Introduction

Eosinophilic Esophagitis (EoE) is a clinicopathological disease that requires an integrated assessment combining clinical, endoscopic, and histological findings. Despite this, treatment decisions often remain symptom based. A treat-to-target strategy has recently been proposed to guide EoE management.

Aims & Methods

Retrospective single-center study of EoE patients followed between March 2012 and January 2024, with ≥12 months of follow-up. Clinical, endoscopic, histological data, and complications were assessed using the I-SEE score.

Results

A total of 82 patients with EoE were evaluated [75.6% (n=62) male, mean age 29 ± 13 years], with 37.8% (n=31) diagnosed during childhood. The most frequent symptom was food impaction (74.4%), and atypical symptoms were more common in pediatric patients (p=0.014). At baseline, 55.1% (n=43) presented with a fibrostenotic phenotype, more frequently in adults (p=0.012), and 32.9% (n=27) had moderate-to-severe disease based on the I-SEE score.
During follow-up, 56.1% (n=46) developed complications, most commonly food impaction requiring endoscopy. The presence of a fibrostenotic phenotype on initial endoscopy was a predictor of complications (OR 3.122; 95% CI 1.210–8.055; p=0.019). Both fibrostenotic phenotype (p=0.018) and moderate-to-severe I-SEE scores (p=0.004) were associated with increased need for therapeutic switching.
At 12 months, 50.0% (n=41) were asymptomatic; however, only 12.2% (n=10) had endoscopic healing and 9.8% (n=8) histologic remission. Throughout the study period, the rates of endoscopic and histologic healing remained below 25%.

Conclusion

The authors highlight the clinical dissociation of inflammatory activity and emphasize the importance of endoscopic and histologic healing to prevent disease progression.

References

Dellon, Evan S., et al. "A clinical severity index for eosinophilic esophagitis: development, consensus, and future directions." Journal of Allergy and Clinical Immunology 150.1 (2022): 33-47.

Introduction

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition caused by PTEN disease-causing variants and characterized by a complex phenotype including gastrointestinal-hamartomas and an increased lifetime risk for malignancies. Current genetic testing enables carriers identification and cascade testing

Aims & Methods

To describe a large cohort of PHTS carriers including unique clinical presentation, genetic diagnosis and treatment approach.
We conducted a retrospective, comprehensive review of medical charts was conducted for individuals with PHTS who were under surveillance at specialized high-risk clinics in Israel. The diagnosis of PHTS was based on the revised diagnostic criteria, which include identification of disease-causing variants in the PTEN gene mutation and/or a combination of major and minor clinical features *.

Results

A total of 53 individuals were included in the study (43% female; median age at diagnosis: 38 years, IQR 29, range 25-75). Pathogenic or likely pathogenic variants in the PTEN gene were identified in 40 individuals (75%), (52% missense, 17% nonsense, and 25% frameshift mutations). Common clinical presentations included gastrointestinal polyps, observed in 75% (n = 40), with five patients having adenomas and one presenting with a ganglion cell polyp. Malignancies were reported in 62% (n = 33), most commonly breast cancer (20%) and thyroid cancer (9%). Macrocephaly was observed in 35% (n = 20), and developmental delay, including autism spectrum disorder, in 8 patients (15%). There were three cases of soft tissue tumors (5.6%): One individual with abdominal desmoid tumor at age 18, one individual with axillary osteosarcoma followed by bilateral chest liposarcoma and one case with a rare soft tissue sarcoma, at the base of the skull.
One case of PHTS with PTEN mosaicism was identified through sequencing of endometrial, salivary, and thyroid tissue samples, following a negative result from blood-based genetic testing. Five individuals (9.4%) received Sirolimus for severe clinical manifestations (multiple thyroid nodules, colonic polyps, gastrointestinal symptoms, and early-onset malignancies). Of them, two patients had substantial reduction in polyp burden and improvement in gastrointestinal symptoms.

Conclusion

In this substantial series we found that PTHS exhibits a wide range of phenotypic presentations, high overall cancer rates and a relatively high prevalence of soft tissue malignancies, which have been rarely described in PHTS. Constitutional mosaicism should be sought in a clinical picture suggestive of PHTS with negative germline genetic testing.

References

* Pilarski R et al: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013
1. Hendricks LAJ et al: PTEN Study Group; Mensenkamp AR, Vos JR. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet. 2022 Dec;65(12):104632. doi: 10.1016/j.ejmg.2022.104632. Epub 2022 Oct 18. PMID: 36270489.
2. Dhawan A et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.
3.Dhawan A, et al: Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumour Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res. 2025 Feb 12;31(9):1754–65. doi: 10.1158/1078-0432.CCR-24-3819. Epub ahead of print. PMID: 39937242; PMCID: PMC12010961.

