Abstract
BackgroundChronic 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.MethodsWe 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.ResultsOur 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.ConclusionsThese 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.
Highlights
Depression is a pervasive neuropsychiatric disorder that is characterized by affective flattening, slow mental processing and hypobulia [1]
The Chronic unpredictable mild stress (CUMS) treatment resulted in a decrease in the total frequency of crossing (F (3, 39) = 14.72, P < 0.001)and rearing (F (3, 39) = 14.97, P = 0.0019) compared with the CON group (Fig. 1c, d), and a marked decrease in the time spent in the central area (F(3,39) = 12.83, P = 0.0063)was observed in the CUMS-exposed rats when compared with the CON group(Fig. 1e)
We further found that butyric acid, which was affected by rifaximin, was negatively correlated with the content of Tumor necrosis factor-α (TNF-α) and IL-1ra and positively correlated with the content of IL-10 and IL-1β in dentate gyrus (DG), suggesting that butyric acid may be a key mediator of rifaximin in regulating the microglial function
Summary
Depression is a pervasive neuropsychiatric disorder that is characterized by affective flattening, slow mental processing and hypobulia [1]. Ramified-state microglia play a neuroprotective role by secreting anti-inflammatory factors, such as Interleukin-10(IL-10) [11]. Regulation of gut brain axis and microglial function may be a new strategy for the treatment of depression. Chronic unpredictable mild stress (CUMS) can lead to depression-like behavior and 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. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. 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
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