Abstract
Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.
Highlights
Background characteristicsAge, yrs Cirrhosis (Y/N) Child Pugh score (A/B/C) AST, IU/L ALT, IU/L γ-GTP, IU/L Alb, g/dL T-bil, mg/dL PT-INR Type IV collagen, ng/mL FBS, mg/dL WBC, × 103/μL Hb, g/dL Plt, × 104/μL TC, mg/dL HDL-C, mg/dL TG, mg/dL Ethanol (g/day) 0–49 50–99 100–149 150–199 200–249 250–299 300–349ALDH2 (Glu487Lys) *1/*1 *1/*2 Total Mean ± SD 52 ± 4 5/3/0 86 ± 16 51 ± 8 370 ± 61 4.1 ± 0.6 1.0 ± 0.4 1.02 ± 0.22
We showed that chronic alcohol consumption induces hypo-reactivity of peripheral monocytes to LPS in Japanese male AD patients, and short-term abstinence partially restored this reactivity
We demonstrated that the immunological defects in the peripheral monocytes of AD patients are partially regulated by genetic polymorphisms in alcohol-metabolizing enzymes and that the most acetaldehyde-exposed patients carrying the combination of ALDH2*1/*2 and ADH1B*2 showed the most impaired function of peripheral monocytes regardless the similar amounts of alcohol intake
Summary
Yrs Cirrhosis (Y/N) Child Pugh score (A/B/C) AST, IU/L ALT, IU/L γ-GTP, IU/L Alb, g/dL T-bil, mg/dL PT-INR Type IV collagen, ng/ mL FBS, mg/dL WBC, × 103/μL Hb, g/dL Plt, × 104/μL TC, mg/dL HDL-C, mg/dL TG, mg/dL
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