Insight into the role of the gut-brain axis in alcohol-related responses: Emphasis on GLP-1, amylin, and ghrelin

Abstract

Alcohol use disorder (AUD) contributes substantially to global morbidity and mortality. Given the heterogenicity of this brain disease, available pharmacological treatments only display efficacy in sub-set of individuals. The need for additional treatment options is thus substantial and is the goal of preclinical studies unraveling neurobiological mechanisms underlying AUD. Although these neurobiological processes are complex and numerous, one system gaining recent attention is the gut-brain axis. Peptides of the gut-brain axis include anorexigenic peptide like glucagon-like peptide-1 (GLP-1) and amylin as well as the orexigenic peptide ghrelin. In animal models, agonists of the GLP-1 or amylin receptor and ghrelin receptor (GHSR) antagonists reduce alcohol drinking, relapse drinking, and alcohol-seeking. Moreover, these three gut-brain peptides modulate alcohol-related responses (behavioral and neurochemical) in rodents, suggesting that the alcohol reduction may involve a suppression of alcohol’s rewarding properties. Brain areas participating in the ability of these gut-brain peptides to reduce alcohol-mediated behaviors/neurochemistry involve those important for reward. Human studies support these preclinical studies as polymorphisms of the genes encoding for GLP-1 receptor or the ghrelin pathway are associated with AUD. Moreover, a GLP-1 receptor agonist decreases alcohol drinking in overweight patients with AUD and an inverse GHSR agonist reduces alcohol craving. Although preclinical and clinical studies reveal an interaction between the gut-brain axis and AUD, additional studies should explore this in more detail.

Semaglutide reduces alcohol intake and relapse-like drinking in male and female rats

“…The findings that semaglutide reduced alcohol and food intake, lowered body weight in both male and female rats, and decreased the intake of rewarding foods in male mice, collectively indicate that semaglutide has an overall suppressive effect on motivation for rewards. On a similar note, other GLP-1R agonists have been shown to attenuate the responses to addictive drugs including nicotine, cocaine and opioids (for review see 97 ). Moreover, activation of GLP-1R has been shown to suppress the reward value associated with food and reduce the motivation to acquire both ordinary chow and highly rewarding food items.…”

“…For instance, ghrelin has been shown to enhance responses to alcohol, drugs of abuse and foods. 97 , 98 …”

Emerging targets for therapy in ALD: Lessons from NASH

“…[116] Although peripheral pathways and gut-derived hormones (ghrelin, leptin, insulin, and neuropeptide YY) through their interaction with the central pathways are mainly involved to control food intake, data are emerging on the role of glucagonlike peptide 1 in mediating alcohol use behavior in humans. [117,118] Although several pharmacotherapies exist and are in development for alcohol use disorder, [119] the development of therapies targeting food addiction is limited due to their potential risk of adverse effects, especially mood disorders. [116]…”

Antismoking agents do not contribute synergistically to semaglutide’s ability to reduce alcohol intake in rats

“…The socioeconomic and medical severity of alcohol use disorder (AUD) is substantial ( Rehm et al, 2009 ), and the limited efficacy of available treatments is thus a major concern ( Heilig and Egli, 2006 ). Novel treatments are therefore needed, and among those that has been identified through preclinical studies are glucagon-like peptide-1 receptor (GLP-1R) agonists, and the antismoking agents varenicline and bupropion (for review see ( Chatterjee and Bartlett, 2010 ; Soderpalm et al, 2020 ; Tufvesson-Alm et al, 2022 ).…”

“…The findings that GLP-1R agonists reduce homeostatic and hedonic feeding and lowers body weight (for review see ( Kanoski, 2021 ), have led to their approval as antiobesity agents ( Wilding et al, 2021 ). Alcohol consumption is another aspect regulated by GLP-1, as acute or repeated administration of various GLP-1R agonists decreases alcohol intake, alcohol seeking and relapse in animals (for review see ( Tufvesson-Alm et al, 2022 ). On a similar note, the GLP-1R agonist exenatide reduces alcohol consumption in overweight AUD patients ( Klausen et al, 2022 ) and polymorphisms of the GLP-1R genes is associated with the AUD diagnosis and high alcohol intake ( Suchankova et al, 2015 ).…”