Gut Microbes最新文献

Commensal bacteria have been a centerpiece for understanding interkingdom impacts on viral replication. Multiple groups have investigated the roles commensal bacteria played in regulating enteric virus infection and it has been found that the mechanisms through which this regulation occurs varies between the viruses and bacteria explored. For noroviruses, commensal bacteria enhance or suppress viral infection in a region-dependent manner. Recently, it was found that the extracellular vesicles (EVs) produced by commensal bacteria can suppress norovirus infection. In this study, we used murine norovirus (MNV) to probe the immunological mechanisms induced by bacterial EVs. Global analysis of gene expression pointed to induction of cytosolic DNA pathways; thus, we evaluate the DNA content packaged within the bacterial EVs and DNA-sensing pathways that activate type I interferons (IFN), including STING and TLR9. Our results showed that loss of sting or tlr9, significantly decreased IFNβ production and recovered MNV replication in the presence of bEVs. Collectively, these data demonstrated bEVs of certain gram-negative bacteria can initiate antiviral DNA-mediated type I IFN production pathways and that these pathways are involved in the suppression of MNV replication. These findings expose novel mechanisms through which the native microbiota aids the host in controlling an enteric viral infection and offers a fresh perspective on interkingdom host‒microbiota interactions.

Maternal prenatal stress confers elevated neuropsychiatric risk to offspring, yet the mechanisms underlying fetal neurodevelopmental impairment remain elusive. The gut microbiota has emerged as a key regulator of brain development and behavior. However, the mechanisms mediating the interactions between the microbiota and the developing brain are still poorly understood. Here, utilizing a prenatal stress mouse model integrated with multi-omics approaches, comprehensive behavioral assays, and molecular validations, we demonstrate that prenatal stress not only induces maternal gut microbiota dysbiosis during pregnancy but also, more critically, leads to fetal blood‒brain barrier (BBB) developmental defects and subsequent abnormalities in emotional behavior and cognitive function in adult offspring. Maternal probiotic supplementation during gestation can reverse both gut microbial dysbiosis and fetal BBB dysfunction. Notably, transcriptomic analysis reveals that the maternal gut microbiota modulates interferon-β (IFN-β) signaling along the placenta‒fetal brain axis under stress. Furthermore, metabolomic profiling suggests that prenatal stress exposure profoundly influences the maternal fecal and serum metabolome. In conclusion, our findings establish a placenta‒brain axis wherein maternal microbial signals orchestrate fetal neurovascular development, identifying microbiota-targeted interventions as a neuroprotective strategy.

Background & objective: Responses to dietary interventions may vary depending on baseline gut microbiota composition. This study aimed to determine whether baseline gut microbiota diversity and composition predict the effectiveness of childhood obesity interventions.

Methods: Anthropometry, triglycerides, HDL-cholesterol, HOMA-IR, and systolic and diastolic blood pressure (SBP, DBP) were evaluated and standardised in 41 children with obesity (8-14yrs). Faecal samples were collected at baseline and after one year. Intervention success was defined by improvements in metabolic risk score (MetScore) or BMI z-score. Associations between baseline microbiota features (diversity and composition) and intervention success were evaluated using Spearman's correlation and linear regression models. Gut microbiota composition and differential abundance were analyzed using ANCOM-BC2. Exploratory biomarker discovery was analyzed using LEfSe, and predictive modelling using a Random Forest (RF) classifier. Receiver operating characteristic (ROC) curve analysis was used to determine a Simpson index cut-off.

Results: Higher baseline Shannon and Simpson indices, and greater abundances of Faecalibacterium and Eubacterium coprostanoligenes group, were associated with greater improvements in MetScore. Faecalibacterium was the most influential feature with the highest importance in the RF model, which achieved an AUC of 0.876 for MetScore and 0.873 for BMI z-score improvement. Eighty-four features differed between MetScore response groups (FDR < 0.05) with some genus-level overlap with the exploratory analysis, including Eubacterium coprostanoligenes and Ruminococcus. A Simpson index cut-off of 0.849 stratified participants high- and low-diversity groups; children above this threshold exhibited greater improvements in MetScore (p = 0.028), SBP (p = 0.043), and in HDL-cholesterol (p = 0.028).

Conclusion: Higher baseline gut microbiota diversity and specific microbial signatures, particularly Faecalibacterium abundance, predicted better outcomes in childhood obesity interventions. These findings support the potential use of microbiota profiling to guide personalised treatment strategies. Further research is needed to optimise interventions.Trial registration: clinicaltrials.gov NCT03749291.

