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.

Exposure to broad-spectrum antibiotics, particularly to third-generation cephalosporins (3GC), increases the risk of colonization by extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E). While clinical risk factors for ESBL-E acquisition are well established, the role of the gut microbiome and resistome remains unclear. We conducted a prospective study of patients with suspected bacterial infections receiving ceftriaxone to identify microbiome and resistome features associated with ESBL-E acquisition. Rectal samples collected before antibiotic administration, during treatment, and 30 d after initiation were analyzed by shotgun metagenomic sequencing. Among 80 patients, 12 (15%) acquired ESBL-E colonization by day 30. Ceftriaxone exposure induced a profound and sustained reduction in microbial richness and diversity across all patients. However, no specific taxonomic signature predicted subsequent ESBL-E colonization. In contrast, patients who did not acquire ESBL-E displayed a significantly richer and more diverse repertoire of β-lactamase-encoding genes at baseline, which was independently associated with protection against colonization. Moreover, patients exposed to multiple antibiotics experienced greater and more sustained microbiome disruption compared with those receiving ceftriaxone alone. These findings provide the first real-world evidence that pre-existing β-lactamasome diversity may confer ecological protection against antibiotic-driven colonization by ESBL-E in infected patients, highlighting the importance of functional resistome diversity over taxonomic composition in colonization resistance.

Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD). Mycobacterium avium, which causes Johne's disease in ruminants, has been suggested as a potential CD trigger due to shared pathology, but early epithelial responses remain unclear. This study established a mouse small intestinal organoid (mSIO) model of M. avium infection to assess CD-related inflammation. Infected mSIOs were examined by confocal microscopy, block-face scanning electron microscopy, and macrophage co-culture to track bacterial localization and immune cell behavior. The data give unprecedent dynamic and super high resolution insights in the responses of gut cells to mycobacterial infection. RNA-seq with GSEA revealed strong induction of inflammatory genes and enrichment of pro-inflammatory pathways. Comparative analysis with CD-humanized mouse data showed overlapping gene expression and enrichment of the IBD signaling pathway. Notably, Mmp7, which can be linked to epithelial remodeling and inflammation, was a common marker in both models. This study presents a robust mSIO model of M. avium infection that recapitulates features of CD-associated inflammation both with high-resolution imaging and transcriptomics and identifies Mmp7 as a potential molecular link between infection and CD-like pathology.

Ankylosing spondylitis (AS) is strongly associated with the human leukocyte antigen B27 (HLA-B27), yet how this genetic risk factor interacts with the gut microbiome remains unclear. We integrated fecal gut microbiota analysis, untargeted metabolomics, and clinical phenotyping in 88 participants, including HLA-B27-positive patients with AS (n = 28), HLA-B27-positive healthy controls (n = 30), and HLA-B27-negative healthy controls (n = 30). HLA-B27 positivity, particularly in AS, was associated with marked alterations in gut microbial composition and metabolic profiles, with forty bacterial species showing progressive disease-related shifts across cohorts. Integrated pathway and metabolomic analyses identified three amino acid-related pathways consistently disrupted in AS: tryptophan metabolism, cysteine metabolism, and pyruvate-centered biosynthesis of branched-chain amino acids, ornithine, and lysine. Correlation network analyses linking differential taxa, metabolites, and clinical indices revealed previously unrecognized microbial and metabolic signatures that robustly distinguished AS from both control groups. To explore causality, fecal microbiota transplantation (FMT) from clinical donors into antibiotic-treated mice recapitulated key disease-relevant features, including impaired intestinal barrier function, systemic inflammation, trabecular bone loss, and polarization of macrophages toward a proinflammatory M1 phenotype. Mechanistic validation identified cinnabarinic acid as a critical microbial-derived metabolite that suppresses M1 macrophage polarization via activation of the aryl hydrocarbon receptor (AhR) pathway and confers protection in the FMT model. Together, these findings support a model in which HLA-B27-associated gut dysbiosis and metabolic reprogramming promote AS pathogenesis through macrophage-mediated inflammation and osteocatabolic signaling, highlighting microbial-metabolic pathways as potential therapeutic targets.

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.

Aging is frequently accompanied by inflammaging-a chronic, low-grade inflammatory state that contributes to functional decline and disease risk. Disruption of the intestinal barrier is increasingly being recognized as a key driver of inflammaging; however, its relationship with the gut microbiota in older adults remains poorly understood. Here, we demonstrate a significant association of intestinal barrier dysfunction markers with systemic inflammatory markers using a cross-sectional study in this population. Notably, the genus Parabacteroides showed a strong negative association with barrier dysfunction. In vitro assays showed that three Parabacteroides lineages predominant in older adults, including P. merdae, enhanced the intestinal barrier integrity in a viability-dependent manner. Fecal sialic acid (Neu5Ac) levels were positively correlated with the abundance of Parabacteroides. Mediation analysis further indicated that Parabacteroides significantly mediated the association between fecal sialic acid and intestinal barrier markers. Culture experiments showed that both sialic acid and mucin, which is rich in terminal sialyl residues, promoted Parabacteroides growth. Transcriptomic analysis of P. merdae cultured with sialic acid revealed upregulation of genes for sialidases, transporters, and enzymes, consistent with sialic acid catabolism and transport, suggesting utilization of mucin-derived sialic acid. Together, these findings indicate that in older adults, Parabacteroides is linked to the intestinal barrier integrity and responds to mucin-associated sialic acid, supporting a model wherein host-derived glycans foster barrier-protective microbes to promote healthy aging. The study findings provide avenues for devising strategies for maintaining the intestinal barrier integrity and reducing age-related inflammation, which may ultimately contribute to the prevention of inflammaging.

Graft-versus-host disease (GvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation and occurs when T cells from the donor graft target recipient-derived antigen on host tissue. The involvement of the gastrointestinal (GI) tract drives morbidity and mortality-not coincidentally, the GI tract also harbors the most complex and abundant human microbial reservoir. In this review, we first revisit how the microbiota initiates, propagates, and protects against GvHD in the context of both innate and adaptive immunity. Historically, the impact of the microbiota on GvHD has been ascribed primarily to the activation of innate immunity, setting the stage for donor alloreactivity. Although established models of GvHD focus on donor-host genetic disparity as the principal driver of donor T-cell activation, commensal microbes in the GI tract, whose collective gene content exceeds that of the human genome by more than two orders of magnitude, constitutes an immense and poorly understood source of potential T-cell antigens. We next discuss the evolution of therapeutic approaches aimed at modifying the microbiota to improve GvHD outcomes, incorporating over 40 clinical studies spanning the last 40 years, from broad decontamination strategies to pre/probiotic approaches and targeted ecosystem replacement, including fecal microbiota transplantation.