TY - JOUR
T1 - Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice
AU - Meng, Jingjing
AU - Banerjee, Santanu
AU - Zhang, Li
AU - Sindberg, Greg
AU - Moidunny, Shamsudheen
AU - Li, Bin
AU - Robbins, David J.
AU - Girotra, Mohit
AU - Segura, Bradley
AU - Ramakrishnan, Sundaram
AU - Roy, Sabita
N1 - Funding Information:
This work was supported by the National Institutes of Health grants R01 DA050542, R01 DA043252, R01 DA037843, R01 DA044582, R01 DA047089, and R01DA034582 to SRo, R01CA219189 to DR, and Miami Center for AIDS Research Microbiome Pilot Award to JM.
Publisher Copyright:
© Copyright © 2020 Meng, Banerjee, Zhang, Sindberg, Moidunny, Li, Robbins, Girotra, Segura, Ramakrishnan and Roy.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/17
Y1 - 2020/1/17
N2 - Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.
AB - Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.
KW - BLT mice
KW - HIV
KW - gut microbiota
KW - intestinal organoid
KW - notch
KW - opioids
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U2 - 10.3389/fimmu.2019.02999
DO - 10.3389/fimmu.2019.02999
M3 - Article
C2 - 32010125
AN - SCOPUS:85078848391
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2999
ER -