The influence of alcohol metabolism on consumption patterns and alcohol-related harm has long been recognized, particularly through studies on genetic polymorphisms, such as ALDH2 variants prevalent in individuals of Asian ancestry. As discussed earlier, these variants significantly increased blood acetaldehyde concentrations after alcohol consumption, leading to heightened aversive effects and reduced risk for AUD. In fact, the very first drug approved for the treatment of AUD was disulfiram, a drug that inhibits ALDH2 and, therefore, capitalizes on the resultant aversive effects of acetaldehyde accumulation after alcohol intake (308). However, with a few exceptions, research on alcohol metabolism has predominantly focused on peripheral processes, particularly hepatic metabolism. The recent observations from rodent studies by Fu and colleagues (105) highlight the need to better understand the coordinated action of the gut-liver axis on alcohol detoxification and ingestive behavior in humans. For example, clinical studies investigating how drugs that modulate bile secretion affect alcohol and acetaldehyde metabolism and alcohol subjective effects would help understand novel mechanisms impacting alcohol consumption in humans. A better understanding of human alcohol pharmacokinetics could help design innovative approaches that involve the modulation of ethanol metabolism for treating AUD (168).
