Gegen-Qinlian decoction alleviates anxiety-like behaviors in methamphetamine-withdrawn mice by regulating Akkermansia and metabolism in the colon.

Background: Anxiety is a prominent withdrawal symptom of methamphetamine (Meth) addiction. Recently, the gut microbiota has been regarded as a promising target for modulating anxiety. Gegen-Qinlian decoction (GQD) is a classical Traditional Chinese Medicine applied in interventions of various gut disorders by balancing the gut microbiome. We aim to investigate whether GQD could alleviate Meth withdrawal anxiety through balancing gut microbiota and gut microenvironment.

Methods: Meth withdrawal anxiety models were established in mice. GQD were intragastric administrated into Meth-withdrawn mice and controls. Gut permeability and inflammatory status were examined in mice. Germ-free (GF) and antibiotics-treated (Abx) mice were used to evaluate the role of gut bacteria in withdrawal anxiety. Gut microbiota was profiled with 16s rRNA sequencing in feces. Metabolomics in colon tissue and in Akkermansia culture medium were performed.

Results: Meth withdrawal enhanced anxiety-like behaviors in wild-type mice, and altered gut permeability, and inflammatory status, while GQD treatment during the withdrawal period efficiently alleviated anxiety-like behaviors and improved gut microenvironment. Next, we found Germ-free (GF) and antibiotics-treated (Abx) mice did not develop anxiety-like behaviors by Meth withdrawal, indicating the essential role of gut bacteria in Meth withdrawal induced anxiety. Then, it was observed that gut microbiota was greatly affected in Meth-withdrawn mice, especially the reduction in Akkermansia. GQD can rescue the gut microbiota and reverse Akkermansia abundance in Meth-withdrawn mice. Meanwhile, GQD can also restore the Meth-impaired Akkermansia growth in vitro. Further, GQD restored several common metabolite levels both in colon in vivo and in Akkermansia in vitro.

Conclusions: We revealed a novel effect of GQD on Meth withdrawal anxiety and identified its pharmacological target axis as "Akkermansia-Akkermansia metabolites-gut metabolites-gut microenvironment". Our findings indicated that targeting gut bacteria with TCM, such as GQD, might be a promising therapeutic strategy for addiction and related withdrawal symptoms.