Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

Abstract

Objective: Metformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin's participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota. Methods: In order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies. Results: First, METH addicts exhibited higher alpha diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice. Discussion: This study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.

Psychiatric Comorbidities and Liver Injury Are Associated With Unbalanced Plasma Bile Acid Profile During Methamphetamine Withdrawal

“…Altered production of secondary BAs in patients with MUDs mayindicate a significant change their gut microbiota. This hypothesis is supported bystudies showing that alterations in gut microbiota play key roles in the regulationof host metabolism and therefore contribute to severe withdrawal symptoms (48,49). In addition, altered circulating BAs may affect CNS function by activating FXR inneurons and TGR5 in glial cells, thereby modulating neuroinflammatory andneuropsychiatric behaviors (50).…”

“…A study with relative larger sample size shouldhypothetically obtain more accurate results. Second, this was an observational studyshowing statistical associations; therefore, causality could not be determined.Third, because the gut microbiota has been shown to affect the neuropsychiatricbehaviors associated with substance withdrawal ( 49 , 51 ), future studies shouldinvestigate the association between the composition of gut microbiota and themechanisms of BA metabolism during METH withdrawal.…”