Introduction

Low mucosal impedance has been associated with reduced mucosal integrity and is measured during ambulatory pH/impedance monitoring, defined as mean nocturnal baseline impedance (MNBI)¹. More recently, techniques to measure impedance during endoscopy are emerging². In a prospective cohort of patients with EoE (SWALLeOeW Study, ISRCTN17786884, recruitment ongoing) we assessed the technicality of comparing mucosal impedance using MNBI with impedance measured during high-resolution impedance manometry (HRIM).

Aims & Methods

Here we aim to assess the practicability of obtaining mucosal impedance measurements during HRIM and to compare this with impedance measured using MNBI in a group of patients with EoE.
Prospective participants with EoE were assessed with HRIM and MNBI and this was repeated following a treatment period (Oro-dispersible Budesonide). The pooling of repeat measures from an individual participant was deemed to be appropriate in this evaluation as the purpose was to technically validate the process of comparing MNBI with HRIM, rather than to compare individual data points.
MNBI was calculated during a quiescent nocturnal period (Laborie, Ohmega) using the average of distal impedance channels 3 and 5 cm above the proximal border of the LOS¹. Impedance data was obtained during the supine resting period during HRIM and manually exported from the software (Medtronic). Extracted frames were at least 3 respiratory cycles and up to 30 seconds, and impedance was calculated based on the sensors 2.5 and 4.5, or 3.5 and 5.5 cm above the proximal border of the LOS, depending on catheter position.

Results

22 paired HRIM and MNBI measurements were obtained to date, from 15 participants. Reasons for unsuccessful MNBI measurements were not attempting test (n=2), non-tolerance (n=10), Nickel allergy (n=1), drop-out (n=2), or unable to intubate (n=1). Reasons for unsuccessful impedance measurement during HRIM were reflux during resting pressure measurement (n=1), catheter failure (n=3), drop-out (n=2), non-tolerance (n=8) or measurement not attempted (n=2).
The mean impedance values as measured by the two methods were not significantly different: mean MNBI (95% CI): 1570 (1210-1930) ohms, HRIM (95% CI) = 1330 (920-1740) ohms, p = 0.18. The mean difference between MNBI and HRIM was 245 ohms (1380-1870) (5-95^th percentiles).
Using a normality threshold of <1500 ohms³ being suggestive of impaired mucosal integrity, the majority (19/22) of the readings showed agreement between the two methods. Of the three that did not agree, MNBI suggested impaired mucosal integrity in one, and HRIM in the other two.

Conclusion

Measuring impedance during HRIM appears to be comparably practicable to MNBI measurement in patients with EoE, with the same numbers of successful measurements achieved by the two methods. Comparison of this preliminary data also indicates good agreement between methods. Impedance measurement during HRIM could provide a faster method of assessing mucosal integrity in EoE, whilst simultaneously assessing oesophageal motility. Further work in the SWALLeOeW study will correlate mucosal impedance findings with the Eosinophilic Oesophagitis Histology Scoring System⁴ and assess impedance change in response to treatment.

References

1. Hoshikawa, Y. et al. Measurement of Esophageal Nocturnal Baseline Impedance: A Simplified Method. J Neurogastroenterol Motil 26, 241–247 (2020).
2. Lei, W.-Y., Vaezi, M. F., Naik, R. D. & Chen, C.-L. Mucosal impedance testing: A new diagnostic testing in gastroesophageal reflux disease. Journal of the Formosan Medical Association 119, 1575–1580 (2020).
3. Sifrim, D. et al. Normal values and regional differences in oesophageal impedance-pH metrics: a consensus analysis of impedance-pH studies from around the world. Gut gutjnl-2020-322627 (2020).
4. Collins, M. H. et al. Newly developed and validated eosinophilic esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for disease diagnosis and monitoring. Diseases of the Esophagus 30, (2016).

Introduction

The Atmo Capsule is a wireless motility capsule that senses and telemetrically transmits measurements of hydrogen (H₂) and carbon dioxide (CO₂) along the gut. In the colon, luminal concentrations of H₂ and CO₂ represent the metabolic activity of the microbial community. We hypothesized that delayed colonic transit would lead to altered gas profiles due to earlier depletion of fermentable substrates relative to transit time and/or facilitation of contact between methanogens and hydrogen (Levitt et al. CGH 2006).

