Gut Microbes最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the United States, yet therapeutic options remain limited. Emerging evidence implicates the gut‒liver axis and intestinal permeability in disease pathogenesis. Previous studies in animal models and human cell culture indicated that bile salt hydrolases (BSHs), which are gut bacterial enzymes that deconjugate host-derived bile acids, damage intestinal barrier integrity and cause liver damage through the generation of unconjugated bile acids (UBAs). However, the relevance of these findings to MASLD patients is unknown. Here, we demonstrate that BSH activity is elevated in fecal samples from MASLD patients with advanced liver fibrosis and correlates with reduced fecal bile acid levels, which is consistent with a proposed model of increased intestinal permeability during MASLD progression. Through anaerobic culturing and activity-guided screening, we identify diverse BSH-active bacteria from patient fecal samples, suggesting broad microbial contributions to bile acid deconjugation in MASLD patients. Importantly, small-molecule BSH inhibitors suppressed BSH activity in both fecal communities and monocultures from MASLD patients without affecting bacterial viability. These findings indicate that BSH activity is a microbial function associated with MASLD progression and suggest that BSH inhibitors could be developed as a microbiome-targeted strategy for MASLD treatment.

Perfluorooctane sulfonate (PFOS), a persistent environmental pollutant, is associated with cognitive dysfunction through mechanisms involving neuroinflammation, oxidative stress, and metabolic disruption. Icaritin, a bioactive flavonoid with antioxidant and anti-inflammatory properties, exhibits therapeutic potential, though its efficacy against PFOS-induced cognitive impairment remains unexplored. Herein, a mouse model of PFOS-induced cognitive dysfunction was established and treated with oral ICT. Integrated 16S rRNA sequencing and untargeted metabolomics revealed that ICT restored gut microbial homeostasis by enriching beneficial genera (e.g. Akkermansia, Lactobacillus) and reducing ammonia-producing bacteria (e.g. Proteus, Helicobacter, Escherichia), thereby improving gut barrier integrity. Metabolomic profiling identified significant perturbations in ammonia-related pathways, particularly arginine and proline metabolism, underscoring ammonia dysmetabolism as a pivotal mediator of PFOS neurotoxicity. These modifications attenuated systemic and cerebral ammonia accumulation, mitigated neuroinflammation and oxidative stress, and ultimately improved cognitive function. Our findings elucidate ammonia dysmetabolism as a central mechanism in PFOS-induced cognitive decline and highlight the microbiota-gut-brain axis as a promising therapeutic target. This study provides a mechanistic foundation for targeting microbial and metabolic pathways in environmental neurotoxicity.

Metabolic and immune development in neonates are shaped by the succession of the gut microbiome. Maternal obesity can perturb this process by altering interactions of human milk bioactive elements, including oligosaccharides (HMOs), microbial populations, and metabolites. We conducted a longitudinal study of Mexican mother-infant dyads to examine maternal BMI-associated variations in HMOs and infant fecal microbiota. Breastmilk samples from 97 mothers were collected at 48 h, one month, and three months postpartum. We used targeted and untargeted metabolomics to profile breastmilk samples, while shotgun metagenomics was used to analyze infant fecal microbiome composition in a subset of samples. Mothers with obesity showed decreased concentration of key HMOs shortly after birth, correlating with an altered succession of their infant's gut microbiota. This included reduced early colonizers (Enterobacteriaceae) and increased abundance of intermediate and late colonizers (Bifidobacterium and members of the Lachnospiraceae family), over subsequent months. These taxa negatively correlated with HMOs such as 6'SL, LNnT, and LNT. Additionally, functional profiling revealed alterations in metabolic pathways related to polyamine biosynthesis, suggesting changes in microbial metabolism linked to maternal BMI. Despite the cohort's size, our study offers unique insights into the relationship between maternal obesity, HMO composition, and early infant microbial colonization in Latin-American mothers. This exploratory research serves as proof of concept, underscoring the need for larger-scale studies to validate these findings and better understand their implications for infant health. More importantly, our results highlight the interplay between maternal BMI and human milk bioactives, underscoring the importance of correlating microbial succession with maternal metabolic health to better understand early immune development in neonates.

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.

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.

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.

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.