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AGING INDUCES HISTOLOGICAL CHANGES IN THE INTESTINAL MUCOSA THAT MAY REDUCE THE RESPONSE TO NUTRITIONAL SUPPORT

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AGING INDUCES HISTOLOGICAL CHANGES IN THE INTESTINAL MUCOSA THAT MAY REDUCE THE RESPONSE TO NUTRITIONAL SUPPORT

Francisco Vara-Luiz 1,2, Ivo Mendes 1,2, Carolina Palma 1,2, Margarida Rajão Saraiva 3, Ana Elisa Teles 1, Filipe Nogueira 1, Inês Costa Santos 1, Gonçalo Nunes 2,1, Marta Patita 1, Irina Mocanu 1, Sara Isabel Ramos Pires 1, Tania Meira 1, Ana Isabel Vieira 1, Unknown Unknown 1, Daniel Gomes-Pinto 1, Paulo Mascarenhas 2, Jorge Fonseca 1,2

Affiliations

1 Hospital Garcia de Orta, Almada, Portugal

2 Egas Moniz Center for Interdisciplinary Research (CiiEM), Egas Moniz School of Health and Science, Almada, Portugal

3 Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

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Abstract

Introduction

There is a widespread agreement that age is a significant predictor of impaired response to nutritional support. For the same amount of protein and energy provided, the increase in weight and fat-free mass is significantly lower in older persons. This is generally attributed to anabolic resistance, and impaired absorption is usually considered non-existent/irrelevant. Nevertheless, in older rats gradual changes of the intestinal mucosa were observed, including reductions in villus height/width and density, which reduce absorption. Despite this, the aging influence on human intestinal mucosa is a matter of debate, and the lack of knowledge is partially explained by the exclusion criteria of older patients from most research protocols.

Aims & Methods

We aimed to evaluate potential histological and ultrastructural changes associated with aging that may reflect reduced absorption in older people.
The present single-center study is observational and prospective. Younger (18-45 years) and older (≥70 years) adults referred for upper endoscopy for reasons unrelated with intestinal alterations were included and underwent duodenal biopsies. Those biopsies were analyzed for histological, histomorphometric and ultrastructural changes. Histologic analysis was performed using optical microscopy with hematoxylin–eosin staining observed by two pathologists, including one expert gastrointestinal pathologist. All samples were analyzed for the presence of mucosal atrophy according to the adapted Marsh–Oberhuber classification and histomorphometric evaluation of duodenal villi length in micrometers, with at least two villi being measured through the use of an automatic scale. For transmission electron microscopy, duodenal fragments were fixed in 3% glutaraldehyde in cacodylate buffer (0.1 M, pH 7.4) overnight at 4 °C. The fixed fragments were rinsed and post-fixed in 1.0% osmium tetroxide for 1 h in the same buffer and dehydrated in graded ethanol passages. The fragments were embedded in a mixture of Epon and Araldite after two 15-min passages in propylene oxide. Thin sections, cut on a ultramicrotome with a diamond knife, were stained on the grid with uranyl acetate and lead citrate and examined with a electron microscope.

Results

A total of 84 patients were included (38 men/46 women), 33 with 18-45 years and 50 with ≥70 years. There were no duodenal endoscopic or microscopic changes apart from mucosal atrophy that was evident in one older adult. The median villi length was 0.35 mm (0.23-0.43 mm) in older persons, lower than in younger adults (0.65 mm; 0.37-0.79 mm) (p<0.01). On ultrastructural evaluation, the enterocytes of older group showed several changes suggesting compromise of the normal cell physiology. These changes were not observed in younger adults, who displayed normal cell architecture with regular microvilli structure and normal organelles.

Variables		18-45 years (n=34)	≥ 70 years (n=50)
Age		34.8 ± 8.2 years	76.2 ± 4.1 years
Gender	Male	16 (47.1%)	22 (44.0%)
Gender	Female	18 (52.9%)	28 (56.0%)
Indication for upper endoscopy		Dyspepsia: 16 (47.1%) Gastroesophageal reflux disease 4 (12.1%) Peptic ulcer disease: 6 (18.2%) Dysphagia: 3 (9.1%) Radiological findings: 3 (9.1%) Iron deficiency anemia: 2 (6.1%)	Dyspepsia: 13 (26.0%) Gastroesophageal reflux disease: 11 (22.0%) Peptic ulcer disease: 10 (20.0%) Dysphagia: 4 (8.0%) Gastric antral vascular ectasia: 6 (12.0%) Gastric polyp: 4 (8.0%) Iron deficiency anemia: 1 (2%) Radiological findings: 1 (2%)
Duodenal histology	Normal	34 (100%)	49 (98.0%)
Duodenal histology	Marsh 3A	0 (0.0%)	1 (2%)
Duodenal villi length		0.57 ± 0.1 mm	0.35 ± 0.06 mm

Conclusion

Aging is associated with histological, histomorphometric and ultrastructural changes in the intestinal mucosa that can be linked with reduced absorptive capacity. Besides anabolic resistance, this could be a reason for the reduced response to nutritional support found in older citizens.

References

Soenen S, Rayner CK, Jones KL, et al. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):12-8.
Patel BA, Patel N, Fidalgo S, et al. Impaired colonic motility and reduction in tachykinin signalling in the aged mouse. Exp Gerontol 2014; 53:24 – 30.
Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age 2014; 36:9603.
Ren WY, Wu KF, Li X, et al. Age-related changes in small intestinal mucosa epithelium architecture and epithelial tight junction in rat models. Aging Clin Exp Res 2014; 26:183 – 191.
Thomson AB. Small intestinal disorders in the elderly. Best Pract Res Clin Gastroenterol. 2009;23(6):861-74.
Nalapareddy K, Zheng Y, Geiger H. Aging of intestinal stem cells. Stem Cell Reports. 2022 Apr 12;17(4):734-740.