Aims & Methods

The Atmo Capsule was administered to subjects with suspected upper and/or lower gut dysmotility. Colonic transit times (CTT) ≥ 59 h were considered delayed. Luminal H₂ and CO₂ concentrations (as time-normalized, area-under-the-curve [TN-AUC], [%.h]/h) were evaluated across the entire colon. Regional colonic profiles were evaluated per quartile of relative colonic transit, with quartiles 1 and 4 indicative of the proximal and distal colon, respectively. Gas measures were included if ≥ 50% of data were available for the corresponding segment. Fermentation profiles were estimated by the ratio of quartile 1:4 values, and time to peak concentrations were evaluated relative to CTT. Data were analyzed via Mann-Whitney test.

Results

The Atmo Capsule was administered to 209 subjects (median age 41; 188 female) with 170 yielding valid data on both colonic transit and colonic gas concentrations. Delayed colonic transit was identified in 60/170 (35%) subjects. In subjects with delayed CTT, H₂ concentrations tended to be higher in the proximal colon and lower in the distal colon with no overall difference across the region compared with those with normal transit (Table 1). CO₂ concentrations were higher throughout the colon except in the distal colon in subjects with delayed CTT. Peak concentrations of colonic H₂ and CO₂ were higher (H2, 8.7 h vs 5.9 %.h/h, p<0.01; CO2, 37.4 vs 29.9 %.h/h, p<0.01) and tended to occur earlier (H₂, 35.9 vs 47.0 % of colonic transit p=0.14; CO₂, 49.1 vs 86.8 % colonic transit, p<0.01) in patients with delayed compared with normal CTT.

Table 1. Gas profiles in patients with delayed colonic transit and correlation with symptom profiles. Data shown as median (interquartile range) and analyzed via Mann-Whitney test.

Conclusion

Colonic gas profiles, as measured via the Atmo Capsule, differed in patients with delayed compared with normal CTT, with patterns suggesting progressive depletion of fermentable substrates and/or conversion of H2 to methane during transit in those with delayed transit.

References

Levitt MD, Furne JK, Kuskowski M, Ruddy J. Stability of human methanogenic flora over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol. 2006 Feb;4(2):123-9. doi: 10.1016/j.cgh.2005.11.006. PMID: 16469670.

Disclosure

These authors disclose the following: Braden Kuo, Anthony J. Lembo, Eammon M.M. Quigley, Satish S.C. Rao, and William D. Chey serve on the Medical Advisory Board of Atmo Biosciences. Michael Cline and Baharak Moshiree served on the Medical Advisory Board of Atmo Biosciences. Braden Kuo has received funding from NIH, Vanda, Atmo Biosciences, and Takeda and has consulted for Evoke, Takeda, Ironwood, Novo Nordisk, Cindome, and Neurogastrx. Thomas Abell has received funding from Gastric Dysrhythmias, Neurogastrx, NIH GpCRC, and Vanda and has consulted for Enterra Medical, Novo Nordisk, Nuvaira, and Vanda. Anthony J. Lembo has received funding from Ardelyx, Biomerica, GSK, Ironwood, Takeda, and Vibrant and holds stock with Allurion, Bristol Myer Squibb, and J&J. Abigail Stocker has received funding from Cindome, Enterra Medical, and Vanda. William D. Chey has received funding from Atmo Biosciences, Commonwealth Diagnostics Intl, QOL Medical, and Salix; has consulted for AbbVie, Ardelyx, Biomerica, Comvita, Gemelli, Ironwood, Nestle, QOL Medical, Phathom, Redhill, Salix, Vibrant, and Takeda; has filed patents with My Nutrition Health, Digital Manometry, and Rectal Expulsion Device; and holds stock options with Coprata, Evinature, Food Marble, Kiwi Bioscience, and Modify Health. The remaining authors disclose no conflicts.

Introduction

Functional dyspepsia (FD) is a chronic gastrointestinal disorder characterised by meal-related symptoms, which a subset of patients attribute to the consumption of gluten-containing foods [1]. Recent evidence suggests that subtle duodenal immune activation is a feature of FD, as evidenced by elevated eosinophils [2] and impaired epithelial barrier function [3]. FD patients also exhibit an altered duodenal mucosa-associated microbiota (d-MAM) when compared to controls [4]. Given the microbiome’s involvement in the digestion of gluten, we hypothesised that the d-MAM determines the capacity for gluten to disrupt the epithelium and drive immune responses in FD patients.

