Introduction

Chronic constipation (CC) is a prodromal and severe symptom in up to the 80% of Parkinson's disease (PD) patients (PD/CC) often refractory to standard laxative treatments. The molecular mechanisms underlying PD/CC are still unclear, although changes of enteric nervous system and intestinal epithelial barrier (IEB) have been thought to play a pathogenetic role.

Aims & Methods

In this study, PD/CC and chronic constipated (CCs) patients were functionally characterized, and possible abnormalities to IEB and the key neuromodulator vasoactive intestinal polypeptide (VIP) were investigated. N=12 PD/CCs (2 females; age range: 51-80 yrs), 20 CCs (15 females; 27-78; yrs) and 23 controls (Ctrls; 11 females; 32-74yrs) were enrolled. PD was diagnosed according to the United Kingdom Parkinson’s Disease Society Brain Bank clinical diagnostic criteria, whereas CC was established following Rome IV criteria. Ctrls were otherwise asymptomatic subjects undergoing screening colonoscopy. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colonic mucosal / submucosal biopsies were obtained in all patients / subjects and tested for gene, protein expression and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1) and zonula occludens-1 (ZO-1) and VIP, by RT-qPCR, immunoblot and immunofluorescence staining.

Results

PD/CCs were clustered in two groups: a) patients with delayed TT and altered AM (60%); b) those with altered AM only (13%). The evaluation of IEB markers on mucosal specimens showed an increase of CLDN4 mRNA in PD/CCs (1.26 ± 0.26) vs. Ctrls (1.00 ± 0.19) and CCs (0.95 ± 0.33), whereas a trend to CLDN4 protein reduction in PD/CCs (0.88 ± 0.33) vs. Ctrls (0.96 ± 0.25) and CCs (1.02 ± 0.51) was observed. Moreover, the OCCL-1 transcript was significantly increased in PD/CCs (1.36 ± 0.36) vs. Ctrls (1.05 ± 0.33) and CCs (0.81 ± 0.18). ZO-1 mRNA relative levels were consistent with those of OCCL-1 showing a significant increase in PD/CCs (1.35 ± 0.38) vs. Ctrls (1.02± 0.27) and CCs (0.85 ± 0.24). Notably, both OCCL-1 and ZO-1 showed a tendency to be reduced in CCs vs. Ctrls. Immunofluorescence highlighted a decrease in OCCL-1 immunoreactivity (IR) in PD/CCs (score= 1.5) vs. CCs and Ctrls (score= 4). Conversely, ZO-1-IR displayed an intense pattern (score=4) in both Ctrls and PD/CCs, but it was decreased in CCs (score= 2). VIP mRNA levels resulted significantly greater in CCs (3.98 ± 3.93, p<0.05) vs. Ctrls (1.52 ± 1.55) and PD/CCs (0.86 ± 1.056), whereas a decreasing trend was observed in PD/CCs vs. Ctrls (p>0.05). Both immunofluorescence and immunoblot confirmed this tendency showing a 15% drop of the VIP protein (PD/CCs 0.86 ± 0.43 vs. Ctrls 1.01 ± 0.56, p>0.05).

Conclusion

Transit and anorectal dysfunctions in PD/CCs are associated with ZO-1, OCCL-1, CLDN-4 and VIP changes, hence suggesting that a leaky IEB contributes to submucosal neurochemical abnormalities underlying PD/CC. These findings suggest that the expression of the IEB markers are subject to both transcriptional and post-translational regulatory mechanisms, presumably distinct in CC and PD/CC.

References

1. Giancola F, Torresan F, Repossi R, Bianco F, Latorre R, Ioannou A, Guarino M, Volta U, Clavenzani P, Mazzoni M, Chiocchetti R, Bazzoli F, Travagli RA, Sternini C, De Giorgio R. Downregulation of neuronal vasoactive intestinal polypeptide in Parkinson's disease and chronic constipation. Neurogastroenterol Motil. 2017 May;29(5):10.1111/nmo.12995.
2. Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F, Heymann MF, Neunlist M, Derkinderen P. Structural alterations of the intestinal epithelial barrier in Parkinson's disease. Acta Neuropathol Commun. 2015 Mar 10;3:12.
3. Neunlist M, Toumi F, Oreschkova T, Denis M, Leborgne J, Laboisse CL, Galmiche JP, Jarry A. Human ENS regulates the intestinal epithelial barrier permeability and a tight junction-associated protein ZO-1 via VIPergic pathways. Am J Physiol Gastrointest Liver Physiol. 2003 Nov;285(5):G1028

Introduction

Patients with an ileostomy often have impaired quality of life, sodium depletion, secondary hyperaldosteronism, and other organ-specific pathologies. The osmolality of oral supplements influences ileostomy output and sodium loss.