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Small Intestine & Nutrition

Submission format

Abstract

Session

The gut ecosystem: From pathogenesis to treatment

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Albert J. Bredenoord

UEG Presentation

A NOVEL DELIVERY-SYSTEM FOR TOPICAL EOSINOPHILIC ESOPHAGITIS TREATMENT WITH MOMETASONE FUROATE: RESULTS OF THE PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED ACESO-TRIAL

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A NOVEL DELIVERY-SYSTEM FOR TOPICAL EOSINOPHILIC ESOPHAGITIS TREATMENT WITH MOMETASONE FUROATE: RESULTS OF THE PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED ACESO-TRIAL

Alfredo J. Lucendo 1, Evan S. Dellon 2, Albert J. Bredenoord 3, Alex Straumann 4, Isabelle Racamier 5, Ghazaleh Gouya-Lechner 6

Affiliations

1 Hospital General de Tomelloso, Tomelloso, Spain

2 University of North Carolina School of Medicine, Chapel Hill, NC, United States

3 Amsterdam UMC, Amsterdam, Netherlands

4 Department of Gastroenterology, University Hospital Zurich, Switzerland, Kappel, Switzerland

5 Esocap AG, Basel, Switzerland

6 GOUYA INISGHTS GmbH &Co KG, Vienna, Austria

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Abstract

Introduction

Eosinophilic esophagitis (EoE) is an increasingly prevalent esophageal disease resulting in dysphagia and food impaction. ESO-101 targets the esophageal mucosa by significantly increasing topical medication contact time through the slow release of mometasone furoate. This innovative application technology consists of a drug-loaded thin-film rolled up in a capsule that unravels and sticks to the esophageal mucosa when swallowed. The current proof-of-concept phase 2 study evaluated the efficacy and safety of ESO-101.

Aims & Methods

This randomized, double-blind, placebo-controlled trial (NCT04849390) investigated the safety and efficacy of ESO-101 in adult patients with EoE and dysphagia. Patients were randomized 2:1 to once-daily treatment with ESO-101 800 µg or placebo and treated for 4-weeks. The primary endpoint was the absolute change in peak eosinophil count (eos/hpf) from baseline. Secondary endpoints were the change in EoE Endoscopic Reference Score (EREFS) and dysphagia symptoms measured by the 11-point numeric rating scale (NRS). Safety was also assessed.

Results

59 patients were screened at 13 European study sites, 43 patients were randomized, and 40 (27 to ESO-101 and 13 to placebo) completed the trial. For all histological and endoscopic endpoints, ESO-101 led to a statistical improvement compared to placebo. The mean decrease in peak eosinophil count was 49.1 (±88.4) eos/hpf with ESO-101, while counts increased by a mean of 6.6 (±65.1) eos/hpf in the placebo group (p=0.0318). Mean EREFS decreased by 3.9 (±2.6) with ESO-101 and there was no change with placebo (-0.1 [2.3]) (p=0.0001). A higher proportion of patients showed a histological response (<15 eos/hpf) with ESO-101 versus placebo (48% vs 0%; p=0.0028). There was also numerical improvement in the dysphagia severity score in the ESO-101 group (median improvement in the dysphagia severity of 4 scores [relative change: -71%]) compared to placebo (improvement in 3 scores [relative change: -57%]). No cases of oropharyngeal or esophageal candidiasis were observed (Table 1).

Table 1: Main Outcome Parameters ACESO Study
Outcome parameters ACESO study	ESO-101 (n=28)	Placebo (n=15)	p-value
Absolute change in peak eosinophil count CFB mean (SD)	-49.11 (88.42)	6.63 (65.11)	0.0318
Histological response < 15 eos/hpf (n [%])	13 (48.1)	0 (0.0)	0.0028
Histological response < 15 eos/hpf and improvement in the dysphagia severity score (n [%])	12 (44.4)	0 (0.0)	0.0035
Absolute change in the EREFS CFB mean (SD)	-3.9 (2.6)	-0.1 (2.3)	0.0001
Absolute change in dysphagia severity score CFB mean (SD)	-3.2 (2.0)	-3.0 (2.2)	n.s.
Relative change in dysphagia severity score CFB mean (SD)	-61.46 (37.87)	-47.27 (30.36)	n.s.
Oropharyngeal or esophageal candidiasis (n [%])	0 (0)	0 (0)	-
Treatment compliance defined as proportion of days IMP was taken (n [%])	96.44 (5.52)	92.88 (17.12)	-

_{SD= standard deviation; CFB=change from baseline; EREFS=endoscopic reference score; IMP=investigational medicinal product}

Conclusion

ESO-101 resulted in statistically significant histologic and endoscopic improvements compared with placebo, even with the 4-week treatment duration. ESO-101 was well tolerated. The ACESO study underscores the promise of topical drug delivery to the esophagus using the ESO-101 drug delivery system and provides a robust foundation for future ESO-101 development for EoE therapy.

Disclosure

Lucendo AJ: Principal Investigator of the ACESO Study sponsored by EsoCap Biotech AG
Dellon ES: Consultant to EsoCap Biotech AG
Bredenoord AJ: Investigator of the ACESO study sponsored by EsoCap Biotech AG
Straumann A: Consultant to EsoCap Biotech AG
Racamier I: CEO of EsoCap Biotech AG
Ghazaleh Gouya-Lechner: Medical Advisor of EsoCap Biotech AG

Event

UEG Week Vienna 2024

Topics

Oesophagus

Submission format

Abstract

Session

Eosinophilic oesophagitis

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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