mSphere最新文献

Studies on human gut microbiota have recently highlighted a significant decline in bacterial diversity associated with urbanization, driven by shifts toward processed diets, increased antibiotic usage, and improved sanitation practices. This phenomenon has been largely overlooked in the Colombian Amazon, despite rapid urbanization in the region. In this study, we investigate the composition of gut bacterial microbiota and intestinal protozoa and soil-transmitted helminths (STHs) in both urban and rural areas of Leticia, located in the southern Colombian Amazon. Despite their geographic proximity, the urban population is predominantly non-indigenous, while indigenous communities mostly inhabit the rural area, resulting in notable lifestyle differences between the two settings. Our analyses reveal a reduction in bacterial families linked to non-processed diets, such as Lachnospiraceae, Spirochaetaceae, and Succinivibrionaceae, in the urban environment compared to their rural counterparts. Prevotellaceae, typically associated with non-processed food consumption, shows a significantly higher abundance in urban Leticia. STH infections were primarily detected in rural Leticia, while intestinal protozoa were ubiquitous in both rural and urban areas. Both types of parasites were associated with higher gut bacterial richness and diversity. Additionally, microbial metabolic prediction analysis indicated differences in pathways related to unsaturated fatty acid production and aerobic respiration between rural and urban bacterial microbiomes. This suggests a tendency toward changes in the urban microbiota that may lead to increased susceptibility to non-communicable chronic diseases. These findings provide new insights into the impact of urbanization on gut microbiota dynamics in the Amazonian context and underscore the need for further research into any associated health outcomes.IMPORTANCEChanges in the diversity and composition of gut microbiota in urban populations have been linked to the rise of non-communicable chronic diseases, such as autoimmune conditions, diabetes, and cancer. As developing countries undergo a demographic shift toward increased urbanization, accompanied by changes in diet, housing, and medication use, there is a concerning loss of microbial diversity. Therefore, it is essential to investigate microbiota changes in overlooked populations, such as indigenous communities in the Colombian Amazon basin. A better understanding of local and generalizable changes in gut microbial composition through urbanization may facilitate the development of targeted programs aimed at promoting lifestyle and diet changes to prevent diseases that healthcare systems may be ill-equipped to effectively address.

Tomato is a staple crop and an excellent model to study host-microbiota interactions in the plant food chain. In this study, we describe a "lab-in-the-field" approach to investigate the microbiota of field-grown tomato plants. High-throughput amplicon sequencing revealed a three-microhabitat partition, phyllosphere, rhizosphere, and root interior, differentiating host-associated communities from the environmental microbiota. An individual bacterium, classified as Acinetobacter sp., emerged as a dominant member of the microbiota at the plant-soil continuum. To gain insights into the functional significance of this enrichment, we subjected rhizosphere specimens to shotgun metagenomics. Similar to the amplicon sequencing survey, a "microhabitat effect," defined by a set of rhizosphere-enriched functions, was identified. Mobilization of mineral nutrients, as well as adaptation to salinity and polymicrobial communities, including antimicrobial resistance genes (ARGs), emerged as a functional requirement sustaining metagenomic diversification. A metagenome-assembled genome representative of Acinetobacter calcoaceticus was retrieved, and metagenomic reads associated with this species identified a functional specialization for plant-growth promotion traits, such as phosphate solubilization, siderophore production, and reactive oxygen species detoxification, which were similarly represented in a tomato genotype-independent fashion. Our results revealed that the enrichment of a beneficial bacterium capable of alleviating plant abiotic stresses appears decoupled from ARGs facilitating microbiota persistence at the root-soil interface.IMPORTANCETomatoes are at center stage in global food security due to their high nutritional value, widespread cultivation, and versatility. Tomatoes provide essential vitamins and minerals, contribute to diverse diets, and support farmer livelihoods, making them a cornerstone of sustainable food systems. Beyond direct dietary benefits, the intricate relationship between tomatoes, their associated microbiota, and antimicrobial resistance gene (ARG) is increasingly recognized. Tomato plants host diverse microbial communities in association with their organs, which influence plant health and productivity. Crop management impacts the composition and function of these communities, contributing to the prevalence of ARGs in the soil and on the plants themselves. These genes can potentially transfer to human pathogens, posing a food safety and public health risk. Understanding these complex interactions is critical for developing sustainable agricultural practices capable of mitigating the impact of climatic modifications and the global threat of antimicrobial resistance.

