Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids

Hardesty, Josiah; Warner, Jeffrey; Song, Ying; Rouchka, Eric C.; Chen, Chih-Yu; Kang, Jing; McClain, Craig J.; Warner, Dennis R.; Kirpich, Irina

doi:10.1038/s41598-020-76959-6

Cited by 3 publications

(6 citation statements)

References 60 publications

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“…In addition, chronic intestinal inflammation can also promote intestinal fibrosis, leading to additional loss of gut barrier function [ 14 ]. We recently reported that fat-1 mice had attenuated EtOH-induced alterations in intestinal homeostasis [ 15 ] that were associated with a markedly plastic transcriptome response to EtOH as well as specific transcriptional signatures [ 16 ]. Cell death, inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…We recently reported that fat-1 mice had attenuated EtOH-induced alterations in intestinal homeostasis [ 15 ] that were associated with a markedly plastic transcriptome response to EtOH as well as specific transcriptional signatures [ 16 ]. Cell death, inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated [ 16 ]. Importantly, however, the molecular mechanisms underlying EtOH and EtOH + LPS-mediated intestinal pathology remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…Since EtOH consumption and acute systemic inflammation contribute to gut pathology, we aimed to elucidate the associated transcriptional responses using an unbiased RNA-seq based approach. Previously, we demonstrated improved intestinal health with n-3 PUFA enrichment in fat-1 transgenic mice (the mice that endogenously convert n6 to n3 PUFAs [ 15 ]) and identified the associated ileum transcriptional responses to EtOH [ 16 ]. The current study builds upon our previous work and aims to identify n-3 PUFA-regulated ileum transcriptional responses to acute systemic inflammation in mice chronically fed EtOH.…”

Section: Introductionmentioning

confidence: 99%

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Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Hardesty

Warner

Song

et al. 2021

IJMS

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Chronic alcohol consumption leads to disturbances in intestinal function which can be exacerbated by inflammation and modulated by different factors, e.g., polyunsaturated fatty acids (PUFAs). The mechanisms underlying these alterations are not well understood. In this study, RNA-seq analysis was performed on ileum tissue from WT and fat-1 transgenic mice (which have elevated endogenous n-3 PUFAs). Mice were chronically fed ethanol (EtOH) and challenged with a single lipopolysaccharide (LPS) dose to induce acute systemic inflammation. Both WT and fat-1 mice exhibited significant ileum transcriptome changes following EtOH + LPS treatment. Compared to WT, fat-1 mice had upregulated expression of genes associated with cell cycle and xenobiotic metabolism, while the expression of pro-inflammatory cytokines and pro-fibrotic genes was decreased. In response to EtOH + LPS, fat-1 mice had an increased expression of genes related to antibacterial B cells (APRIL and IgA), as well as an elevation in markers of pro-restorative macrophages and γδ T cells that was not observed in WT mice. Our study significantly expands the knowledge of regulatory mechanisms underlying intestinal alterations due to EtOH consumption and inflammation and identifies the beneficial transcriptional effects of n-3 PUFAs, which may serve as a viable nutritional intervention for intestinal damage resulting from excessive alcohol consumption.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Hardesty

Warner

Song

et al. 2021

IJMS

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“…Raw FASTQ sequencing files provided by GeneWiz were analyzed by the Kentucky Biomedical Research Infrastructure Network (KBRIN) Bioinformatic Core as described previously. 25 Briefly, sequencing data were processed in the KBRIN Tuxedo Data Analysis Pipeline after quality control evaluation. Data were aligned to the mouse genome followed by transcript assembly, data normalization, and determination of differential gene expression.…”

Section: Liver Tissue Rna-sequencing (Rna-seq) Analysismentioning

confidence: 99%

Resolvin D1 attenuated liver injury caused by chronic ethanol and acute LPS challenge in mice

et al. 2022

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Alcohol‐associated liver disease (ALD) is a major health problem with limited effective treatment options. Alcohol‐associated hepatitis (AH) is a subset of severe ALD with a high rate of mortality due to infection, severe inflammation, and ultimately multi‐organ failure. There is an urgent need for novel therapeutic approaches to alleviate the human suffering associated with this condition. Resolvin D1 (RvD1) promotes the resolution of inflammation and regulates immune responses. The current study aimed to test the therapeutic efficacy and mechanisms of RvD1‐mediated effects on liver injury and inflammation in an experimental animal model that mimics severe AH in humans. Our data demonstrated that mice treated with RvD1 had attenuated liver injury and inflammation caused by EtOH and LPS exposure by limiting hepatic neutrophil accumulation and decreasing hepatic levels of pro‐inflammatory cytokines. In addition, RvD1 treatment attenuated hepatic pyroptosis, an inflammatory form of cell death, via downregulation of pyroptosis‐related genes such as GTPase family member b10 and guanylate binding protein 2, and reducing cleavage of caspase 11 and gasdermin‐D. In vitro experiments with primary mouse hepatocytes and bone marrow‐derived macrophages confirmed the effectiveness of RvD1 in the attenuation of pyroptosis. In summary, our data demonstrated that RvD1 treatment provided beneficial effects against liver injury and inflammation in an experimental animal model recapitulating features of severe AH in humans. Our results suggest that RvD1 may be a novel adjunct strategy to traditional therapeutic options for AH patients.

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“…These changes differ significantly from those detected in the presence of PUFA. Ethanol also reduces the expression of CD73 (ecto-5 nucleotidase), which is responsible for the conversion of ATP to adenosine, which is an important signal in the anti-inflammatory pathway [143].…”

Section: Gastrointestinal Tractmentioning

confidence: 99%

Current View on the Mechanisms of Alcohol-Mediated Toxicity

Birková

Hubková

Čižmárová

et al. 2021

IJMS

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Alcohol is a psychoactive substance that is widely used and, unfortunately, often abused. In addition to acute effects such as intoxication, it may cause many chronic pathological conditions. Some of the effects are very well described and explained, but there are still gaps in the explanation of empirically co-founded dysfunction in many alcohol-related conditions. This work focuses on reviewing actual knowledge about the toxic effects of ethanol and its degradation products.

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Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids

Cited by 3 publications

References 60 publications

Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs

Resolvin D1 attenuated liver injury caused by chronic ethanol and acute LPS challenge in mice

Current View on the Mechanisms of Alcohol-Mediated Toxicity

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