Changes in Circulating Metabolome Precede Alcohol‐Related Diseases in Middle‐Aged Men: A Prospective Population‐Based Study With a 30‐Year Follow‐Up

Abstract

Background: Heavy alcohol use has been associated with altered circulating metabolome. We investigated whether changes in the circulating metabolome precede incident diagnoses of alcohol-related diseases. Methods: This is a prospective population-based cohort study where the participants were 42-to 60-year-old males at baseline (years 1984 to 1989). Subjects who received a diagnosis for an alcohol-related disease during the follow-up were defined as cases (n = 92, mean follow-up of 13.6 years before diagnosis). Diagnoses were obtained through linkage with national health registries. We used 2 control groups: controls who self-reported similar levels of alcohol use as compared to cases at baseline (alcohol-controls, n = 92), and controls who self-reported only light drinking at baseline (control-controls, n = 90). A nontargeted metabolomics analysis of baseline serum samples was performed. Results: There were significant differences between the study groups in the baseline serum levels of 64 metabolites: in amino acids (e.g., glutamine [FDR-corrected q-value = 0.0012]), glycerophospholipids (e.g., lysophosphatidylcholine 16:1 [q = 0.0008]), steroids (e.g., cortisone [q = 0.00001]), and fatty acids (e.g., palmitoleic acid [q = 0.0031]). The main finding was that after controlling for baseline levels of self-reported alcohol use and the biomarker of alcohol use, gamma-glutamyl transferase, and when compared to both alcohol-control and control-control group, the alcohol-case group had lower serum levels of asparagine (Cohen's d = À0.48 [95% CI À0.78 to À0.19] and d = À0.49 [À0.78 to À0.19], respectively) and serotonin (d = À0.45 [À0.74 to À0.15], and d = À0.46 [À0.75 to À0.16], respectively), with no difference between the two control groups (asparagine d = 0.00 [À0.29 to 0.29] and serotonin d = À0.01 [À0.30 to 0.29]). Conclusions: Changes in the circulating metabolome, especially lower serum levels of asparagine and serotonin, are associated with later diagnoses of alcohol-related diseases, even after adjustment for the baseline level of alcohol use.

Microbiota-derived metabolites as drivers of gut–brain communication

“… 69 , 148 , 149 For example, reduced circulating serotonin levels precede future diagnosis of alcohol use-related diseases even when baseline alcohol drinking is accounted for. 70 However, the regulation of circulating serotonin levels is multifaceted and influenced by external factors, such as diet. 148 , 150 The situation of serotonin system in the brain is even more complex, since serotonin is an important modulator of neurotransmission and therefore the brain levels are controlled differently to the levels in the blood.…”

Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder

“…This effect could be associated with an increase in lipolysis, which ghrelin can induce on its own, and/or indirectly by increasing growth hormone levels (Kopchick et al, 2020;Theander-Carrillo et al, 2006;Vestergaard et al, 2008). Acute and chronic alcohol consumption have been associated with increased circulating levels of fatty acids (Frayn et al, 1990;Kärkkäinen et al, 2020;Steiner & Lang, 2017). Additionally, increased levels of fatty acids, especially 18-carbon fatty acyls such as FA 18:1 and FA 18:3, have been linked…”

“…Alcohol use is associated with changes in the human metabolome, such as levels of amino acids (e.g., decreased glutamine and asparagine), steroid hormones (e.g., increased cortisol), neurotransmitters (e.g., decreased serotonin, increased glutamate), lipids (e.g., increased fatty acids [FA], like palmitoleic acid, docosapentaenoic acid, FA 16:1, and FA 22:5), and microbiota-associated metabolites (e.g., increased lactate and decreased 3-indolepropionic acid) (Heikkinen et al, 2019;Irwin et al, 2018;Jaremek et al, 2013;Kärkkäinen et al, 2020Kärkkäinen et al, , 2021Lehikoinen et al, 2018;Mostafa et al, 2016;Voutilainen & Kärkkäinen, 2019;Würtz et al, 2016). Furthermore, some of these metabolites, such as microbiota-associated metabolites, have been shown to influence ghrelin-mediated signaling (Leeuwendaal et al, 2021;Torres-Fuentes et al, 2019).…”

RNA biomarkers for alcohol use disorder

“…Challenges and future directions for RNA biomarkers are also discussed. The discussion of other omics-based intermediary phenotypes in peripheral tissues for use in AUD management is outside the scope of this Review, but interested readers are referred to articles regarding DNA methylation markers (Zhang H. et al, 2013;Hagerty et al, 2016;Clark et al, 2018Clark et al, , 2022Liu et al, 2018;Philibert et al, 2018;Wilson et al, 2019;Xu et al, 2019;Dugue et al, 2021;Liang et al, 2021;Miller et al, 2021), proteomic markers (Freeman et al, 2010(Freeman et al, , 2011Waszkiewicz et al, 2014;Lai et al, 2015;Liangpunsakul et al, 2015;Batista et al, 2019;Niu et al, 2022) or metabolomic markers (Mittal and Dabur, 2015;Hinton et al, 2017;Mostafa et al, 2017;Karkkainen et al, 2020;Nahar et al, 2022). Ferguson et al 10.3389/fnmol.2022.1032362…”