Journal of Lipid Research
Volume 60, Issue 12, December 2019, Pages 2034-2049
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Research Articles
Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury

https://doi.org/10.1194/jlr.RA119000200Get rights and content
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Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpi and Leap2) in fat-1 versus WT mice fed EtOH. fat-1 mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.

intestine
inflammation
omega-3 fatty acids
diet and dietary lipids
gut microbiome
bile acid metabolism
alcoholic liver disease
polyunsaturated fatty acid

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This work was supported by National Institutes of Health Grants R01AA024102-01A1 (I.A.K.), U01AA022489 (C.J.M.), 1U01AA021901-01 (C.J.M.), 1U01AA021893-01 (C.J.M.), R01AA023681 (C.J.M.), S10OD020106 (X.Z.), P20GM103436 (E.C.R.), and P30GM106396 (E.C.R.); U.S. Department of Veterans Affairs Grant I01BX000350 (C.J.M.). Research reported in this publication was also supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant P20GM113226 (C.J.M.) and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Grant P50AA024337 (C.J.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article.

The online version of this article (available at http://www.jlr.org) contains a supplement.

    Abbreviations:

    AA

    arachidonic acid

    Adh

    alcohol dehydrogenase

    ALD

    alcoholic liver disease

    Aldh

    aldehyde dehydrogenase

    Alpi

    intestinal alkaline phosphatase

    ALT

    alanine aminotransferase

    AMP

    antimicrobial peptide

    BA

    bile acid

    CAE

    chloroacetate esterase

    Car

    constitutive androstane receptor

    CDCA

    chenodeoxycholic acid

    DSS

    dextran sulfate sodium

    EtOH

    ethanol

    fat-1

    ω-3 FA desaturase-1

    5-HT

    5-hydroxytryptamine

    ISC

    intestinal stem cell

    I3S

    3-indoxyl sulfate

    LCA

    lithocholic acid

    Leap2

    liver-enriched antimicrobial peptide 2

    LPS

    lipopolysaccharide

    OTU

    operational taxonomic unit

    PF

    pair-fed

    Pxr

    pregnane X receptor

    RvD1

    resolvin D1

    SPM

    specialized pro-resolving mediator

    TG

    triglyceride

    Tlr

    Toll-like receptor

    Tph-1

    tryptophan hydroxylase-1

    UC

    ulcerative colitis

    UDCA

    ursodeoxycholic acid