Mechanical Stimuli Affect E. Coli Heat Stable Enterotoxin (ST)-Cyclic GMP Signaling in a Human Enteroid Intestine-Chip Diarrhea Model

Author:

Sunuwar Laxmi,Yin Jianyi,Kasendra Magdalena,Karalis Katia,Kaper James,Fleckenstein JamesORCID,Donowitz Mark

Abstract

ABSTRACTModeling host-pathogen interactions with human intestinal epithelia using enteroid monolayers on permeable supports (such as Transwells) represents an alternative to animal studies or use of colon cancer-derived cell lines. However, the static monolayer model does not expose epithelial cells to mechanical forces normally present in the intestine, including luminal flow and serosal blood flow (shear force) or peristaltic forces. To determine the contribution of mechanical forces in the functional response of human small intestine to a pathogen virulence factor, human jejunal enteroids were cultured as monolayers in microengineered fluidic-based Organ-Chips (Intestine-Chips), exposed to enterotoxigenic E. coli heat-stable enterotoxin A (ST), and evaluated under conditions of static fluid, apical and basolateral flow, and flow plus repetitive stretch. Application of flow increased epithelial cell height, transcription of the cyclic nucleotide transporting protein MRP4, and apical and basolateral secretion of cGMP under baseline, unstimulated conditions. Addition of ST under flow conditions increased apical and basolateral secretion of cGMP relative to static conditions, but did not enhance intracellular cGMP accumulation. Cyclic stretch did not have any significant effect beyond that contributed by flow. This study demonstrates that fluid flow application initiates changes in intestinal epithelial cell characteristics relative to static culture conditions under both baseline conditions and with exposure to ST enterotoxin, and suggests that further investigations of application of these mechanical forces will provide insights into physiology and pathophysiology that more closely resembles intact intestine than study under static conditions.

Publisher

Cold Spring Harbor Laboratory

Reference47 articles.

1. Adult Stem Cells in the Small Intestine Are Intrinsically Programmed with Their Location‐Specific Function

2. Molecular Basis and Differentiation-Associated Alterations of Anion Secretion in Human Duodenal Enteroid Monolayers;Cellular and molecular gastroenterology and hepatology,2018

3. Enterotoxigenic E. Coli (ETEC) Pathogenesis Modeled in Human Enteroid Monolayers Demonstrates MRP-Related Cyclic Nucleotide Secretion;Gastroenterology,2017

4. The Contributions of Human Mini-Intestines to the Study of Intestinal Physiology and Pathophysiology;Annual review of physiology,2017

5. Development and Characterization of a Human and Mouse Intestinal Epithelial Cell Monolayer Platform;Stem cell reports,2017

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