Gut Microbes最新文献

Chronic intestinal pseudo-obstruction (CIPO) is characterized by bowel dilation and obstructive symptoms without any structural blockage. Although the microbiota is known to affect gastrointestinal function, its role in CIPO is poorly understood. We aimed to characterize the CIPO microbiota, investigate its role in disease expression and explore the therapeutic role of fecal microbiota transplantation (FMT). CIPO patients (n = 14) and healthy controls (HC, n = 12) were recruited from Italy and Canada. Microbiota profiles and functions were assessed by 16S rRNA sequencing and PICRUSt. Germ-free NIH Swiss mice were colonized with HC and CIPO microbiota, their intestinal transit and bowel distension were assessed by videofluoroscopy and computed tomography (CT), and the expression of host genes by NanoString®. The CIPO microbiota exhibited reduced microbial diversity with dominance of Proteobacteria and altered metabolic function. Mice with CIPO microbiota developed marked bowel distension and slow intestinal transit associated with altered expression of multiple genes related to immunity, the intestinal barrier and neuromuscular function. FMT from a HC improved the microbiota profile, intestinal transit and bowel distension in both CIPO mice and a selected CIPO patient, in whom a marked clinical improvement was sustained for 8 y. Thus, our findings support the use of microbiota-directed therapies to induce clinical improvement in CIPO patients.

Emerging evidence reveals a strong connection between the gut microbiota and cancer. However, the exact role of gut microbiota dysbiosis in multiple myeloma (MM) is poorly understood, and the therapeutic potential of microbiota-targeted interventions represents a promising strategy that demands urgent mechanistic and translational investigation. First, we conducted a comprehensive microbiome-metabolite analysis between MM patients and healthy individuals. The result revealed a marked compositional difference characterized by reduced abundances of butyrate-producing bacteria and diminished butyrate levels in the MM cohort. Subsequent fecal microbiota transplantation demonstrated that the gut microbiota critically modulates MM progression, with healthy donor-derived microbiota reducing the tumor burden and concomitantly elevating serum butyrate. Furthermore, through function-based culturomics screening, Clostridium butyricum (C. butyricum) was identified as a key butyrate-producing specialist. C. butyricum or its metabolite butyrate significantly reduced the systemic tumor burden in 5TGM1 mice. Notably, C. butyricum and butyrate alleviated bone marrow inflammation and osteolytic lesions by suppressing Th17 cells and IL-17 levels in the bone marrow. Moreover, cellular assays and transcriptome sequencing further revealed that butyrate could induce MM cells' apoptosis via HDAC inhibition-mediated upregulation of PPARγ, leading to sequential suppression of the PI3K/AKT pathway and antiapoptotic BCL-2 expression. This apoptotic signaling cascade was reversed by PPARγ antagonism. The direct antitumor effect was further confirmed in M-NSG mice. Our research systematically verifies the specific role of the gut microbiota in MM and provides the first evidence of the immune and molecular mechanisms by which C. butyricum alleviates MM progression, offering preclinical support for probiotic-based therapies against MM.

Objective: This study investigates whether live Akkermansia muciniphila Muc^T supplementation can counteract obesity and metabolic dysfunctions induced by a high-fat diet (HFD) by modulating intestinal mucus production, secretion and composition.

Design: C57BL/6J mice were fed an HFD with or without live A. muciniphila Muc^T (2 × 10⁸ CFU per day) supplementation or a control diet for 6 weeks. Body weight, fat mass gain and metabolic markers were measured. Intestinal mucus characteristics were assessed via gene expression analysis of mucins and analysed mucin glycosylation by tandem mass spectrometry (MS/MS).

Results: Mice receiving live A. muciniphila Muc^T exhibited reduced body weight gain and fat mass accumulation compared to HFD controls, without changes in muscle mass. A. muciniphila improved gut barrier integrity by increasing antimicrobial peptide expression in the jejunum and in the colon of HFD-fed mice. Furthermore, live A. muciniphila Muc^T influenced markers of goblet cell differentiation and restored the expression of mucin markers altered by HFD. Specifically, live A. muciniphila Muc^T counteracted HFD-induced mucin 3 (Muc3) expression depletion in the colon. Although the overall mucus thickness was not affected by live A. muciniphila Muc^T, the bacteria significantly modulated mucin glycans composition. Live A. muciniphila Muc^T did not change the gut microbiota composition.

Conclusion: These findings highlight the protective effects of live A. muciniphila Muc^T against diet-induced metabolic dysfunctions by modulating adiposity, mucus layer composition, and glycan profiles. This reinforces its potential as a therapeutic strategy for metabolic disorders associated with gut microbiota alterations.

Intestinal immune homeostasis is crucial for intestinal function and health. Increasing evidence suggests that certain gut microbiota can enhance the host's intestinal immune regulatory capacity. However, the mechanisms by which the microbiota confers beneficial traits and robust immunity to the host, as well as the cross-species reproducibility of these effects, remain unclear. This study, through multi-omics integration comparison and functional validation, revealed that Streptococcus hyointestinalis from Min pigs regulates macrophage polarization homeostasis by targeting and inhibiting the excessive activation of the STING signaling pathway and its downstream pro-inflammatory cascade reactions through its extracellular vesicles (EVs), thereby shifting them toward the M2 phenotype. This process ensures the integrity of the intestinal barrier and alleviates colitis induced by the combined effects of low temperature and sodium sulfate-induced colitis (DSS). Notably, in Sting^-/- mice, the EV-mediated intestinal protective effect was eliminated, confirming its targeted efficacy. Our data reveal a microbial EV‒STING‒macrophage axis in which symbiotic bacterial exosomes promote reparative macrophage programs by regulating STING signaling and maintaining intestinal integrity under environmental stress. These findings reveal a novel host-microbiota communication pathway with therapeutic potential for the treatment of inflammation-driven intestinal diseases.

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.