Introduction
Functional dyspepsia (FD) is one of the most frequent disorders of gut-brain interaction, but according to the recent UEG consensus there is a lack of effective treatment options.(1) An important role for duodenal immune activation and increased mucosal permeability has been implied in the pathophysiology of FD. In a recent in vitro study on duodenal biopsies from FD patients palmitoylethanolamide (PEA), an endogenously produced anti-inflammatory compound, was shown to stabilize acid-induced activation of mast cells.(2) PEA is produced in several cell types and tissues to counteract inflammatory and other noxious responses, and diminished levels have been reported in duodenal biopsies from FD patients.(2)
Aims & Methods
In this randomized double blind placebo-controlled trial, we aimed to evaluate the effect of PEA supplementation on symptoms, mucosal integrity and duodenal low grade inflammation. After a 2-week run-in, patients were randomized to placebo or PEA 400 mg t.i.d. for 8 weeks. Before and after the treatment phase, patients underwent upper gastrointestinal endoscopy with biopsies and a 13C-octanoic acid gastric emptying breath test to measure gastric emptying half time (GE T1/2). Biopsies were used to measure transepithelial electrical resistance (TEER) and paracellular flux of 4kDa-fluorescein labelled dextran (FITC D4) in Ussing chambers and to count mast cells. Symptoms were recorded using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) and Leuven Postprandial Distress Scale (LPDS). The primary endpoint was the improvement in LPDS score. Symptoms and pathophysiological parameters were compared between PEA and placebo after 8 weeks of treatment.
Results
In this study, 61 patients were included of which 33 were assigned to placebo and 28 to PEA. The baseline characteristics are shown in Table 1. After treatment, no significant differences were found between the PEA and placebo group regarding LPDS scores (1.5±0.2 vs. 1.3±(0.2), p=0.47), GE T1/2 (83 (76-98) vs. 95 (72-109) min, p=0.57), TEER (27.3±0.8 vs. 28.0±1.0 Ω * cm2, p=0.21), and duodenal mast cell counts (589±43 vs. 557±34 mast cells / mm2, p=0.56). FITC D4 flux tended to be lower after PEA (27.9±1.9 vs. 33.3±2.2 pmol, p=0.06), with a more robust effect in patients taking a proton pump inhibitor (Δ FITC D4 flux -3.8±3.4 vs. 7.2±2.8 pmol, p=0.027). In patients that received PEA, the Δ FITC D4 flux correlated negatively with the Δ total PAGI-SYM score (r -0.49, p=0.02) and Δ of mast cell counts correlated positively with Δ PAGI-SYM fullness subscale (r=0.49, p=0.04).
| Table 1 | PEA group (N=28) | Placebo group (N=33) | p-value |
Age (years)
| 36 (25-54)
| 38 (27-45)
| 0.95
|
BMI (kg/m2)
| 20.9 (20.2-23.7)
| 23.0 (20.4-26.1)
| 0.34 |
Gender N(%) females
| 20 (80.0)
| 23 (74.2)
| 0.61 |
PPI use ON PPI
| 8 (32.0) | 13 (41.9) | 0.45 |
| LPDS score | 1.64±0.78
| 1.63±0.75
| 0.99 |
Permeability TEER (Ω * cm2)
| 27.1 ±1.0
| 26.8 ±0.8
| 0.80 |
Permeability FITC D4 flux (pmol)
| 28.4 (21.5-34.8)
| 30.8 (20.5-36.1)
| 0.78 |
Duodenal mast cells (count/mm2)
| 609 ±31
| 553 ±28
| 0.20 |
Gastric emptying T1/2 (min)
| 101 (78-117)
| 89 (80-112)
| 0.46 |
Data shown as median (IQR), mean ±SEM, or N(%). PEA: Palmitoylethanolamide, PPI: proton pump inhibitor, LPDS: Leuven Postprandial Distress Scale, TEER: Transepithelial electrical resistance, FITC D4 flux: flux of 4 kDa dextran labelled fluoresceine.
Conclusion
In FD, PEA does not improve gastrointestinal symptoms but improves duodenal barrier function mainly in patients that are taking a PPI. The interaction between PEA and PPI and its relevance for disorders of gut-brain interaction deserves further study.
References
1: Wauters L, Dickman R, Drug V, Mulak A, Serra J, Enck P, Tack J; ESNM FD Consensus Group; Accarino A, Barbara G, Bor S, Coffin B, Corsetti M, De Schepper H, Dumitrascu D, Farmer A, Gourcerol G, Hauser G, Hausken T, Karamanolis G, Keszthelyi D, Malagelada C, Milosavljevic T, Muris J, O'Morain C, Papathanasopoulos A, Pohl D, Rumyantseva D, Sarnelli G, Savarino E, Schol J, Sheptulin A, Smet A, Stengel A, Storonova O, Storr M, Törnblom H, Vanuytsel T, Velosa M, Waluga M, Zarate N, Zerbib F. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on functional dyspepsia. United European Gastroenterol J. 2021 Apr;9(3):307-331. doi: 10.1002/ueg2.12061. PMID: 33939891; PMCID: PMC8259261.
2: Sarnelli G, Pesce M, Seguella L, Lu J, Efficie E, Tack J, Elisa De Palma FD, D'Alessandro A, Esposito G. Impaired Duodenal Palmitoylethanolamide Release Underlies Acid-Induced Mast Cell Activation in Functional Dyspepsia. Cell Mol Gastroenterol Hepatol. 2021;11(3):841-855. doi: 10.1016/j.jcmgh.2020.10.001. Epub 2020 Oct 14. PMID: 33065341; PMCID: PMC7858681.