Alterations in the gut microbiota, known as gut dysbiosis, are associated with inflammatory bowel disease (IBD). There is a need for model systems that can recapitulate the IBD gut microbiome to better understand the mechanistic impact of differences in microbiota composition and its functional consequences in a controlled laboratory setting. To this end, we introduced fecal samples from patients with Crohn's disease (CD) and ulcerative colitis (UC), as well as from healthy control subjects, to miniature bioreactor arrays (MBRAs) and analyzed the microbial communities over time. We then performed two functional assessments. First, we evaluated the colitogenic potential of the CD microbiotas in genetically susceptible germ-free IL-10-deficient mice and found that colitogenic capacity was preserved in a bioreactor-cultivated CD microbiota. Second, we tested impaired colonization resistance against Clostridioides difficile in UC microbiotas using the MBRA system and found that UC microbiotas were innately susceptible to C. difficile colonization while healthy microbiotas were resistant, consistent with what is seen clinically. Overall, our results demonstrate that IBD microbiotas perform comparably to healthy donor microbiotas in the MBRA system, successfully recapitulating microbial structure while preserving IBD-specific functional characteristics. These findings establish a foundation for further mechanistic research into the IBD microbiota using MBRAs.

Background: Premature ovarian insufficiency (POI) significantly impairs female fertility and poses substantial health risks; however, its pathogenesis is incompletely understood, and effective therapeutic interventions are limited. Although gut bacteriome has been closely associated with ovarian dysfunction, the role and therapeutic potential of gut viruses, which far outnumber bacteria, remain largely unexplored.

Results: Therefore, we recruited 60 healthy reproductive-aged women and recently diagnosed POI patients and investigated these concerns using various techniques, including whole-genome shotgun sequencing of virus-like particle (VLP) and fecal virome transplantation (FVT) in CTX-induced POI rats. We found considerable interindividual variability in the gut virome. The virome of POI patients exhibited significant dysbiosis, characterized by a marked reduction in virulent phage, significant changes in predominant phages, and a notable increase in horizontal gene transfer of resistance genes and virulence factors. Furthermore, gut VLPs from the healthy reproductive-aged women significantly improved the condition of POI rats. Conversely, gut VLPs from POI patients markedly impaired the ovarian function and reproductive capacity of healthy rats. The above regulatory effect is primarily due to modulations of gut bacteriome, specifically the estrobolome, and intestinal barrier integrity, which subsequently affect hypothalamic-pituitary-ovarian axis hormone levels and regulate ovarian oxidative stress and inflammation, thereby influencing ovarian function.

Conclusions: Our findings demonstrate the critical roles of the gut virome in regulating ovarian function and provide new insights into the pathogenesis of POI. This study also underscores the therapeutic potential of the gut virome in improving ovarian dysfunction and female infertility including POI.

Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease; however, current therapeutic options such as statins are limited by issues including hepatotoxicity and patient intolerance. Probiotics and their metabolites show promise in modulating cholesterol metabolism through the gut‒liver axis, yet the specific commensal bacteria and molecular mechanisms underlying these effects remain poorly understood. In this study, we isolated and characterized EPS-D1, a novel exopolysaccharide (15.003 kDa) derived from Lactiplantibacillus plantarum H6, which is composed primarily of mannose (46.10%) and glucose (33.98%) and features a highly branched structure (branching degree of 29.5%). The administration of EPS-D1 significantly reduced the serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) by 40.31%, 37.55%, and 43.15%, respectively, in high-cholesterol diet (HCD) mice. Additionally, it improved hepatic steatosis and reduced markers of liver injury. Through 16S rRNA sequencing and fecal microbiota transplantation (FMT), we identified Muribaculum as the key commensal bacterium enriched by EPS-D1. Direct administration of Muribaculum (Muribaculum intestinale) replicated the cholesterol-lowering effects, decreasing ileal and fecal cholesterol levels by 74.79% and 53.16%, respectively. Mechanistically, both EPS-D1 and M. intestinale activated the enterohepatic FXR‒FGF15 axis, which resulted in the upregulation of hepatic cholesterol 7α-hydroxylase (CYP7A1) expression and the downregulation of ileal ASBT and NPC1L1, thereby promoting bile acid synthesis and inhibiting cholesterol absorption. Furthermore, M. intestinale increased intestinal short-chain fatty acids (SCFAs), particularly acetic acid and caproic acid, by 37.88% while also modulating the composition of the bile acid pool. These findings establish M. intestinale as a precise microbial target for cholesterol management and demonstrate that EPS-D1 from L. plantarum H6 enhances cholesterol metabolism through microbiota-mediated activation of the enterohepatic FXR‒FGF15 axis, providing a novel therapeutic strategy for managing hypercholesterolemia.

