ZFIN ID: ZDB-PUB-190809-3
Epithelial delamination is protective during pharmaceutical-induced enteropathy
Espenschied, S.T., Cronan, M.R., Matty, M.A., Mueller, O., Redinbo, M.R., Tobin, D.M., Rawls, J.F.
Date: 2019
Source: Proceedings of the National Academy of Sciences of the United States of America   116(34): 16961-16970 (Journal)
Registered Authors: Cronan, Mark, Espenschied, Scott "Ted", Matty, Molly, Rawls, John F., Tobin, David
Keywords: MDR efflux pump, NSAID, intestine, microbiota, zebrafish
MeSH Terms:
  • ATP-Binding Cassette Transporters/antagonists & inhibitors
  • ATP-Binding Cassette Transporters/metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal*/adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal*/pharmacology
  • Enterocytes/metabolism*
  • Enterocytes/microbiology
  • Enterocytes/pathology
  • Gastrointestinal Microbiome*
  • Glafenine/adverse effects*
  • Glafenine/pharmacology
  • Inflammation/chemically induced
  • Inflammation/metabolism
  • Inflammation/microbiology
  • Inflammation/pathology
  • Intestinal Diseases*/chemically induced
  • Intestinal Diseases*/metabolism
  • Intestinal Diseases*/microbiology
  • Intestinal Diseases*/pathology
  • Zebrafish*/metabolism
  • Zebrafish*/microbiology
PubMed: 31391308 Full text @ Proc. Natl. Acad. Sci. USA
Intestinal epithelial cell (IEC) shedding is a fundamental response to intestinal damage, yet underlying mechanisms and functions have been difficult to define. Here we model chronic intestinal damage in zebrafish larvae using the nonsteroidal antiinflammatory drug (NSAID) Glafenine. Glafenine induced the unfolded protein response (UPR) and inflammatory pathways in IECs, leading to delamination. Glafenine-induced inflammation was augmented by microbial colonization and associated with changes in intestinal and environmental microbiotas. IEC shedding was a UPR-dependent protective response to Glafenine that restricts inflammation and promotes animal survival. Other NSAIDs did not induce IEC delamination; however, Glafenine also displays off-target inhibition of multidrug resistance (MDR) efflux pumps. We found a subset of MDR inhibitors also induced IEC delamination, implicating MDR efflux pumps as cellular targets underlying Glafenine-induced enteropathy. These results implicate IEC delamination as a protective UPR-mediated response to chemical injury, and uncover an essential role for MDR efflux pumps in intestinal homeostasis.