Methamphetamine Disturbs Gut Homeostasis and Reshapes Serum Metabolome, Inducing Neurotoxicity and Abnormal Behaviors in Mice

Abstract

As an illicit psychostimulant, repeated methamphetamine (MA) exposure results in addiction and causes severe neurotoxicity. Studies have revealed complex interactions among gut homeostasis, metabolism, and the central nervous system (CNS). To investigate the disturbance of gut homeostasis and metabolism in MA-induced neurotoxicity, 2 mg/kg MA or equal volume saline was intraperitoneally (i.p.) injected into C57BL/6 mice. Behavioral tests and western blotting were used to evaluate neurotoxicity. To determine alterations of colonic dysbiosis, 16s rRNA gene sequencing was performed to analyze the status of gut microbiota, while RNA-sequencing (RNA-seq) and Western Blot analysis were performed to detect colonic damage. Serum metabolome was profiled by LC–MS analysis. We found that MA induced locomotor sensitization, depression-, and anxiety-like behaviors in mice, along with dysfunction of the dopaminergic system and stimulation of autophagy as well as apoptosis in the striatum. Notably, MA significantly decreased microbial diversity and altered the component of microbiota. Moreover, findings from RNA-seq implied stimulation of the inflammation-related pathway after MA treatment. Western blotting confirmed that MA mediated colonic inflammation by activating the TLR4-MyD88-NF-κB pathway and impaired colonic barrier. In addition, serum metabolome was reshaped after MA treatment. Specifically, bacteroides-derived sphingolipids and serotonin were obviously altered, which were closely correlated with locomotor sensitization, depression-, and anxiety-like behaviors. These findings suggest that MA disrupts gut homeostasis by altering its microbiome and arousing inflammation, and reshapes serum metabolome, which provide new insights into understanding the interactions between gut homeostasis and MA-induced neurotoxicity.

Sex‐specific metabolic signatures in methamphetamine addicts

“…Recently, the metabolomic profiling in METH addicts and METH‐exposed animals were evaluated in several studies 11–14 . In the present study, we found that METH addicts had signs of malnutrition, as indicated by reduced levels of Tbil, Cr and BUN in the blood of METH addicts.…”

“…Recently, the metabolomic profiling in METH addicts and METHexposed animals were evaluated in several studies. [11][12][13][14] In the present study, we found that METH addicts had signs of malnutrition, as indicated by reduced levels of Tbil, Cr and BUN in the blood of METH addicts. Consistent with previous reports, 12 we found that METHaltered metabolites were mainly related to amino acid metabolism and energy metabolism.…”

“…Metabolomics of tissue, especially from serum, benefit for the discovery of novel biomarkers for diagnosis and treatment of psychiatric disorders such as drug addiction. Recently, several clinical and animal studies have conducted to investigate the effects of METH abuse on metabolomics in blood, 6,7 urine 8 and hair 9,10 . Lin et al 11 found that METH caused 35 metabolites distinctly expressed in human serum, which are enriched in amino acid metabolisms, citrate cycle and glucose–alanine cycle.…”

Effect of aerobic exercise on brain metabolite profiles in mice models of methamphetamine addiction: LC-MS-based metabolomics study

“…MA-administered rats exhibited rapid and marked changes in energy metabolism, nervous system, and membrane lipid metabolism [33,34], inducing neurotoxicity and locomotor sensitization, depression-, and anxiety-like behaviors [35]. Human brain tissue and cerebrospinal uid are not readily available due to ethical and safety constraints [36].…”

Gut microbiome metabolites as key actors in atherosclerosis co-depression disease

“…Kemp used an exposure to early life stress model to investigate the relationship between altered gut microbiome and depression and cardiovascular disease, showing that the model reduced microbial alpha diversity and altered microbial composition ( Kemp et al, 2021 ). A recent study found that dysregulation of gut microbiome composition contributed to the development of depression-like behavior induced by chronic myocardial infarction, suggesting that exogenous modulation of gut microbiome composition may be a potentially important strategy for treating depression-like behavior caused by adverse cardiac events ( Zhang et al, 2022 ). Our previous study similarly showed that mainly Desulfovibrio and Akkermansia were altered within the gut microbiome of the AS co-depression mouse model compared to the Control group of mice and confirmed that some lipid metabolites in the brain are strongly associated with some bacteria ( Hu et al, 2022 ).…”