Attaching effacing (A/E) bacteria, such as enteropathogenic Escherichia coli (EPEC) and Citrobacter rodentium colonize intestinal epithelial cells (IECs) by inducing remodeling of the epithelial cytoskeleton and the formation of prominent actin pedestals at bacterial attachment sites. While non-muscle myosin II (NM II) is a key regulator of the actin cytoskeleton, whether it regulates IEC colonization by A/E pathogens is not known. To address this question, we targeted NM IIA and NM IIC, the NM II paralogs expressed in IECs. Our in vivo studies utilized mouse models with either intestinal epithelial-specific deletion of NM IIA (NM IIA cKO mice), expression of a NM IIA motor domain mutant, or total deletion of NM IIC (NM IIC tKO mice). In vitro experiments utilized IECs (HT-29cF8 and Caco-2BBE) with CRISPR-Cas9-mediated deletion of NM IIA or NM IIC. In addition, NM II activity in vitro was modulated pharmacologically, using either the pan-myosin inhibitor, blebbistatin, or a specific NM IIC activator, 4-hydroxyacetophenone (4-HAP). NM IIA cKO and NM IIA mutant mice demonstrated higher C. rodentium colonization, along with more severe mucosal inflammation and colonic crypt hyperplasia as compared to their controls. By contrast, NM IIC tKO mice was indistinguishable from their control with regard to C. rodentium colonization. Blebbistatin treatment increased EPEC attachment to IECs monolayers, whereas 4-HAP did not affect bacterial attachment. Genetic knockout of NM IIA, but not NM IIC, increased EPEC adhesion to IEC monolayers. Importantly, the increase in EPEC attachment exhibited by NM IIA-deficient IECs required an intact bacterial Type 3 secretion system and functional Tir effector, indicating that NM IIA functions in actin pedestal assembly. In summary, we describe a novel role for NM IIA in limiting intestinal epithelial colonization by A/E pathogens via the inhibition of pathogen-induced remodeling of the actin cytoskeleton.

The mechanisms by which gut microbiota modulate host immune responses remain incompletely understood. Here, we screened Lactobacillus and Bifidobacterium strains isolated from healthy individuals to identify symbionts capable of suppressing gut inflammation. Among them, Bifidobacterium adolescentis (Bifi-94) induced IL-10 production in mononuclear cells in vitro. Oral administration of Bifi-94 to mice treated with dextran sulfate sodium attenuated weight loss and reduced colonic inflammation scores. In wild-type C57BL/6 mice, Bifi-94 increased IL-10 levels in colonic tissue homogenates without altering the frequency of regulatory T cells. Instead, CD19⁺CD11b⁺ regulatory B (Breg) cells emerged as the primary source of IL-10, with their numbers significantly increasing in the peritoneal cavity (PEC) after treatment. IL-10 secretion by PEC cells was robustly activated by live, heat-killed, and formalin-fixed Bifi-94. Bifi-94-derived peptidoglycan (PG) selectively stimulated IL-10 production in CD19⁺CD11b⁺ Breg cells, and multi-omics analyses showed that Bifi-94 exhibits increased expression of PG biosynthetic enzymes (MurE, MurD, Alr, UppP) relative to the type strain. Mechanistically, Bifi-94-derived PG promoted TLR2-dependent activation of ERK and p38 MAPK signaling in Breg cells. Notably, PG similarly enhanced IL-10 production in CD19⁺ B cells from human colonic tissue. These findings demonstrate that Bifi-94-derived PG promotes IL-10 production in Breg cells via TLR2-mediated signaling, thereby contributing to the attenuation of gut inflammation.

Mycobacterial lung diseases, including tuberculosis (TB) and nontuberculous mycobacterial pulmonary disease (NTM-PD), are increasingly recognized as disorders influenced not only by host immunity but also by microbiota. Emerging evidence identifies the gut-lung axis (GLA) as a key bidirectional communication network linking intestinal and pulmonary homeostasis. Mycobacterial infection itself induces airway and gut dysbiosis through immune and metabolic disturbances, which is further exacerbated by prolonged antibiotic therapy. Dysbiosis within either site reciprocally affects the other via GLA, leading to reduced microbial diversity, impaired epithelial integrity, and systemic inflammation. These alterations disrupt metabolite-mediated immunoregulation and attenuate IL-22-driven epithelial defense, thereby weakening bacterial clearance and promoting chronic inflammation. Distinct microbial features, such as the depletion of beneficial SCFA-producing taxa and enrichment of pro-inflammatory anaerobes, are observed in both TB and NTM-PD. Moreover, therapy-induced microbiome remodeling influences treatment response and disease relapse. Restoring microbial balance through probiotics, prebiotics, postbiotics, dietary modulation, or fecal microbiota transplantation offers a promising adjunctive strategy. This review integrates current evidence linking microbiome dysbiosis to mycobacterial pathogenesis and highlights microbiome-targeted interventions as an emerging therapeutic frontier in pulmonary mycobacterial diseases.