Potential Contribution of the Intestinal Microbiome to Phenethylamine-Induced Hyperthermia

Abstract

Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result in rhabdomyolysis, coagulopathy, and even death. Here, we review recent evidence that suggests a potential link between the gut-brain axis and PIH. Within the preoptic area of the hypothalamus, phenethylamines lead to changes in catecholamine levels, that activate the sympathetic nervous system (SNS) and increase the peripheral levels of norepinephrine (NE), resulting in: (1) the loss of heat dissipation through α<sub>1</sub> adrenergic receptor (α<sub>1</sub>-AR)-mediated vasoconstriction, (2) heat generation through β-AR activation and subsequent free fatty acid (FFA) activation of uncoupling proteins (UCPs) in brown and white adipose tissue, and (3) alteration of the gut microbiome and its link to the gut-brain axis. Recent studies have shown that phenethylamine derivatives can influence the composition of the gut microbiome and thus its metabolic potential. Phenethylamines increase the relative level of <i>Proteus</i>which has been linked to enhanced NE turnover. Bidirectional fecal microbial transplants (FMT) between PIH-tolerant and PIH-naïve rats demonstrated that the transplantation of gut microbiome can confer phenotypic hyperthermic and tolerant responses to phenethylamines. These phenethylamine-mediated changes in the gut microbiome were also associated with epigenetic changes in the mediators of thermogenesis. Given the significant role that the microbiome has been shown to play in the maintenance of body temperature, we outline current studies demonstrating the effects of phenethylamines on the gut microbiome and how these microbiome changes may mechanistically contribute to alterations in body temperature.

The connection between epigenetics and gut microbiota‐current perspective

“…For instance, the metabolic disorder T2DM 150 and atopic dermatitis in both humans and dogs all enhance these epigenetic activities 151 . In the rat model, phenotypic hyperthermic and the tolerant responses to phenethylamines were induced by FMT 152 . Introducing Prevotella amplicon sequence variants through FMT, it was observed to directly correlate with methylation of actin filament‐associated protein ( AFAP1 ).…”

“…151 In the rat model, phenotypic hyperthermic and the tolerant responses to phenethylamines were induced by FMT. 152 Introducing Prevotella amplicon sequence variants through FMT, it was observed to directly correlate with methylation of actin filamentassociated protein (AFAP1). This gene performs in mitochondrial function and eventually epigenome of immune cells.…”

Related Effects of Methamphetamine on the Intestinal Barrier via Cytokines, and Potential Mechanisms by Which Methamphetamine May Occur on the Brain-Gut Axis

“…Gut bacteria collaborate with their animal hosts to regulate immune, metabolic, and nervous system development and function through dynamic two-way communication along the “gut-brain axis ( 54 ).” Besides, the intestinal flora may play an important role in the communication between the gut and the brain, for example, the gut microbiome plays an important role in anxiety and depression ( 55 , 56 ). In animal models of phenethylamine-induced hyperthermia (PIH), certain changes in gut bacteria promote the bidirectional regulation between the brain and gut ( 57 ) (PIH). In METH treated mouse models, METH increased the relative abundance of pathogenic bacteria ( 58 ), promoted intestinal inflammation, and reduced intestinal TJ protein expression, but decreased the relative abundance of probiotics and changed fecal metabolites.…”

Effect of Aerobic Exercise on Intestinal Microbiota with Amino Acids and Short-Chain Fatty Acids in Methamphetamine-Induced Mice

“…The reduction of various oxidative enzymes in the serum of patients with MUD after 12 weeks of aerobic exercise improves cognition and working memory [ 16 ]. Short-term moderate-intensity aerobic exercise can suppress cue cravings and enhance the appetite of patients with MUD [ 17 , 18 , 19 ] Most existing studies focused on the mechanism by which exercise modulates the function of the circulatory system or central nervous system in MUD, but the mechanism by which exercise improves the MA-induced microbiota–gut–brain axis, which is a multi-system combination of the digestive and endocrine systems, needs further investigation [ 20 ].…”

“…The impact of the “microbiota–gut–brain axis” on the brain has been extensively demonstrated, and disruptions in this system are highly correlated with various neurological disorders and altered behavioral abilities [ 21 ], which has led many scholars in the field of MA addiction to investigate the impact of gut microbiota on MUD and brain function [ 20 ]. MA administration resulted in changes in the composition of the gut microbiome [ 21 , 22 , 23 ], which increased the abundance of pathogenic bacteria, decreased the abundance of beneficial bacteria, and caused neurotoxicity in mice [ 24 ].…”