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Results MA-Induced Neurotoxicity in Mice MA-Induced Locomotor Sensitization and Depression/Anxiety-Like Behaviors in Mice Compared to saline treatment, MA injections from day 3 significantly increased the total distance traveled ( I p i < 0.01), and this was sustained throughout the development phase (Figure 1B). Determination of MA Concentration The concentration of MA in serum and fecal samples from MA group mice were determined using LC-MS/MS method. Keywords: methamphetamine; gut microbiome; serum metabolome; colonic inflammation; neurotoxicity EN methamphetamine gut microbiome serum metabolome colonic inflammation neurotoxicity 1 16 16 04/21/22 20220418 NES 220418 Introduction Methamphetamine (MA) is a highly addictive and illegal psychostimulant with serious health effects ([14]; [9]). MA Altered Serum Metabolome in Mice Effects of MA on Serum Metabolic Composition We performed UPLC-TOF/MS analyses to determine the status of serum metabolome. [Extracted from the article]

Methamphetamine (METH) is a psychostimulant abused worldwide. Its abuse induces intestinal toxicity. Moreover, the gut microbiota is altered by drugs, which induces intestinal injury. Whether gut microbiota mediates METH-induced intestinal toxicity remains to be validated. In the present study, wild-type and TLR4−/− mice were treated with METH. Gut microbiota was determined using 16S rRNA gene sequencing. Transcriptomics of the intestinal mucosa was performed by RNA-Sequencing. Blood levels of pro-inflammatory cytokines and lipopolysaccharide (LPS), the intestinal barrier, and inflammation were also assessed. METH treatment weakened the intestinal barrier and increased pro-inflammatory cytokines and LPS levels in the blood. Moreover, METH treatment significantly decreased the diversity of probiotics but increased the abundance of pathogenic gut microbiota, contributing to the over-production of LPS and disruption of intestinal barrier. Inflammatory pathways were enriched in the intestinal mucosa of METH-treated mice by KEGG analysis. Consistently, activation of the TLR4 pathway was determined in METH-treated mice, which confirmed intestinal inflammation. However, pretreatment with antibiotics or Tlr4 silencing significantly alleviated METH-induced gut microbiota dysbiosis, LPS over-production, intestinal inflammation, and disruption of the intestinal barrier. These findings suggested that the gut microbiota and LPS-mediated inflammation took an important role in METH-induced intestinal injury. Taken together, these findings suggest that METH-induced intestinal injury is mediated by gut microbiota dysbiosis and LPS-associated inflammation. • METH treatment induced intestinal injury. • METH treatment altered gut microbiota and resulted in the over-production of LPS. • Inflammatory pathways were enriched in intestinal mucosa of METH groups by RNA-Seq. • TLR4 pathway was activated by METH treatment in intestinal mucosa. • Antibiotics or Tlr4 silencing alleviated intestinal injury. [ABSTRACT FROM AUTHOR]

Methamphetamine (Meth), an addictive psychostimulant of abuse worldwide, has been a common cause of acute toxic hepatitis in adults. Gut microbiota has emerged as a modulator of host immunity via metabolic pathways. However, the microbial mechanism of Meth-induced hepatic inflammation and effective therapeutic strategies remain unknown. Here, mice were intraperitoneally (i.p.) injected with Meth to induce hepatotoxicity. Cecal microbiome and bile acids (BAs) composition were analyzed after Meth administration. Fecal microbiota transplantation (FMT) technology was utilized to investigate the role of microbiota. Additionally, the protective effects of obeticholic acid (OCA), an agonist of farnesoid X receptor (FXR), were evaluated. Results indicated that Meth administration induced hepatic cholestasis, dysfunction and aroused hepatic inflammation by stimulating the TLR4/MyD88/NF-κB pathway in mice. Meanwhile, Meth disturbed the cecal microbiome and impaired the homeostasis of BAs. Interestingly, FMT from Meth administered mice resulted in serum and hepatic BA accumulation and transferred similar phenotypic changes into the healthy recipient mice. Finally, OCA normalized Meth-induced BA accumulation in both serum and the liver, and effectively protected against Meth-induced hepatic dysfunction and inflammation by suppressing the TLR4/MyD88/NF-κB pathway. This study established the importance of microbial mechanism and its inhibition as a potential therapeutic target to treat Meth-related hepatotoxicity. [Display omitted] • Gut microbiota mediates Meth-induced hepatic inflammation by stimulating the TLR4/MyD88/NF-κB pathway. • Gut microbiota participates in Meth-induced impairment of bile acid homeostasis. • Obeticholic acid ameliorates Meth-induced hepatic inflammation by repressing the TLR4/MyD88/NF-κB pathway. • Obeticholic acid improves Meth-induced impairment of bile acid homeostasis. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is an addictive and illegal psychostimulant drug that can cause multiple organ dysfunction, especially in the central nervous system (CNS). Gut microbiota have been implicated in development of various CNS-related diseases, via the gut-brain axis (GBA). However, effect of METH in the alteration of gut microbiota and fecal metabolites is unclear, whereas the relationship with METH-induced neurotoxicity remains unknown. In the current study, we investigated effect of METH on neurotoxicity in striatum and colonic damage by exposing BALB/c mice to an escalating dose-multiple binge regimen, and then analyzed protein expression using Western blot analysis. We further detected and sequenced the 16 S rRNA gene in fecal samples, and performed ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze gut microbes and fecal metabolites. Exposure to METH significantly downregulated tyrosine hydroxylase (TH) proteins, but upregulated MAOA, Beclin1, Atg5, and LC3-Ⅱ. METH up-regulated inflammation-related factors, such as caspase1, TNF-α and IL-18, by activating the toll-like receptors 4 (TLR4)/myeloid differentiation factor 88 (Myd88)/nuclear factor κB (NF-κB) pathway and reduced occludin protein expression. In addition, METH exposure changed α and β diversities of gut microbiota. Specifically, METH exposure elevated relative abundances of pathogenic bacteria, but reduced those of probiotics. Metabolomics, combined with enrichment analyses revealed that METH exposure altered fecal metabolites. Our findings suggest that METH exposure induced autophagy in the CNS, elevated intestinal autophagy flora, leading to accumulation of fecal metabolites in the autophagy pathway, and causing enteritis. Moreover, METH promoted intestinal inflammation by increasing the relative abundance of the pathogenic bacteria in the intestinal tract, and reduced intestinal TJ protein expression. • Methamphetamine (METH) induces neurotoxicity and colonic inflammatory in mice. • METH-exposed altered gut microbiota and fecal metabolites. • METH-induced neurotoxicity, gut microbiota and fecal metabolites were closely related to autophagy. [ABSTRACT FROM AUTHOR]