The gut‐immune‐liver axis in patients with alcohol use disorder and clinically low serum zinc levels

Abstract

AbstractBackgroundAlcohol use disorder (AUD) with chronic and heavy alcohol consumption causes alcohol‐associated liver disease (ALD). Early‐stage ALD exhibits dyshomeostasis of zinc. We investigated the role of zinc deficiency in gut‐barrier dysfunction, proinflammatory response, hepatocyte injury, and death, as well as potential sex differences in AUD patients.MethodsThirty‐nine male and female AUD patients were grouped by normal [≥71 μg/dL (Group 1, number (n) = 26)] and low [<71 μg/dL (Group 2, n = 13)] serum zinc levels. Demographics, alcohol intake markers [Lifetime Drinking History (LTDH), heavy drinking days in the past 90‐days (HDD90), total drinks in the past 90‐days (TD90), number of drinking days in the past 90‐days (NDD90), average drinks per day in the past 90 days (AvgDPD90)] were collected. Blood samples were tested for complete blood count (CBC), comprehensive metabolic panel (CMP), coagulation markers, gut‐barrier dysfunction markers, cytokines, and hepatocyte death markers.ResultsGroup 2 females exhibited lower LTDH than Group 2 males (p = 0.028), but higher recent drinking. Aspartate transaminase: alanine transaminase (AST:ALT) ratio was higher (p = 0.049) in Group 2 males compared to Group 1 males. Overall, Group 2 showed threefold higher interleukin 8 (IL‐8) levels than Group 1 (p = 0.92); these were sevenfold higher in Group 2 females than Group 1 females. Group 2 females also had higher K18M65, but lower K18M30 than Group 1 females. Necrotic type of cell death (K18M65) was well‐described only in Group 2 by the arrangement of lipopolysaccharide (LPS), soluble cluster of differentiation 14 (sCD14), and tumor necrosis factor alpha (TNF‐α) (R2 = 0.633, p = 0.037).ConclusionOur findings demonstrated the role of the gut‐immune‐liver axis in describing hepatocyte injury and death in zinc‐deficient AUD patients. These patients represented an arrangement of gut‐barrier dysfunction and an exacerbated immune response. Shift in the cell‐death mechanism from apoptosis in zinc‐replete females to necrosis in zinc‐deficient females suggests a subclinical to clinical transition of ALD associated with zinc status.