Haonan Zheng

Despite advancements in interventional coronary reperfusion technologies following myocardial infarction, a notable portion of patients continue to experience elevated mortality rates as a result of myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury is crucial for devising strategies to minimize myocardial damage and enhance patient survival. Here, it is discovered that during MI/R, double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal accumulates, accompanied by high rates of myocardial ferroptosis. The specific deletion of cgas or Sting in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis and I/R injury. Conversely, activation of STING exacerbates ferroptosis and I/R injury. Mechanistically, STING directly targets glutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes and lysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking the STING-GPX4 interaction through mutations in T267 of STING or N146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4 administration alleviates ferroptosis induced by STING, resulting in enhanced cardiac functional recovery from MI/R injury. Additionally, the inhibition of STING by H-151 stabilizes GPX4 to reverse GPX4-induced ferroptosis and alleviate MI/R injury. Collectively, a novel autophagy-dependent ferroptosis mechanism is identified in this study. Specifically, STING autophagy induced by anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseases associated with I/R.

SCOPE: The gut microbiota plays a prominent role in gut-brain interactions and gut dysbiosis is involved in neuroinflammation. However, specific probiotics targeting neuroinflammation need to be explored. In this study, the antineuroinflammatory effect of the potential probiotic Roseburia hominis (R. hominis) and its underlying mechanisms is investigated. METHODS AND RESULTS: First, germ-free (GF) rats are orally treated with R. hominis. Microglial activation, proinflammatory cytokines, levels of short-chain fatty acids, depressive behaviors, and visceral sensitivity are assessed. Second, GF rats are treated with propionate or butyrate, and microglial activation, proinflammatory cytokines, histone deacetylase 1 (HDAC1), and histone H3 acetyl K9 (Ac-H3K9) are analyzed. The results show that R. hominis administration inhibits microglial activation, reduces the levels of IL-1α, INF-γ, and MCP-1 in the brain, and alleviates depressive behaviors and visceral hypersensitivity in GF rats. Moreover, the serum levels of propionate and butyrate are increased significantly in the R. hominis-treated group. Propionate or butyrate treatment reduces microglial activation, the levels of proinflammatory cytokines and HDAC1, and promotes the expression of Ac-H3K9 in the brain. CONCLUSION: These findings suggest that R. hominis alleviates neuroinflammation by producing propionate and butyrate, which serve as HDAC inhibitors. This study provides a potential psychoprobiotic to reduce neuroinflammation.

Abnormal brain-gut interaction is considered the core pathological mechanism behind the disorders of gut-brain interaction (DGBI), in which the intestinal microbiota plays an important role. Microglia are the "sentinels" of the central nervous system (CNS), which participate in tissue damage caused by traumatic brain injury, resist central infection and participate in neurogenesis, and are involved in the occurrence of various neurological diseases. With in-depth research on DGBI, we could find an interaction between the intestinal microbiota and microglia and that they are jointly involved in the occurrence of DGBI, especially in individuals with comorbidities of mental disorders, such as irritable bowel syndrome (IBS). This bidirectional regulation of microbiota and microglia provides a new direction for the treatment of DGBI. In this review, we focus on the role and underlying mechanism of the interaction between gut microbiota and microglia in DGBI, especially IBS, and the corresponding clinical application prospects and highlight its potential to treat DGBI in individuals with psychiatric comorbidities.

Abstract Maternal health, specifically changes in the gut microbiota, can profoundly impact offspring health; however, our understanding of how gut microbiota alterations during the preconception period influence the offspring remains limited. In this study, we investigated the impact and mechanisms of preconception maternal gut dysbiosis on the development of the enteric nervous system (ENS) in mice. We found that preconception maternal exposure to antibiotics led to the abnormal development of the ENS in offspring, increasing their susceptibility to water avoidance stress at the adult stage. Metagenomic, targeted metabolomic, and transcriptomic analyses revealed that preconception antibiotic exposure disrupted the expression of genes crucial for embryonic ENS development by altering maternal gut microbiota composition. Multi‐omics analysis combined with Limosilactobacillus reuteri and propionate gestational supplementation demonstrated that the maternal gut microbiota and metabolites may influence embryonic ENS development via the GPR41–GDNF/RET/SOX10 signaling pathway. Our findings highlight the critical importance of maintaining a healthy maternal gut microbiota before conception to support normal ENS development in offspring.

playing a crucial role.