Metabolic and Intestinal Changes Induced by Proton Pump Inhibitors: Assessing the Role of Intestinal Alkaline Phosphatase in Liver Protection

• Grant number: 24/21464-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2025
• End date: March 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Andrey dos Santos
• Grantee: Ana Maria Yukie Sasajima
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Proton pump inhibitors (PPIs) are among the most prescribed medications worldwide. PPIs induce microbiota modulation like what is observed in animal models of obesity and human obesity. However, PPIs can modulate microbiota without the need for a high-fat diet or weight gain. In previous studies, we investigated the effect of a 60-day PPI treatment on Toll-like Receptor 4 (TLR-4) signaling and liver histology to compare microbiota modulation with some aspects of Non-Alcoholic Steatohepatitis (NASH), recently renamed Metabolic Dysfunction-Associated Steatohepatitis (MASH). Our data demonstrated that prolonged use of PPIs can alter the microbiota and intestinal permeability, contributing to microvesicular steatosis and fibrosis. One factor contributing to the inflammatory process was the increase in circulating lipopolysaccharides (LPS), a highly inflammatory component present in Gram-negative bacteria. Recent findings have revealed an intriguing connection between beneficial gut bacteria and the production of an enzyme called intestinal alkaline phosphatase (IAP), which has the ability to neutralize LPS. IAP is an enzyme produced by intestinal epithelial cells and plays a key role in lipid metabolism regulation. Studies have shown that reduced IAP levels are associated with obesity, insulin resistance, liver fat accumulation, and the progression of liver disease. Diets rich in saturated fats and low in fiber have been linked to reduced IAP levels, potentially contributing to the development of metabolic disorders.In this context, we aim to investigate how IAP supplementation, concomitant with pantoprazole treatment, could inhibit inflammation caused by prolonged PPI use.