Long-Chain Acylcholines Link Butyrylcholinesterase to Regulation of Non-neuronal Cholinergic Signaling

Abstract

Acylcholines are comprised of an acyl chain esterified to a choline moiety; acetylcholine is the best-characterized member of this class, functioning as a neurotransmitter in the central and peripheral nervous systems as well as an inhibitor of cytokine production by macrophages and other innate immune cells. Acylcholines are metabolized by a class of cholinesterases, including acetylcholinesterase (a specific regulator of acetylcholine levels) and butyrylcholinesterase (BChE, an enigmatic enzyme whose function has not been resolved by genetic knockout models). BChE provides reserve capacity to hydrolyze acetylcholine, but its importance is arguable given acetylcholinesterase is the most catalytically efficient enzyme characterized to date. While known to be substrates of BChE in vitro, endogenous production of long-chain acylcholines is a recent discovery enabled by untargeted metabolomics. Compared to acetylcholine, long-chain acylcholines show greater stability in circulation with homeostatic levels–dictated by synthesis and clearance–suggested to impact cholinergic receptor sensitivity of acetylcholine with varying levels of antagonism. Acylcholines then provide a link between BChE and non-neuronal acetylcholine signaling, filling a gap in understanding around how imbalances between acylcholines and BChE could modulate inflammatory disease, such as the “cytokine storm” identified in severe COVID-19. Areas for further research, development, and clinical testing are outlined.

Multi-Omic Analyses Reveal Bifidogenic Effect and Metabolomic Shifts in Healthy Human Cohort Supplemented With a Prebiotic Dietary Fiber Blend

“…Long-chain acylcholines have been found to have associations with a number of disease states (115), including elevated concentrations in endometrial cancer patients (116) and patients at high risk of pulmonary embolism (117), and lower concentrations in patients with myalgic encephalomyelitis/chronic fatigue syndrome (118) and chronic thromboembolic pulmonary hypertension (119). Acylcholines are known to have cholinergic signaling properties, with important implications for signaling through the nicotinic acetylcholine receptor (α7 nAChR), and effects on cytokine synthesis in macrophages and T cells (115,120).…”

Metabolomic Differences in Connective Tissue Disease–Associated Versus Idiopathic Pulmonary Arterial Hypertension in the PVDOMICS Cohort

“…Endogenous acylcholines are choline molecules acylated with unsaturated FAs that have been discovered recently with broader use of untargeted metabolomics (36). In our cohort, higher circulating acylcholines (eg, dihomo‐linolenoyl‐choline and stearoylcholine) were nominally associated with more favorable outcomes.…”

The efficacy of anti‐proteolytic peptide R7I in intestinal inflammation, function, microbiota, and metabolites by multi‐omics analysis in murine bacterial enteritis

“…Numerous diseases have been described that cause disruptions in energy production and intermediate metabolism in organisms, characterized by the production and excretion of unusual acylcholines. 57 P-cresol is a neurotoxic and nephrotoxic carcinogenic aromatic substance produced by gut microbe fermentation, and it is the precursor of the prototypical protein-bound uremic toxin p-cresol sulfate (p-CS). 58,59 Glucuronidation is used to assist in the excretion of toxic substances, drugs, or other substances that cannot be used as an energy source.…”

“…In contrast, metabolites such as cortisol, cholestane‐3,7,12,25‐tetrol‐3‐glucuronide, palmitoyl glucuronide, trans‐2‐dodecenoylcarnitine, and rock bile acid were significantly upregulated in R7I‐20 group (Tables S12 and S13). Numerous diseases have been described that cause disruptions in energy production and intermediate metabolism in organisms, characterized by the production and excretion of unusual acylcholines 57 . P‐cresol is a neurotoxic and nephrotoxic carcinogenic aromatic substance produced by gut microbe fermentation, and it is the precursor of the prototypical protein‐bound uremic toxin p‐cresol sulfate (p‐CS) 58,59 .…”