Background Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions. Methods We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis. Results Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS. Conclusions These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.

Exposure to a harsh environment in early life increases in the risk of post-traumatic stress disorder (PTSD) of an individual. Brain derived neurotrophic factor (BDNF) plays an important role in neurodevelopment in developmental stages. Both chronic and traumatic stresses induce a decrease in the level of BDNF and reduce neural plasticity, which is linked to the pathogenesis of PTSD. Also, studies have shown that stress alters the epigenetic marker H3K9me2, which can bind to the promoter region of the Bdnf gene and reduce BDNF protein level. However, the long-term effects of traumatic stress during adolescence on H3K9me2, BDNF expression and dendrite development are not well-known. The present study established a model of PTSD in adolescent rats using an inescapable foot shock (IFS) procedure. Anxiety-like behaviors, social interaction behavior and memory function were assessed by the open field test, elevated plus maze test, three-chamber sociability test and Morris water maze test. In addition, neuronal development and H3K9me2/BDNF expression in hippocampus (HIP) and prefrontal cortex (PFC) were evaluated by Golgi staining, western blotting, qRT-PCR analysis and CHIP-qPCR analysis. Additionally, the Unc0642, a small molecule inhibitor of histone methyltransferase (EHMT2) was used for intervention. The results showed that the IFS procedure induced the PTSD-like behaviors in rats, resulted in fewer dendrite branches and shorter dendrite length in CA1 of HIP and PFC, increased H3K9me2 level and decreased BDNF expression in HIP and PFC. Also, although all the changes can persist to adulthood, Unc0642 administration relieved most of alterations. Our study suggests that traumatic stress in adolescence leads to immediate and long-term mental disorders, neuronal morphological changes, lower BDNF level and increased H3K9me2 level in the HIP and PFC, indicating that H3K9me2/BDNF dysfunction plays a key role in pathogenesis of PTSD.

Post‐traumatic stress disorder (PTSD) is characterized by depression/anxiety and memory failure, primarily fear memory. According to the reports, neuroinflammation and synaptic plasticity can play a role in the neurophysiological mechanisms underlying PTSD. Bromodomain‐containing protein 4 (Brd4) intriguingly affects regulating of inflammatory responses and learning and memory. This study aimed to explore the effect of inhibiting Brd4 on depression/anxiety‐like behaviors, spatial and fear memory, and underlying mechanisms in a model of PTSD. Inescapable foot shocks (IFS) with a sound reminder in 6 days were used to induce PTSD‐like behaviors which were tested using contextual and cue fear tests, sucrose preference test, open‐field test, elevated plus maze test, and Y‐maze test. Meanwhile, the Brd4 inhibitor JQ1 was used as an intervention. The results found that IFS induced PTSD‐like behaviors and indicated obvious Brd4 expression in microglia of the prefrontal cortex (PFC), hippocampus, and amygdala, pro‐inflammatory cytokines over‐expression, microglial activation, and nuclear factor‐kappa B over‐expression in PFC and hippocampus but not in amygdala. Meanwhile, the alterations of immediate early genes (IEGs) were found in PFC, hippocampus, and amygdala. Besides, dendritic spine density was reduced in PFC and hippocampus but was elevated in amygdala of rats with IFS. In addition, treatment with JQ1 significantly reduced freezing time in the contextual and cue fear test, reversed the behavioral impairment, decreased the elevated neuroinflammation, and normalized the alteration in IEGs and dendritic spine densities. The results suggested that Brd4 was involved in IFS‐induced PTSD‐like behaviors through regulating neuroinflammation, dynamics of IEGs, and synaptic plasticity.

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