267–1274

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

Anti-TNF are the first biologic treatment option in inflammatory bowel diseases (IBD). Few data is available on the long term risk of relapse after anti-TNF withdrawal in paediatric-onset IBD, especially at the population level.

Aims & Methods

All paediatric-onset (<17 years) IBD diagnosed between 1988 and 2011 were included in a prospective population-based study and were retrospectively followed until 2013. Among patients treated with first-line anti-TNF, the cumulative probability of relapse after anti-TNF withdrawal was evaluated using a composite outcome (intestinal resection, and/or flare-related hospitalization, and/or IBD treatment initiation, and/or active disease). Factors associated with relapse were investigated with a Cox model.

Results

Among a total of 1,344 patients (Crohn’s disease (CD): n=1,007; Ulcerative colitis (UC): n=337), 562 were treated with anti-TNF. Anti-TNF was stopped in 73 patients (CD: n=66; UC: n=7) during remission defined by Harvey-Bradshaw score < 4 in CD and Mayo score ≤ 2 in UC. Among them, median time to anti-TNF initiation was 1.6 years (IQR, 0.7-4.0) and median duration of treatment was 1.0 year (0.3-1.7). The first line anti-TNF therapy was infliximab in 68 (93%) patients. At anti-TNF withdrawal, 47 (64%) patients received immunosuppressant. The cumulative probability of relapse after anti-TNF withdrawal at 1, 3 and 5 years was respectively 62%, 85% and 93%. Median delay of relapse was 9.5 months (7.5-12.0). The cumulative probability of flare-related hospitalization at 1, 3 and 5 years was respectively 7%, 7% and 8%. No patient required intestinal resection after a median follow-up of 8.7 (5.8-13.8) years. In multivariate analysis, median time to anti-TNF initiation >1 year was the only factor associated with the risk of relapse (HR 0.58, CI95% [0.35-0.97], p=0.036). Among relapsers, 46 (63%) were retreated with anti-TNF. Retreatment with anti-TNF was effective in 45 (98%) patients after a median delay of 3.9 months (3.5-10.0). Infusion reaction occurred in only 2 patients.

Conclusion

In a population-based cohort of paediatric-onset IBD, the risk of relapse after anti-TNF withdrawal was high, but was not associated with major complication. Retreatment with anti-TNF was effective and well tolerated.

Disclosure

Consultant fees from Sandoz and AbbVie

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

Hypermobile Ehlers-Danlos syndrome (hEDS) is a hereditary non-inflammatory disorder of connective tissue laxity characterized by joint hyperextensibility in association with musculoskeletal symptoms. The prevalence of gastrointestinal (GI) symptoms, such as abdominal pain, nausea, and constipation is high in hEDS. Research on the relationship between EDS and GI symptoms has mostly been restricted to disorders of the gut-brain axis, whereas the relationship between hEDS and GI dysmotility remains to be clarified.

Aims & Methods

This study aimed to explore antro-duodenal manometry (ADM) patterns in patients with hEDS presenting with GI symptoms.

In a prospective open-label study, patients with hEDS and GI symptoms presumed to be the results of GI dysmotility underwent a 6-hour high resolution ADM. The manometry tracings were analyzed by two investigators (KS and JC) independently. Antral contraction frequency (contractions per minute) < 1.0 was considered as antral hypomotility. Pylorospasm was defined as isolated pyloric pressure waves within 60 minutes postprandial. The following neuropathic enteric patterns were scored: presence of retrograde peristalsis, bursts, clustered contractions, and absence of phase III contractions. Abnormal ADM was defined as having antral hypomotility and/ or pylorospasm and/ or neuropathic enteric patterns.

Results

Fifty patients (48 women, mean age 30.4 ± 11.1 yrs.) were included. At baseline, 74% of patients were dependent on enteral feeding and the mean BMI was 20.4 ± 4.4 kg/m².
Overall, ADM tracings with one or more abnormal patterns were identified in 53% of patients. Antral hypomotility and pylorospasm were detected in 29% and 15% of patients, respectively. Neuropathic enteric patterns were only seen in 17% of patients. In all cases, no more than one neuropathic pattern was identified. Among the observed neuropathic enteric patterns, 15% of patients showed retrograde peristalsis, 13% absence of phase III contractions, and 2% bursts. Clustered contractions were not identified in this cohort.

Conclusion

Hypermobile Ehlers-Danlos patients presenting with gastrointestinal symptoms showed low numbers of abnormal ADM patterns. In particular, enteric dysmotility was observed in only a small minority of cases. Antroduodenal dysmotility therefore does not appear to be a principle pathomechanism in the majority of hEDS cases studied. Further research is needed to understand the mechanisms that underlie GI symptom generation in this population.

Clinical Case Summary

A 2-week-old full-term female infant presented to the pediatric emergency department with five days of vomiting, loss of appetite, and bloody stools. Initially fed a cow milk-based formula, she did not gain weight. On admission, she appeared lethargic, with vital signs indicating low blood pressure, elevated heart rate, increased respiratory rate, and a body temperature of 36.6°C. Cold extremities, delayed capillary refill time, and marbled skin were noted. Abdominal examination revealed distension without peritonitis or skin discoloration, and no hepatosplenomegaly was present. Laboratory tests showed metabolic acidosis with an elevated anion gap and high lactate levels. The patient vomited stomach contents and fecal material, prompting the use of a nasogastric tube, which drained extensively. An abdominal x-ray revealed diffuse pneumatosis in the intestinalis without bowel perforation. Managed in the pediatric intensive care unit with nil per os, total parenteral nutrition, and empirical parenteral antibiotics. Blood and urine cultures, as well as stool PCR testing for common viral and bacterial pathogens, were negative. The infant showed improvement after two weeks of conservative treatment, including abdominal X-rays, which revealed normal gas patterns without signs of pneumatosis intestinalis. Introduction of an amino acid-based formula was well-tolerated without recurrence of symptoms.

Pneumatosis intestinalis mainly occurs during the neonatal period and is more common among preterm neonates. The main etiology is necrotizing enterocolitis (NEC). However, it can present among term neonates, infants, children, and even adults. The differential diagnosis is wide, including cow’s milk protein allergy, infectious diseases, trauma, ischemia, child abuse, and intestinal failure.
The working diagnosis of this case was pneumatosis intestinalis secondary to milk protein allergy, which was managed successfully and conservatively without any invasive procedure.

References

1. Im J, Anjum F. Pneumatosis Intestinalis. [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564381/
2. Abramov A, Luks VL, De Bie F, Hwang R, Allukian M 3rd, Nace GW Jr. Pneumatosis intestinalis in children beyond the neonatal period: is it always benign?. Pediatr Surg Int. 2022;38(3):399-407
3. Overman RE Jr, Criss CN, Gadepalli SK. Necrotizing enterocolitis in term neonates: A different disease process? J Pediatr Surg. 2019 Jun;54(6):1143-1146.
4. Narumoto S, Sakamoto S, Uchida H, et al. Necrotizing enterocolitis in the setting of milk allergy after pediatric living donor liver transplantation. Pediatr Transplant. 2018 Feb;22(1).
5. Reppucci ML, Nolan MM, Cooper E, et al. Pneumatosis Intestinalis in Children With Intestinal Failure: The Result of Intestinal Stress From Enteral Feeding?. J Pediatr Gastroenterol Nutr. 2023;76(5):560-565.