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Background: Patients with chronic pain frequently suffer from anxiety symptoms. It has been well established that gut microbiota is associated with the pathogenesis of pain and anxiety. However, it is unknown whether the gut microbiota, particularly the specific bacteria, play a role in the comorbidity of chronic pain and anxiety. Methods: Chronic inflammatory pain was induced in mice by a single injection of complete Freund's adjuvant (CFA). Mice were then separated into anxiety-susceptible and anxiety-resilient phenotypes by hierarchical clustering analysis of behaviors. Fecal samples were collected to perform 16S rRNA gene sequencing. Chronic diazepam intervention served as a therapeutic strategy and its effect on the composition of gut microbiota was also determined. Results: α-Diversity and β-diversity both showed significant differences among the groups. A total of 12 gut bacteria were both altered after CFA injection and reversed by chronic diazepam treatment. More importantly, the pain hypersensitivity and anxiety-like behaviors were relieved by chronic diazepam treatment. Interestingly, we also found that Desulfovibrio was increased in anxiety-resilient group compared to control and anxiety-susceptible groups. Conclusion: Abnormal composition of gut microbiota plays an essential role in chronic pain as well as in anxiety. Besides, the increased level of Desulfovibrio in anxiety-resilient mice indicated its therapeutic effects on the comorbidity of pain and anxiety. Collectively, targeting gut microbiota, especially increasing the Desulfovibrio level, might be effective in the alleviation of chronic pain-anxiety comorbidity. [ABSTRACT FROM AUTHOR]

Rationale: Growing evidence supports the role of microbiota in regulating gut-brain interactions and, thus, contributing to the pathogenesis of depression and the antidepressant actions. Adipose-derived mesenchymal stem cells (ADSCs), as important members of the stem cell family, were demonstrated to alleviate depression behaviors. However, the role of gut microbiota in ADSCs alleviating depression in chronic social defeat stress (CSDS) model is unknown. Objectives: To examine the effects of ADSCs on depression symptoms and detect the changes in the composition of gut microbiota. Results: We found that ADSCs administration significantly ameliorated CSDS-induced depression behaviors, which was accompanied by alteration in the gut microbiota. The principal co-ordinates analysis (PCoA) results showed that there was a significant difference between the gut microbiota among the groups. Remarkably, receiver operating characteristic (ROC) curves revealed that order Micrococcales, order Rhizobiales and species Bacteroides acidifaciens are potentially important biomarkers for the antidepressant effects of ADSCs in CSDS model. Conclusions: ADSCs are effective in treating depression behaviors in CSDS model, which might be partly due to the regulation of abnormal composition of gut microbiota. Thus, ADSCs offer a promising therapeutic strategy for treating depression in patients. [ABSTRACT FROM AUTHOR]

The non-competitive glutamatergic N -methyl- d -aspartate receptor (NMDAR) antagonist, (R , S)-ketamine (ketamine), is known to exert rapid and long-lasting antidepressant-like effects. However, the widely use of ketamine is restricted owing to severe psychotomimetic side-effects and abuse liability. Very recently, we demonstrated that a major metabolite of ketamine, norketamine, in particular the (S)-enantiomer, had a potent antidepressant-like effect. We here examined the effects of a low-dose of norketamine enantiomers on depression symptoms and detected the changes in the composition of gut microbiota. In the behavioral tests, (S)-norketamine, but not (R)-norketamine, showed antidepressant-like effects in the lipopolysaccharide (LPS)-induced mice. At the genus level, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increase in the levels of Escherichia-Shigella and Adlercreutzia , as well as the reduction in the levels of Harryflintia. At the species level, both (S)-norketamine and (R)-norketamine significantly attenuated the increase in the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Notably, (S)-norketamine was more potent than (R)-norketamine at reducing the levels of bacterium ic1379 and Bacteroides sp. Marseille-P3166. Furthermore, (S)-norketamine, but not (R)-norketamine, significantly attenuated the increased levels of Bacteroides caecigallinarum. In conclusion, this study suggests that the antidepressant-like effects of (S)-norketamine might be associated with the changes in the composition of gut microbiota. Therapeutic strategies improving the gut microbiota might facilitate the benefits for depression treatment. • (S)-norketamine, but not (R)-norketamine, exerted antidepressant effects in lipopolysaccharide-induced depression model. • Lipopolysaccharide-induced depression behaviors might be related to the abnormal composition of gut microbiota. • Gut microbiota might play a critical role in the antidepressant effects of (S)-norketamine. [ABSTRACT FROM AUTHOR]

Social dominance is a universal phenomenon among grouped animals that profoundly affects survival, health, and reproductive success by determining access to resources, and exerting a powerful influence on subsequent behavior. However, the understanding of pain and anxiety comorbidities in dominant or subordinate animals suffering from chronic pain is not well-defined. Here, we provide evidence that subordinate mice are more susceptible to pain-induced anxiety compared to dominant mice. We propose that the gut microbiota may play a mediating role in this mechanism. Our findings demonstrate that transplantation of fecal microbiota from subordinate mice with chronic inflammatory pain, but not dominant mice, into antibiotics-treated pseudo-germ-free mice significantly amplifies anxiety-like phenotypes, highlighting the critical involvement of gut microbiota in this behavioral response. Using chronic inflammatory pain model, we carried out 16S rRNA sequencing and untargeted metabolomic analyses to explore the relationship between microbiota and metabolites in a stable social hierarchy of mice. Interestingly, anxiety-like behaviors were directly associated with some microbial genera and metabolites, especially bile acid metabolism. Overall, we have demonstrated a close relationship between social status and anxiety susceptibility, highlighting the contributions of gut microbiota and the associated metabolites in the high-anxiety state of subordinate mice with chronic inflammatory pain. • Social hierarchy modulates pain and anxiety comorbidity. • Subordinate mice are more susceptible to pain-induced anxiety-like behavior. • Gut microbiota and metabolites relate to anxiety in subordinate mice with chronic pain. [ABSTRACT FROM AUTHOR]

The discovery of the robust antidepressant actions of ketamine is regarded as one of the greatest advancements in depression treatment in the past 60 years. Recent findings have provided strong evidence for the presence of bidirectional communication networks between the gastrointestinal tract and the brain in depression. Moreover, increasing evidence supports the antidepressant role of ketamine in regulating the gut microbiome and microbiota-derived molecules; however, the mechanisms underpinning such effects are still ambiguous. This review summarizes the current understanding of the anti-depressant mechanisms of ketamine and its metabolites regarding the bidirectional regulation by microbiota–gut–brain axis. We review the relationship between gut microbiota and the antidepressant mechanisms of ketamine, and discuss the role of stress response, brain-derived neurotrophic factor (BDNF)-mediated neurogenesis, anti-inflammatory effect and neurotransmitters. • Ketamine and its metabolites exert rapid-acting and sustained antidepressant effects. • Gut microbiota contributes to the pathogenesis of depression and the antidepressant actions of ketamine and its metabolites. • The relationship between gut microbiota and the antidepressant effects of ketamine and its metabolites is related to stress response, BDNF expression, neurogenesis, anti-inflammatory effect and neurotransmitters. [ABSTRACT FROM AUTHOR]