Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Shukla, Pradeep Kumar; Meena, Avtar S.; Dalal, Kesha; Canelas, Cherie; Samak, Geetha; Pierre, Joseph F.; Rao, Radhakrishna

doi:10.1038/s41598-020-80637-y

Cited by 45 publications

(69 citation statements)

References 78 publications

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“…Numerous studies have shown that alcohol use alters the abundance and composition of gut microbiota 29–31 . Our recent study demonstrated that corticosterone further modulates alcohol‐induced alteration of gut microbiota in mice 15 . However, the precise mechanism involved in alcohol‐ or stress‐induced dysbiosis of gut microbiota is poorly defined.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 97%

“…9,36,37 Restraint stress and alcohol feeding in rodents elevate plasma corticosterone. 15,38 Glucocorticoids play a role in neuroimmune functions 39,40 ; however, their role in alcohol-induced peripheral tissue injury is unclear. Cortisol and corticosterone actions are mediated by the glucocorticoid receptor (GR).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Shukla et al (2021) proposed the gut-liver-brain (GLB) axis hypothesis and reported that chronic stress and corticosterone can exacerbate alcoholinduced mucosal barrier dysfunction, endotoxemia, and the systemic alcohol response. The authors also demonstrated that gut microbiota modulation probably plays a key role in oxidative stress induced by alcohol [67]. In addition, the metabolites of the gut microbiota, including lipopolysaccharides, ethanol, ammonia, and acetaldehyde, also promote the development of chronic hepatitis [68].…”

Section: Rbe Exerted Protective Effects Against Liver Damage In Male Offspring Rats Via Alterations Of Gut Microbiotamentioning

confidence: 94%

Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota

Liao

Chen

Shih

et al. 2021

IJMS

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Resveratrol can affect the physiology or biochemistry of offspring in the maternal–fetal animal model. However, it exhibits low bioavailability in humans and animals. Fifteen-week SD pregnant female rats were orally administered bisphenol A (BPA) and/or resveratrol butyrate ester (RBE), and the male offspring rats (n = 4–8 per group) were evaluated. The results show that RBE treatment (BPA + R30) compared with the BPA group can reduce the damage caused by BPA (p < 0.05). RBE enhanced the expression of selected genes and induced extramedullary hematopoiesis and mononuclear cell infiltration. RBE increased the abundance of S24-7 and Adlercreutzia in the intestines of the male offspring rats, as well as the concentrations of short-chain fatty acids (SCFAs) in the feces. RBE also increased the antioxidant capacity of the liver by inducing Nrf2, promoting the expression of HO-1, SOD, and CAT. It also increased the concentration of intestinal SCFAs, enhancing the barrier formed by intestinal cells, thereby preventing BPA-induced metabolic disruption in the male offspring rats, and reduced liver inflammation. This study identified a potential mechanism underlying the protective effects of RBE against the liver damage caused by BPA exposure during the peri-pregnancy period, and the influence of the gut microbiota on the gut–liver axis in the offspring.

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“…DNA was extracted with TRIzol (Invitrogen, Carlsbad, CA, USA) as per the manufacturers' instructions. 16S ribosomal RNA was analyzed by qPCR for different bacterial phyla or species using SYBR Green/ROX master mix (Qiagen) in an Applied Biosystems QuantStudio6 FlexReal-Time PCR instrument (Norwalk, CT, USA) as described in our published papers [37,38]. Primer sequences for 16S ribosomal RNA genes for Bacteroidetes, Firmicutes, Bifidobacteria, and Lactobacillus were detailed in Table S1.…”

Section: Microbiome Analysismentioning

confidence: 99%

“…Immunofluorescence staining in the colon was performed as described previously [38,40]. Colon sections were examined for components of the inflammasome (NLRP3, ASC, and caspase-1), F-actin, tight junction (TJ) proteins occludin and ZO1, and adherens junction (AJ) proteins E-cadherin, and β-catenin by confocal microscopy as described previously.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Shukla

Delotterie

Xiao

et al. 2021

Cells

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Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis

Cited by 45 publications

References 78 publications

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

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

Resveratrol Butyrate Esters Inhibit BPA-Induced Liver Damage in Male Offspring Rats by Modulating Antioxidant Capacity and Gut Microbiota

Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

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