Aims & Methods

Duodenal biopsies were collected from 10 FD patients and 7 asymptomatic controls. The d-MAM was cultured from biopsies in a habitat simulating media [5] containing 1% wheat-gluten, for up to 48hrs. Microbial cell pellets were frozen for future microbiome sequencing and the cell-free supernatants, containing d-MAM-digested gluten, were collected. Caco2 cells were challenged with the d-MAM-digested gluten, in a Transwell model of the intestinal epithelium (n=3, 2 technical replicates). Transepithelial electrical resistance (TEER) and protein expression of markers of epithelial integrity were measured in Caco2 cells and compared between treatments. Peripheral blood mononuclear cells (PBMCs) from FD patients (n=20) and controls (n=20) were stimulated with pooled samples of FD or control d-MAM-digested gluten, or left untreated, for 44 hours. For comparison to host enzymatic breakdown of gluten, matched PBMCs were also treated with α-chymotrypsin digested, deaminated gluten (CT gluten). The T cell phenotype and presence of activation-induced markers was assessed in PBMCs by flow cytometry.

Results

Challenge of Caco2 cells with gluten digested by the FD d-MAM resulted in a significant increase in Zonula occludens-1 (p=0.007), and reduction in Myd88 (p=0.03), compared to Caco2 cells challenged with control d-MAM-digested gluten. However, TEER readings were not altered between treatment groups in Caco2 experiments. In PBMC experiments, in response to stimulation with FD or control d-MAM-digested gluten, both FD and control PBMCs exhibited heightened expression of activation markers (CD4⁺OX40⁺CD25⁺), when compared to their respective unstimulated cells (p<0.05). When assessing the T-cell phenotype we observed that FD d-MAM-digested gluten promoted an increase in T-helper (Th) 2 cells in both FD (p=0.007) and control (p=0.0001) PBMCs. Meanwhile, control d-MAM-digested gluten stimulation resulted in elevated Th17.1 cells in FD (p<0.0001) and control (p=0.02) PBMCs, when compared to unstimulated cells. Alternatively, CT gluten stimulation did not alter any of the assessed lymphocyte populations in FD or control PBMCs when compared to unstimulated cells, suggesting host digestion of gluten isn’t sufficient to induce immune responses in FD.

Conclusion

Our findings suggest that the d-MAM of FD patients digest gluten in a way that promotes epithelial barrier remodelling and altered immune responses compared to the d-MAM from asymptomatic individuals. The promotion of a Th2 T-cell phenotype by the FD d-MAM is consistent with reports of increased Th2-associated cells, such as eosinophils, in FD patients [6]. These results highlight the likely role of microbiome-gluten interactions in FD, indicating the potential for novel dietary therapies and microbial approaches to management.

References

1. Potter, M., et al., Incidence and prevalence of self-reported non-coeliac wheat sensitivity and gluten avoidance in Australia. Med J Aust, 2020. 212(3): p. 126-131.
2. Shah, A., et al., Duodenal Eosinophils and Mast Cells in Functional Dyspepsia: A Systematic Review and Meta-Analysis of Case-Control Studies. Clinical Gastroenterology and Hepatology, 2022. 20(10): p. 2229-2242.e29.
3. Puthanmadhom Narayanan, S., et al., Duodenal Mucosal Barrier in Functional Dyspepsia. Clin Gastroenterol Hepatol, 2022. 20(5): p. 1019-1028.e3.
4. Shanahan, E.R., et al., Alterations to the duodenal microbiota are linked to gastric emptying and symptoms in functional dyspepsia. Gut, 2023. 72(5): p. 929-938.
5. Schooth, L., Defining the Role of the Mucosa-Associated Microbiota in Digestive Health and Disease Using Novel ex-vivo Combinations of Microbe Culture with Metagenomics. 2024 [Doctoral thesis, The University of Queensland], UQ eSpace.
6. Burns, G.L., et al., Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia. Front Immunol, 2022. 13: p. 1051632.

Disclosure

JP, EH, CN, SS, SR, MS, KH, GB, and KD have no disclosures to report.
NT: Financial support from: BluMaiden (microbiome advisory board) (2021), Comvita Mānuka Honey (2021) (digestive health), Biocodex (functional dyspepsia tool), Microba (microbiome advisory board) outside the submitted work. In addition, Dr. Talley has a patent Nepean Dyspepsia Index (NDI) 1998, Biomarkers of IBS licensed, a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley, a patent issued, “Diagnostic marker for functional gastrointestinal disorders” Australian Patent Application WO2022256861A1via the University of Newcastle and UniQuest (University of Queensland) and ”Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Application No. 63/537,725. Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre for Research Excellence in Digestive Health and he holds an NHMRC Investigator grant.
SK: Grants from National Health and Medical Research Council (Ideas Grant and Centre for Research Excellence), grants from Viscera Labs (Research contract), grants from Microba Life Science (Research contract), personal fees from Gossamer Bio, personal fees from Anatara Lifescience, personal fees from Immuron, personal fees from Microba Life Science.