Decreased ω-6:ω-3 PUFA ratio attenuates ethanol-induced alterations in intestinal homeostasis, microbiota, and liver injury

• Published in: Journal of lipid research 2019-12, Vol.60 (12), p.2034-2049
• Main Authors: Warner, Dennis R., Warner, Jeffrey B., Hardesty, Josiah E., Song, Ying L., King, Taylor N., Kang, Jing X., Chen, Chih-Yu, Xie, Shanfu, Yuan, Fang, Prodhan, Md Aminul Islam, Ma, Xipeng, Zhang, Xiang, Rouchka, Eric C., Maddipati, Krishna Rao, Whitlock, Joan, Li, Eric C., Wang, Gary P., McClain, Craig J., Kirpich, Irina A.
• Format: Article
• Language: English
• Subjects: alcoholic liver disease; Animals; bile acid metabolism; Bile Acids and Salts - metabolism; diet and dietary lipids; Ethanol - adverse effects; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Omega-6 - metabolism; Feces - chemistry; Female; Gastrointestinal Microbiome - drug effects; gut microbiome; Homeostasis - drug effects; inflammation; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; intestine; Lipopolysaccharides - pharmacology; Mice; Mice, Inbred C57BL; omega-3 fatty acids; polyunsaturated fatty acid
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.RA119000200

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.