Alcohol-induced changes in gut flora and intestinal metabolites increase portal endotoxin level, which is directly associated with intestinal barrier dysfunction and is one of the well-recognized contributing factors to the pathogenesis of ALD. Gut fucosylation is a key force in maintaining a homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how host fucosylation machinery contributes to alcohol-associated barrier function and microbial translocation. It is shown that epithelial α1,2-fucosylation regulates the colonization of E. faecalis, which causes more severe alcoholic hepatitis. Our initial studies found that alcohol consumption reduces the levels of neurons-derived peptide VIP in the gut. Neuropeptide VIP has previously been implicated in circadian regulation, food consumption and goblet cell mucus secretion. Our preliminary data further found that neuropeptide VIP administration or deletion of VIP receptor (VIPR1) can regulate intestinal fucosylation. Membrane-bound fucosylated glycoproteins on mucosal ECs function as important communication tools between the host and luminal microbes. Many intestinal Bifidobacteria use α1,2-L-fucosidases to ferment the glycans of host glycoconjugates to produce fucose for its colonization. We found that fucose-derived propionate could contribute to the induction of IL-22 producing group 3 innate lymphoid cells (ILC3s), which can regulate epithelial integrity in ALD. Therefore, we hypothesize that a high amount of alcohol consumption is associated with disturbances in gut VIP secretion, reductions in IECs fucosylation and beneficial symbionts, and subsequently overgrowth of cytolysin-positive E. faecalis, all of which lead to intestinal barrier dysfunction and contribute to the development of ALD. We postulate that prebiotic and probiotic supplementation will attenuate alcohol-induced intestine and liver injury, in part by inhibiting of E. faecalis colonization and increasing IL-22+ ILC3 in the intestine. Following specific aims will be carried out: Aim 1: Determine the impact of VIP signaling on the gut fucosylation and the effects of this impact on intestinal barrier integrity in ALD. We will document the impact of VIP/VIPR1 signaling changes on intestinal fucosylation and integrity in ALD; We will explore the mechanisms by which fucosylation is enhanced by VIP. Aim 2: Investigate whether probiotic fucosidase-producing Bifidobacterium attenuates ALD via inhibition of E. faecalis colonization and activation of IL-22+ILC3. We will examine the effect of fucosidase-producing Bifidobacterium and fucose-derived propionate on E. faecalis colonization; We will investigate whether fucosidase-producing Bifidobacterium attenuates ALD via the activation of gut ILC3 and IL-22/ IL-22RA signaling. Aim 3: Evaluate the efficacy of VIP-fucosylation-based therapeutic interventions in ALD. We will first evaluate and compare the efficacy of dietary prebiotic 2'-FL with VIP supplementati...