Dataset Information

Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.

ABSTRACT:

Aims

Clear roles and mechanisms in explaining gut microbial dysbiosis and microbial metabolites short-chain fatty acids (SCFAs) alterations in chronic cerebral ischemic pathogenesis have yet to be explored. In this study, we investigated chronic cerebral hypoperfusion (CCH)-induced gut microbiota and metabolic profiles of SCFAs as well as the effects and mechanisms of fecal microbiota transplantation (FMT) and SCFAs treatment on CCH-induced hippocampal neuronal injury.

Methods

Bilateral common carotid artery occlusion (BCCAo) was used to establish the CCH model. Gut microbiota and SCFAs profiles in feces and hippocampus were evaluated by 16S ribosomal RNA sequencing and gas chromatography-mass spectrometry. RNA sequencing analysis was performed in hippocampal tissues. The potential molecular pathways and differential genes were verified through western blot, immunoprecipitation, immunofluorescence, and ELISA. Cognitive function was assessed via the Morris water maze test. Ultrastructures of mitochondria and synapses were tested through a transmission electron microscope.

Results

Chronic cerebral hypoperfusion induced decreased fecal acetic and propionic acid and reduced hippocampal acetic acid, which were reversed after FMT and SCFAs administration by changing fecal microbial community structure and compositions. Furthermore, in the hippocampus, FMT and SCFAs replenishment exerted anti-neuroinflammatory effects through inhibiting microglial and astrocytic activation as well as switching microglial phenotype from M1 toward M2. Moreover, FMT and SCFAs treatment alleviated neuronal loss and microglia-mediated synaptic loss and maintained the normal process of synaptic vesicle fusion and release, resulting in the improvement of synaptic plasticity. In addition, FMT and SCFAs supplement prevented oxidative phosphorylation dysfunction via mitochondrial metabolic reprogramming. The above effects of FMT and SCFAs treatment led to the inhibition of CCH-induced cognitive impairment.

Conclusion

Our findings highlight FMT and SCFAs replenishment would be the feasible gut microbiota-based strategy to mitigate chronic cerebral ischemia-induced neuronal injury.

SUBMITTER: Su SH

PROVIDER: S-EPMC10314111 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.

Su Shao-Hua SH Chen Ming M Wu Yi-Fang YF Lin Qi Q Wang Da-Peng DP Sun Jun J Hai Jian J

CNS neuroscience & therapeutics 20230110

<h4>Aims</h4>Clear roles and mechanisms in explaining gut microbial dysbiosis and microbial metabolites short-chain fatty acids (SCFAs) alterations in chronic cerebral ischemic pathogenesis have yet to be explored. In this study, we investigated chronic cerebral hypoperfusion (CCH)-induced gut microbiota and metabolic profiles of SCFAs as well as the effects and mechanisms of fecal microbiota transplantation (FMT) and SCFAs treatment on CCH-induced hippocampal neuronal injury.<h4>Methods</h4>Bil ...[more]

PMID: 36627762

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Project description:BackgroundLittle is known about the association between gut microbiota and intestinal injury under a state of chronic cerebral hypoperfusion (CCH). Here, the effects of gut microbiota and short-chain fatty acids (SCFAs), as important metabolic products, on intestinal function and potential mechanisms after CCH were investigated.MethodsRats were subjected to bilateral common carotid artery occlusion (BCCAo) to induce CCH. The gut microbiota and metabolites of SCFAs were assessed by 16S rRNA sequencing and targeted metabolomics, respectively. Transcriptomic analysis of colon tissues was also conducted. Subsequently, potential molecular pathways and differentially expressed genes were verified by western blot, immunoprecipitation, and immunofluorescence analyses. Furthermore, the integrity of the colonic barrier was evaluated by hematoxylin and eosin and mucin 2 staining and expression levels of tight junction proteins. Besides, colonic inflammation was further assessed by flow cytometry and expression levels of inflammatory cytokines. In addition, colonic mitochondrial dysfunction was analyzed via membrane potential, reactive oxygen species, electron transport chain (ETC) activities, adenosine triphosphate content, and mitochondrial ultrastructure.ResultsCCH modified gut microbial composition and microbial metabolism of SCFAs, which may be associated with inhibition of mitochondrial ETC activities and oxidative phosphorylation, leading to dysregulation of mitochondrial energy metabolism. Furthermore, CCH induced differentiation of pathogenic Th17 cells, promoted the formation of complexes of interferon regulatory factor 4 and signal transducer and activator of transcription 3 (STAT3), and increased the phosphorylation of STAT3. This was associated with an impairment of colonic barrier function and chronic colonic inflammation. In contrast, FMT and SCFA replenishment ameliorated CCH-induced gut microbial dysbiosis by increasing the intestinal content of Ruminococcus_sp_N15_MGS_57 and modulating microbial metabolism of SCFAs by increasing acetic acid contents associated with an improvment of the balance between Tregs and Th17 cells, mitochondrial ETC activities, and oxidative phosphorylation to prevent colonic inflammation and dysregulation of mitochondrial energy metabolism.ConclusionThese findings indicate that FMT and SCFA replenishment present a promising therapeutic strategy against colonic dysfunction under a state of chronic cerebral ischemia.

Project description:ObjectiveSepsis is the leading cause of death in critically ill patients. The gastrointestinal tract has long been thought to play an important role in the pathophysiology of sepsis. Antibiotic therapy can reduce a patient's commensal bacterial population and raise their risk of developing subsequent illnesses, where gut microbiota dysbiosis may be a key factor.MethodsIn this study, we analyzed the 16S rRNA of fecal samples from both healthy people and patients with sepsis to determine if alterations in gut bacteria are associated with sepsis. Then, we developed a mouse model of sepsis using cecal ligation and puncture (CLP) in order to examine the effects of fecal microbiota transplantation (FMT) and short-chain fatty acids (SCFAs) on survival rate, systemic inflammatory response, gut microbiota, and mucosal barrier function.ResultsSepsis patients' gut microbiota composition significantly differed from that of healthy people. At the phylum level, the amount of Proteobacteria in the intestinal flora of sepsis patients was much larger than that of the control group, whereas the number of Firmicutes was significantly lower. Mice with gut microbiota disorders (ANC group) were found to have an elevated risk of death, inflammation, and organ failure as compared to CLP mice. However, all of these could be reversed by FMT and SCFAs. FMT and SCFAs could regulate the abundance of bacteria such as Firmicutes, Proteobacteria, Escherichia Shigella, and Lactobacillus, restoring them to levels comparable to those of healthy mice. In addition, they increased the expression of the Occludin protein in the colon of mice with sepsis, downregulated the expression of the NLRP3 and GSDMD-N proteins, and reduced the release of the inflammatory factors IL-1β and IL-18 to inhibit cell pyroptosis, ultimately playing a protective role in sepsis.DisccusionFMT and SCFAs provide a microbe-related survival benefit in a mouse model of sepsis, suggesting that they may be a viable treatment for sepsis.

Project description:BACKGROUND:Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment. METHODS:The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1?), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1? and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy. RESULTS:CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1?. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway. CONCLUSION:These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.

Dataset Information

Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.

Aims

Methods

Results

Conclusion

Publications

Fecal microbiota transplantation and short-chain fatty acids protected against cognitive dysfunction in a rat model of chronic cerebral hypoperfusion.

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