Human milk oligosaccharide (HMO)-degrading Bifidobacterium species are key early colonizers of the gut and influence gut and immune maturation. Loss of these taxa, particularly Bifidobacterium infantis, in many industrialized populations has raised concern. O'Brien et al. showed that supplementation with B. infantis EVC001 in exclusively breastfed U.S. infants aged 2-4 months leads to rapid and abundant colonization that persists 1 month after supplementation, demonstrating effective colonization beyond the neonatal period (C. E. O'Brien, S. A. Frese, K. Cernioglo, K. Damian-Medina, et al., mSphere e00518-25, 2025, https://doi.org/10.1128/msphere.00518-25). These findings align with observational cohort data showing that B. infantis can overcome priority effects and dominate the gut microbiome in breastfed infants by 2-3 months of age. Key questions remain regarding colonization in mixed- or formula-fed infants, the HMO thresholds required to sustain dominance during milk- and complementary feeding, and the critical developmental windows of B. infantis colonization for beneficial immune effects. Ongoing clinical trials with B. infantis will further clarify its role in disease prevention.

Halogenated phenazine (HP) compounds have shown promise as antimicrobial agents, particularly against biofilm-associated Gram-positive pathogens. Among these compounds, HP-29 demonstrates potent activity against methicillin-resistant Staphylococcus aureus by inducing rapid iron starvation. As maintenance of trace metals homeostasis is critical for the survival of Streptococcus mutans, this study investigated the antimicrobial efficacy of HP-29 and the impact of metal supplementation on this major oral and occasional systemic pathogen. As anticipated, HP-29 inhibited S. mutans growth in a dose-dependent manner, with iron supplementation alleviating the antimicrobial effect. Cobalt, manganese, or nickel supplementation also mitigated the inhibitory activity of HP-29, but, unexpectedly, the addition of zinc greatly enhanced HP-29 antimicrobial activity. This zinc-driven potentiation of HP-29 extended to other Gram-positive pathogens, including Enterococcus faecalis and S. aureus. Inductively coupled plasma mass spectrometry analysis revealed that intracellular iron content decreased significantly following exposure to HP-29. When combined with zinc, HP-29 triggered a 5-fold increase in intracellular zinc and reduced manganese levels by ~50%. Transcriptome analysis showed that HP-29 treatment, with or without zinc, altered expression of genes linked to iron and manganese uptake as well as zinc efflux, suggesting broad disruption of metal ion regulation. These findings highlight HP-29 as a potent antimicrobial that broadly impairs metal homeostasis. The unexpected synergy of HP-29 with zinc points toward a promising dual-agent therapeutic strategy against Gram-positive pathogens.IMPORTANCEWidespread development of antibiotic resistance has created a constantly moving target when combating infectious microbes. Here, we further explore an antimicrobial halogenated phenazine, HP-29, which is effective against Gram-positive bacteria through disruption of intracellular trace metal equilibrium. We showed that HP-29 inhibits growth of the oral and systemic pathogen Streptococcus mutans and that its antimicrobial effect is greatly potentiated by the addition of zinc. The zinc-mediated enhancement of HP-29's efficacy was also observed in other Gram-positive pathogens, including Enterococcus faecalis and Staphylococcus aureus. Intracellular trace metal quantifications and transcriptome analysis confirmed that HP-29 treatment impairs trace metal homeostasis, an outcome that is exacerbated when S. mutans is treated with both HP-29 and zinc. The observed synergy of HP-29 with zinc supports the development of a dual-agent therapeutic strategy against Gram-positive pathogens.

