PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host–microbe intersection during SIV infection

Katti R. Crakes, Clarissa Santos Rocha, Irina Grishina, Lauren A. Hirao, Eleonora Napoli, Christopher A. Gaulke, Anne Fenton, Sandipan Datta, Juan Arredondo, Maria L. Marco, Sumathi Sankaran-Walters, Gino Cortopassi, Cecilia Giulivi, Satya Dandekar

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Chronic gut inflammatory diseases are associated with disruption of intestinal epithelial barriers and impaired mucosal immunity. HIV-1 (HIV) causes depletion of mucosal CD4+ T cells early in infection and disruption of gut epithelium, resulting in chronic inflammation and immunodeficiency. Although antiretroviral therapy (ART) is effective in suppressing viral replication, it is incapable of restoring the “leaky gut,” which poses an impediment for HIV cure efforts. Strategies are needed for rapid repair of the epithelium to protect intestinal microenvironments and immunity in inflamed gut. Using an in vivo nonhuman primate intestinal loop model of HIV/ AIDS, we identified the pathogenic mechanism underlying sustained disruption of gut epithelium and explored rapid repair of gut epithelium at the intersection of microbial metabolism. Molecular, immunological, and metabolomic analyses revealed marked loss of peroxisomal proliferator-activated receptor-α (PPARα) signaling, predominant impairment of mitochondrial function, and epithelial disruption both in vivo and in vitro. To elucidate pathways regulating intestinal epithelial integrity, we introduced probiotic Lactobacillus plantarum into Simian immunodeficiency virus (SIV)inflamed intestinal lumen. Rapid recovery of the epithelium occurred within 5 h of L. plantarum administration, independent of mucosal CD4+ T cell recovery, and in the absence of ART. This intestinal barrier repair was driven by L. plantarum-induced PPARα activation and restoration of mitochondrial structure and fatty acid β-oxidation. Our data highlight the critical role of PPARα at the intersection between microbial metabolism and epithelial repair in virally inflamed gut and as a potential mitochondrial target for restoring gut barriers in other infectious or gut inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)24819-24829
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number49
DOIs
StatePublished - Dec 3 2019

Keywords

  • Gut epithelium
  • HIV/AIDS
  • Mitochondria
  • PPARα
  • SIV

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'PPARα-targeted mitochondrial bioenergetics mediate repair of intestinal barriers at the host–microbe intersection during SIV infection'. Together they form a unique fingerprint.

  • Cite this