Changes in the metabolic profile of human male postmortem frontal cortex and cerebrospinal fluid samples associated with heavy alcohol use

Abstract

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry‐based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2‐piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2‐piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use.

Microbiota-derived metabolites as drivers of gut–brain communication

“…Selectivity of the BBB restricts the passage of most metabolites to the brain although transporters, diffusion, or transcytosis could facilitate crossing of the BBB of certain compounds ( Figure 2 ) corroborating the evidence from GF mice. 28 , 54 , 131 Nevertheless, microbial metabolites such as 5-AVAB, TMAO, p -cresol sulfate, and hippuric acid among others have been found in the human brain. 54 In addition to translocation to the brain, the metabolites could alter barrier function to some extent but the physiological significance of this in humans is yet to be determined.…”

“… 28 , 54 , 131 Nevertheless, microbial metabolites such as 5-AVAB, TMAO, p -cresol sulfate, and hippuric acid among others have been found in the human brain. 54 In addition to translocation to the brain, the metabolites could alter barrier function to some extent but the physiological significance of this in humans is yet to be determined. In Alzheimer’s disease patients the increase in microbially produced deoxycholic acid and its taurine or glycine conjugated forms in the serum had a strong association with cognitive impairment 76 and cerebrospinal fluid t-tau aggregation.…”

“… 174 , 175 Also, the GABAergic neurons can utilize β-hydroxybutyrate to produce neurotransmitters GABA and glutamate, 176 which are altered in the postmortem brains of persons with history of heavy alcohol use. 54 …”

Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease

“…Furthermore, it seems that betainized compounds, in general, are positively associated with neurite outgrowth and normal offspring development [2], even though elevated 5-AVAB levels have been associated with the complex pregnancy disorder pre-eclampsia [52,53]. It is noteworthy that 5-AVAB has been detected in human postmortem brain samples, pointing to the potential importance of the metabolite also in human cerebral metabolism [54].…”

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

“…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).…”