Candida albicans is a fungal commensal and also a prevalent pathogen of humans. p24 proteins are a family of type I membrane proteins regarded as cargo receptors for endoplasmic reticulum (ER) to Golgi transport and are thought to be involved in regulating secretion. Here, we sought to explore the impact of this family of proteins on C. albicans pathogenicity. The expression of all four members of the p24 family is upregulated during invasive candidiasis. Their expression is independent of yeast-to-hypha transition but is highly induced by tissue culture conditions. We then generated single deletion mutants for each member of the p24 family for phenotypic characterization. All these mutants exhibit significantly attenuated virulence in a mouse model of systemic infection and reduced survival in macrophages but are dispensable for vegetative growth and morphogenesis. They also show lower abundance of chitin and phosphomannan in the cell wall and enhanced sensitivity to fluconazole, an azole antifungal drug. Importantly, the absence of p24 proteins leads to defective protein secretion in C. albicans, including pathogenicity-related effectors and lipases, and reduces commensal fitness. These results suggest that p24 proteins are critical for cell wall integrity, secretion of virulence factors, and virulence in C. albicans.IMPORTANCECandida albicans is an important opportunistic fungal pathogen of immunocompromised individuals and a top-ranking WHO fungal priority pathogen due to the high frequency and mortality of invasive candidiasis. The eukaryotic p24 family of proteins has long been known to be key regulators of protein trafficking along the secretory pathway, but their potential roles regarding pathogenesis in C. albicans remain unknown. Here, we discover that all members of the p24 family are required for cell wall integrity, proper secretion of virulence factors, survival in macrophages, and virulence in a systemic infection model. However, they are dispensable for vegetative growth and yeast-to-hypha transition, the best-known virulence attribute. Our study systematically investigates C. albicans p24 proteins and highlights the critical role that the early secretory pathway plays in fungal pathogenicity.

To evaluate the association between respiratory tract microorganisms at birth and the subsequent development and severity of bronchopulmonary dysplasia (BPD) in preterm infants. This prospective cohort study enrolled 98 preterm infants (gestational age < 32 weeks, birth weight < 2,000 g). Tracheal aspirate samples were collected through endotracheal intubation within 2 h after birth. Using 16S rRNA sequencing, we characterized the airway microbiome and performed co-occurrence network analysis with compositionally robust methods. Among 98 preterm infants analyzed, the incidence of BPD was 68.4%, comprising 31 grade I, 20 grade II, and 16 grade III cases. Airway microbiota in infants with BPD exhibited distinct severity-stage patterns: Escherichia-Shigella and Streptococcus were significantly enriched in grade I, while Chryseobacterium increased markedly in grade III, accompanied by a significant reduction in Streptococcus. Microbial co-occurrence network analysis yielded three key insights. (i) Network complexity declined sharply with BPD severity, being sparsest in grade III. (ii) Distinct keystone taxa were identified across different groups: Acinetobacter and Fusobacterium in the non-BPD group; Brevundimonas and Fusobacterium in grade I; Fusobacterium and Acinetobacter at grade II and grade III. (iii) In a multivariable model adjusted for key clinical confounders, a higher microbial network density at birth was independently associated with a substantially reduced risk (OR = 0.12, P < 0.05). The ecological architecture of the neonatal airway microbiome at birth, defined by network complexity and keystone taxa, is associated with BPD severity. This highlights microbial network stability as a novel factor and ecological interactions as a target for future research.

Importance: Bronchopulmonary dysplasia (BPD) remains the most common chronic lung disease in preterm infants. While its pathogenesis is incompletely understood, the role of the early respiratory microbe is increasingly recognized. Previous studies have largely focused on individual pathogenic taxa, overlooking the complex ecological interactions within microbial communities. Our analysis reveals that the architecture of microbial co-occurrence networks in the neonatal airway varies significantly with BPD severity. Notably, network complexity decreased markedly as BPD severity increased. We identified specific keystone taxa uniquely associated with disease outcomes, suggesting that microbial ecosystem stability rather than individual species may be a critical factor in BPD pathogenesis. These findings shift the focus from single microbes to the stability of the microbial ecosystem as a novel risk factor for severe BPD, offering new avenues for risk stratification and early intervention.

The study of the human microbiome (mirroring broader practice across biomedical science) has historically defaulted to the use of simplified, socially constructed "boxes," such as racial and ethnic labels, that fail to accurately capture human variation and fundamentally misdirect the search for mechanisms to explain differences in health outcomes. Five years ago, I proposed a "frameshift," a fundamental conceptual shift away from relying on these categories and toward a more nuanced, careful approach to the complexity of human variation. Moving "out of the box" means tackling the difficult but essential work of analyzing microbial variation through a systems lens, connecting large-scale ecosocial drivers to individual mechanisms and outcomes. In this Full Circle review, I discuss rapid progress in the field toward this new framework and argue that by adopting transdisciplinary methods, we can generate more accurate, actionable, and equitable solutions for human health.

