Recent efforts to understand the role of leaky gut in ASH and ALD highlight the use of potential therapeutics to reduce the gut leakiness and peripheral inflammation associated with alcohol dependence. Endocannabinoids oleoylethanolamine (OEA) and palmitoylethanolamine (PEA), which are PPARα agonists, reverse cytokine-induced permeability of intestinal cells in vitro (Karwad et al., 2017). Likewise, cannabidiol accelerates recovery of cytokine-induced intestinal permeability via cannabinoid receptor 1 (Alhamoruni et al., 2012). Flaxseed oil, which increases endocannabinoid levels, reduces inflammatory cytokine expression in a mouse model of ALD and ameliorates disease symptoms (Zhang et al., 2017). Because plasma markers of inflammation correlate with drug craving in human alcoholics (Leclercq et al., 2012), gut-based therapeutics also have the potential to ameliorate alcohol-dependent behavioral phenotypes. For example, preclinical studies show that targeting the endocannabinoid system or PPARα activation decreases ethanol intake (Blednov et al., 2014a; Sloan et al., 2017). It is not known whether the effects of PPARα activation or other anti-inflammatory therapies on alcohol behaviors are primarily due to peripheral or central immune modulation.