Aims & Methods

We hypothesized the existence of an osmolality range where fluid absorption and secondary natriuresis are optimal. This was a single-center, quasi-randomized crossover intervention study, including patients with an ileostomy and no home parenteral support. After an 8-hour fasting period, each patient ingested 500 mL of between 3 and 18 different oral supplements and a standardized meal during separate intervention periods, followed by a 6-hour collection of ileostomy and urine outputs. The primary outcome was 6-hour ileostomy output.

Results

A total of 14 adult patients with an ileostomy (median age 64.5 years (range 22 - 77)) were included. The association between osmolalities in the entire range of 5-1352 mOsm/kg and ileostomy output forecasted an S-curve. In a mixed-effect model with the patients as a random effect, we observed a linear association between the osmolality of oral supplements in the range of 290-600 mOsm/kg and ileostomy output, which increased with 57g/6 hours (95% CI 21 – 94) when the oral supplement osmolality increased 100 mOsm/kg (p<0.005).

Conclusion

Osmolality in oral supplements correlated with ileostomy output in patients with an ileostomy. Our results indicate that patients with an ileostomy may benefit from increasing their ingestion of oral supplements with osmolalities between 100 and 290 mOsm /kg. We suggest this range is called the Goldilocks zone, indicating optimal fluid absorption.

Disclosure

This work was supported by Helga and Peter Kornings fond, Aarhus, Denmark, and the A. P. Møller fonden, Copenhagen, Denmark. Josephine R. Quist have received financial support from Aarhus University for PhD courses and biostatistical advisory service (BIAS). Aarhus University have not had any input to or influence on the manuscript preparation. CH received funding from Novo Nordisk Foundation (grant no. NNF22OC0074080).

Introduction

The incidence of caustic ingestion has remained stable in recent years due to its difficult prevention and limited changes in its management.

Aims & Methods

Aims:
1. To explore changes in the epidemiological and clinical characteristics of caustic ingestion over the last decades
2. To identify epidemiological risk factors of adverse outcomes.
Methods: We present data from an observational study that prospectively collected caustic ingestions in our centre since 1995 and included all adult patients whose acute episode was evaluated in the emergency department. Epidemiological data and variables related to the type of ingestion, prognostic risk factors and the adverse outcomes, defined as the need for admission to the intensive care unit, emergency surgery, patient death and oesophageal or gastric stricture development, were analysed; the results were compared for the periods 1995-2009 and 2010-2024.

Results

A total of 582 episodes of caustic ingestion were included, 305 during the first period and 277 during the second.
Epidemiological characteristics and type of ingestion were overall similar in both periods, as were the clinical, analytical, endoscopic and radiologic indicators of severity.
Adverse outcomes were also similar in the two time periods, both in the short term (comparable frequency of intensive care unit admission, need for surgery and death) and in the long term (stricture development).
The main risk groups for severe ingestions were patients older than 45 years (OR 4.3; 95%CI: 2.3-7.9) and psychiatric comorbidity (OR 5.2; 95%CI: 3.0-9.1), especially depressive syndrome (OR 7.2; 95%CI: 4.2-12.4).
Recurrent ingestions were more frequent in men (OR 1.9; 95%CI: 1.0-3.5) and psychiatric illness (OR 7.6; 95%CI: 3.5-16.5), mainly personality disorder (OR 11.0; 95%CI: 5.5-21.9).

	1995-2009	2010-2024	p value
Women	164 (53,8)	133 (48,0)	0,192
Age	44 (30)	50 (30)	0,193
Voluntary intake	154 (50,5)	121 (44,0)	0,139
pH of caustic Strong acid Weak acid Weak alkali Strong alkali	50 (16,9) 17 (5,8) 215 (72,9) 13 (4,4)	40 (14,7) 25 (9,2) 200 (73,3) 8 (2,9)	0,318
Psychiatric illness Depression Bipolar disorder Personality disorder Psychotic disorder Alcohol/toxic substances consumption	155 (50,8) 112 (36,7) 5 (1,6) 28 (9,2) 16 (5,2) 23 (7,5)	119 (43,0) 75 (27,1) 11 (4,0) 20 (7,2) 13 (4,7) 26 (9,4)	0,007 0,016 0,143 0,479 0,908 0,515
Intensive care unit admission	40 (13,1)	29 (10,5)	0,391
Emergency surgery	8 (2,6)	10 (3,6)	0,655
Death	15 (4,9)	19 (6,9)	0,412
Stricture formation	11 (5,1)	8 (3,7)	0,624

Conclusion

No relevant changes were identified in the epidemiological and clinical characteristics of caustic ingestions over the last decades, nor in their evolution. The most vulnerable groups to prioritise prevention measures would be patients with psychiatric cormobility.