Patients with chronic kidney disease (CKD) frequently experience constipation, often linked to gut microbiota disruptions. We hypothesized that constipation is not merely a comorbidity but a driver of adverse outcomes through a specific host-microbial metabolic axis. Employing a multi-cohort design for evidence triangulation, we first employed a large U.S. database and mortality data up to 31 December 2019 to investigate the association between constipation and overall mortality in patients with CKD using weighted Cox proportional hazards models. To explore potential microbial and metabolic mechanisms that could underlie such clinical observations, we then used genetic data from the independent FINRISK cohort to investigate causal relationships between specific gut microbiota, their metabolites, and CKD. In the observational cohort, we identified functional constipation as a potent, independent predictor of both all-cause (HR: 1.33; 95% CI: 1.11-1.58) and cardiovascular mortality. This association remained robust across sensitivity analyses and showed a distinct U-shaped dose-response relationship with stool frequency. In the causal inference phase, while the direct causal effect of constipation on CKD was not significant, MR identified a significant causal depletion of the genus Herbidospora driven by constipation. Further analyses revealed that Herbidospora exerts a protective effect against CKD. Crucially, mediation analysis demonstrated that phosphatidylcholine (14:0_18:2) [PC 14:0_18:2] metabolites mediate 12.5% of the protective pathway from Herbidospora to CKD. Constipation is a key and independent predictor of mortality in patients with CKD. We found that constipation leads to a reduction in the number of Herbidospora, thereby disrupting the protective function of the kidney. This is because PC (14:0_18:2) is lacking. This study emphasizes the importance of restoring this microbial metabolic axis as a novel therapeutic strategy for CKD.IMPORTANCEFor millions living with chronic kidney disease (CKD), a common issue such as constipation can be a hidden danger, increasing their mortality risk by over one-third. Our research uncovers why: an unhealthy gut, often indicated by constipation, lacks specific "good"" bacteria essential for producing a protective fat molecule. This natural molecule acts as a key, activating the kidney's own defense and repair systems. This discovery of a "gut-lipid-kidney" connection offers a groundbreaking new strategy: therapies aimed at restoring gut health and supplementing this key protective fat could provide a powerful new way to slow disease progression and improve survival in CKD patients.

Cryptococcus neoformans, the etiological agent of cryptococcal meningitis (CM) is a globally distributed environmental yeast that mainly causes infections in immunocompromised individuals. Particularly in low-resource countries, the mortality rate of CM can reach 81% and accounts for ~19% of HIV/AIDS-related deaths each year. In immunocompromised individuals, once inhaled, C. neoformans escapes from the lungs and disseminates with special predilection for the central nervous system (CNS). Once in the brain, C. neoformans interacts with microglia, the tissue-resident macrophages of the CNS. Previous studies indirectly showed that microglia are ineffective at controlling this fungal infection. The mechanisms underlying this fungal survival and proliferation within the CNS, however, remain unclear. In this study, we use and validate the C20 immortalized human microglia cell line to study cryptococcal-microglia interactions. We show that microglia have limited phagocytic activity that is specific to C. neoformans and partly dependent on cryptococcal antiphagocytic proteins that alter cell size and cell wall structure. We also show that human microglia respond to cryptococcal strains differently than peripheral macrophages. Further, we show that human microglia are ineffective at killing phagocytosed C. neoformans, and that this could be due to the ability of this yeast to disrupt phagosome maturation and induce phagosome membrane damage in these cells. These findings provide us with fundamental knowledge regarding cryptococcal pathogenesis in the CNS, specifically the insight into how C. neoformans is recognized by microglia under different conditions and demonstrate the usefulness of C20 cells to further study how this yeast survives and replicates within the CNS environment.

Importance: While Cryptococcus neoformans is acquired through inhalation, the fatal pathology of cryptococcal infection occurs when the yeast disseminates to the central nervous system (CNS) and causes cryptococcal meningitis. Microglia are the first immune cells that C. neoformans will encounter once it reaches the CNS, and they are the largest population of macrophages in the brain. While microglia are professional phagocytes, they are unable to control C. neoformans infection. The mechanisms behind uncontrolled growth of C. neoformans within the CNS remain understudied, partly due to incomplete knowledge regarding microglia-cryptococcal interactions. This study provides fundamental knowledge into these interactions and establishes a powerful model to specifically study how C. neoformans is recognized by microglia and how cryptococcal phagosomes mature in these phagocytes. This work opens new avenues of research to further our understanding of cryptococcal-host interactions, which can be leveraged to develop more effective therapeutics for cryptococcal meningitis.