Gut Microbes最新文献

Background: Antibiotics are not recommended to treat influenza A virus (IAV). However, antibiotic misuse for IAV persists worldwide. How to scientifically use antibiotics for IAV-infected patients remains a considerable challenge.

Results: Here, we investigated the impact of antibiotics on viral pathogenicity, pulmonary-intestinal antiviral immunity, and antiviral drug efficacy. Our findings indicated that antibiotic intervention exacerbated IAV-caused mortality and lung injury in mice, manifested as increased mortality rates, shortened survival time, aggravated pulmonary injury, and excessive inflammatory responses. Furthermore, antibiotic pretreatment significantly diminished the efficacy of antivirals. Metagenomic sequencing revealed that antibiotics reduced the diversity and abundance of beneficial gut microbiota, including Lactobacillus and Bifidobacterium, while promoting the proliferation of pathogenic bacteria such as Klebsiella pneumoniae and Escherichia coli. Mechanistically, antibiotic intervention exacerbated IAV-caused excessive inflammatory responses by the blockage of pulmonary-intestinal antiviral immune pathways, which were caused by the upregulation of PKR, RIG-I, ISG15, and TRIM25 levels while downregulating IPS-1 mRNA levels. However, it is noteworthy that the combination of antibiotics and antiviral drugs effectively offset the adverse effects of antibiotic pretreatment on influenza mortality by upregulating IPS-1 levels and partially restoring pulmonary-intestinal immune homeostasis.

Conclusions: Pulmonary-intestinal immune homeostasis imbalance caused by antibiotic misuse can not only markedly exacerbate the lethality of IAV, but also significantly attenuate the efficacy of antiviral drugs. A mechanistic study confirmed that gut microbes dysbiosis caused by antibiotic pretreatment exacerbates the homeostasis imbalance of host antiviral immunity by blocking the RIG/MDA5/IPS-1 antiviral signaling pathway. However, combination therapy with antibiotics and antivirals effectively reversed the fatal outcome exacerbated by antibiotic pretreatment. Collectively, our findings not only provide a scientific explanation from the perspective of antiviral immunity as to why antibiotics should not be arbitrarily used to treat viral infections but also lay the scientific foundation for the rational clinical use of antivirals and antibiotics for treating influenza.

Tamoxifen (TAM) is a widely used estrogen receptor modulator for breast cancer treatment. However, TAM exhibits significant hepatotoxicity in the clinic, affecting nearly 50% of patients and thereby limiting its clinical utility. The specific mechanisms underlying TAM-induced liver injury remain poorly understood. In this study, we elucidated the mechanistic role of the gut microbiota in the hepatotoxicity associated with TAM. TAM administration induced substantial liver injury and gut microbiota dysbiosis in mice, characterized by an increased abundance of Escherichia and a reduction in Lachnospiraceae NK4A136 group. These microbial shifts resulted in decreased levels of total fecal bile acids (BA), particularly hyodeoxycholic acid (HDCA), which was inversely correlated with TAM-induced liver injury. Additionally, TAM disrupted BA homeostasis by enhancing intestinal Farnesoid X receptor (FXR) activity and concurrently stimulating hepatic BA synthesis through an alternative nonintestinal FXR mechanism. Notably, gut microbiota depletion reversed these effects, demonstrating the critical role of the microbiota in modulating the gut‒liver FXR axis in TAM-induced liver injury. Fecal microbiota transplantation (FMT) further confirmed that TAM directly stimulated hepatic BA synthesis through a microbiota-dependent mechanism. The disruption of the gut‒liver BA‒FXR axis impaired enterohepatic BA circulation, contributing to the liver toxicity associated with TAM administration. Importantly, HDCA supplementation restored the gut‒liver BA‒FXR axis and alleviated TAM-induced liver injury. These findings highlight the intricate relationship between TAM, gut microbiota, and BA metabolism, suggesting that targeting the gut-liver FXR axis with HDCA may serve as a promising therapeutic strategy for alleviating TAM-associated liver injury.

Species of the genus Blautia are commonly found in the human gut and are known to be beneficial for the human well-being. However, only little is known about the physiology and the specific role of Blautia species in the human gut. In this study, we investigated the heterotrophic metabolism of the formate dehydrogenase lacking gut acetogen Blautia luti. We identified acetate, succinate, lactate, formate, and hydrogen as end products of sugar fermentation. Interestingly, formate is produced by the pyruvate-formate lyase reaction and used as electron acceptor in the Wood-Ljungdahl pathway of CO₂ fixation. Thus, formate connects the oxidative branch of glucose metabolism with the reductive branch. The use of formate as an intraspecies electron carrier seems to be common in gut acetogens. This study highlights the role of formate as electron carrier in the gut microbiome and improves our understanding of the physiology of Blautia species in the human gut. It also introduces B. luti as potential candidate for biotechnological applications due to the production of highly desired succinate.

Colonization resistance is a fundamental host defense mechanism that relies on the synergistic interaction between the gut microbiota and the host immune system to prevent enteric pathogen colonization and infection. This review synthesizes current knowledge of the multifaceted mechanisms governing colonization resistance against intestinal pathogens. We examine how commensal microbes directly suppress pathogens through niche and nutrient competition, contact-dependent inhibition, and the production of antimicrobial compounds and metabolites. From the host perspective, we outline the essential roles of gut barriers, innate and adaptive immunity, and antimicrobial peptides in maintaining microbiota homeostasis while selectively restricting pathogen expansion. We also emphasize the role of IL-22 signaling and its regulation of epithelial glycosylation, which modulates nutrient availability and shapes microbial competitiveness. Finally, we discuss key challenges and future research directions in colonization resistance and related translational research, with the goal of informing novel strategies to prevent and treat intestinal infections and inflammatory diseases.