Central role of intestinal epithelial glucocorticoid receptor in alcohol‐ and corticosterone‐induced gut permeability and systemic response

Abstract

Corticosterone, the stress hormone, exacerbates alcohol‐associated tissue injury, but the mechanism involved is unknown. We examined the role of the glucocorticoid receptor (GR) in corticosterone‐mediated potentiation of alcohol‐induced gut barrier dysfunction and systemic response. Hepatocyte‐specific GR‐deficient (GRΔHC) and intestinal epithelial‐specific GR‐deficient (GRΔIEC) mice were fed ethanol, combined with corticosterone treatment. Intestinal epithelial tight junction integrity, mucosal barrier function, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation were assessed. Corticosterone potentiated ethanol‐induced epithelial tight junction disruption, mucosal permeability, and inflammatory response in GRΔHC mouse colon; these effects of ethanol and corticosterone were absent in GRΔIEC mice. Gut microbiota compositions in ethanol‐fed GRΔHC and GRΔIEC mice were similar to each other. However, corticosterone treatment in ethanol‐fed mice shifted the microbiota composition to distinctly different directions in GRΔHC and GRΔIEC mice. Ethanol and corticosterone synergistically elevated the abundance of Enterobacteriaceae and Escherichia coli and reduced the abundance of Lactobacillus in GRΔHC mice but not in GRΔIEC mice. In GRΔHC mice, corticosterone potentiated ethanol‐induced endotoxemia and systemic inflammation, but these effects were absent in GRΔIEC mice. Interestingly, ethanol‐induced liver damage and its potentiation by corticosterone were observed in GRΔHC mice but not in GRΔIEC mice. GRΔIEC mice were also resistant to ethanol‐ and corticosterone‐induced inflammatory response in the hypothalamus. These data indicate that the intestinal epithelial GR plays a central role in alcohol‐ and corticosterone‐induced gut barrier dysfunction, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation. This study identifies a novel target for potential therapeutic for alcohol‐associated tissue injury.

TRPV6 deficiency attenuates stress and corticosterone-mediated exacerbation of alcohol-induced gut barrier dysfunction and systemic inflammation

“…Corticosterone was injected at a dose of 25 mg/kg per day (s.c.) in some groups of pair-fed and EtOH-fed mice for four weeks, as reported before ( 37 ). The vehicle was administered to control mice.…”

“…The analysis of particular mRNA was performed by RT-PCR as described previously ( 37 ). cDNAs were synthesized from 1.5 μg of RNA using the ThermoScript RT-PCR instrument for first-strand synthesis (Invitrogen).…”

“…Using a Pierce LAL Chromogenic Endotoxin Quantitation Kit (Thermo Scientific), plasma endotoxin concentration was measured as described in our previous studies ( 20 , 37 ).…”

“…Evidence suggests alcohol abuse disrupts the HPA axis and increases plasma glucocorticoids ( 33 – 35 ). Chronic stress and alcohol consumption increases plasma corticosterone levels in animal models ( 19 , 36 , 37 ). A previous study demonstrated that chronic stress and corticosterone exacerbate alcohol-induced pathophysiology in the Gut-Liver-Brain axis ( 20 ).…”

Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms

“…However, oral GCs, even for short-term treatment, increase the risk of GI bleeding [ 64 , 82 ], and GCs promote intestinal BA reabsorption [ 65 ]. Moreover, a recent study demonstrates that the activation of intestinal epithelial GR worsens AH in mice due to gut barrier dysfunction, microbiota dysbiosis, endotoxemia, systemic inflammation, liver damage, and neuroinflammation [ 83 ]. Currently, most sAH patients receive high doses of oral GCs, which may explain the elevated risk of infections and circulating bacterial DNA in sAH patients treated with prednisolone [ 84 ].…”