Enid Martinez, MD
Boston Children's Hospital
West Roxbury, Massachusetts
Disclosure information not submitted.
Jinggang Lan, PhD
Lab Manager
Massachusetts General Hospital, United States
Disclosure information not submitted.
Alba Miranda-Ribera, PhD
Research Fellow
Massachusetts General Hospital, United States
Disclosure information not submitted.
Maria Fiorentino, PhD
Assistant Professor of Pediatrics
Massachusetts General Hospital, United States
Disclosure information not submitted.
Nilesh Mehta, MD
Senior Associate in Critical Care Medicine
Boston Children's Hospital, United States
Disclosure information not submitted.
Alessio Fasano, MD
Professor of Pediatrics
Massachusetts General Hospital, United States
Disclosure information not submitted.
Title: Novel Role of Zonulin in the Pathophysiology of Gastric Motility: A Clinical-Translational Study
Introduction: Gastric dysmotility affects up to 80% of critically ill children and is associated with morbidity. Non-specific zonulin family peptides have been associated with gastric dysmotility. Zonulin, known as pre-haptoglobin (HP) 2 in humans, increases intestinal epithelial barrier leak and is produced in patients who have the HP2 isotype. We aimed to examine the relationship between zonulin (pre-HP2) and gastric motility in intensive care unit (ICU) patients and in a translational mouse model of systemic inflammation.
Methods: Gastric motility, serum cytokines, HP isotype (HP1 or 2) and HP2 isoform quantification, as proxy for zonulin, were examined before and after spinal surgery in ICU patients < 21years old. Gastric dysmotility by the acetaminophen absorption test was defined as ≥20% decrease in the area under the curve at 60 minutes (AUC60) after surgery compared to baseline. C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice were injected with lipopolysaccharide (LPS) to trigger inflammation or vehicle as control. Gastro-duodenal transit by fluorescein-isothiocyanate (FITC), serum cytokines and gastric-duodenal mRNA expression of zonulin were examined, 6 and 12 hours after injection.
Results: Twenty patients [14 years, IQR (12.25, 18), 40% male] were included. Post-operative IL-6, IL-8, IL-10 levels were increased from baseline, p-values < 0.05. Eight (40%) patients developed post-operative gastric dysmotility, all had the HP2 isotype. HP2 isoform levels correlated with the decrease in post-operative AUC60 i.e. gastric dysmotility (r= -0.51, CI -0.81 to 0.003 , p=0.048). In all mice, LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels (p< 0.0001). Gastric dysmotility was reduced similarly in LPS-injected Ztm and WT mice in a time-dependent manner. Ztm mice, however, had 16% faster duodenal motility than WT mice 6H after LPS injection, p=0.01. Zonulin mRNA expression by dCT was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p=0.04.
Conclusion: Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression. Zonulin may be a diagnostic and therapeutic target for gastric dysmotility in critically ill patients.