The human microbiome constitutes a complex multikingdom community that symbiotically interacts with the host across multiple body sites. Host-microbiome interactions impact multiple physiological processes and a variety of multifactorial disease conditions. In the past decade, microbiome communities have been suggested to influence the development, progression, metastasis formation, and treatment response of multiple cancer types. While causal evidence of microbial impacts on cancer biology is only beginning to be unraveled, enhanced molecular understanding of such cancer-modulating interactions and impacts on cancer treatment are considered of major scientific importance and clinical relevance. In this review, we describe the molecular pathogenic mechanisms shared throughout microbial niches that contribute to the initiation and progression of cancer. We highlight advances, limitations, challenges, and prospects in understanding how the microbiome may causally impact cancer and its treatment responsiveness, and how microorganisms or their secreted bioactive metabolites may be potentially harnessed and targeted as precision cancer therapeutics.
Background At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders. Methods To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants). Results In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. Conclusion In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.
We have developed a carbon-based, fast-response potentiometric pH microsensor for use as a scanning electrochemical microscopy (SECM) chemical probe to quantitatively map the microbial metabolic exchange between two bacterial species, commensal Streptococcus gordonii and pathogenic Streptococcus mutans. The 25-μm diameter H+ ion-selective microelectrode or pH microprobe showed a Nernstian slope of 59 mV/pH and high selectivity against major ions such Na+, K+, Ca2+ and Mg2+. In addition, the unique conductive membrane composition aided us in performing an amperometric approach curve to position the probe and obtain a high-resolution pH map of the microenvironment produced by the lactate-producing S. mutans biofilm. The x-directional pH scan over S. mutans also showed the influence of the pH profile on the metabolic activity of another species, H2O2-producing S. gordonii. When these bacterial species were placed in close spatial proximity, we observed an initial increase in the local H2O2 concentration of approximately 12±5 μM above S. gordonii, followed by a gradual decrease in H2O2 concentration (>30 min) to almost zero as lactate was produced, and a subsequent decrease in pH with a more pronounced metabolic output of S. mutans. These results were supported by gene expression and confocal fluorescence microscopic studies. Our findings illustrate that H2O2-producing S. gordonii is dominant while the buffering capacity of saliva is valid (~pH 6.0) but is gradually taken over by S. mutans as the latter species slowly starts decreasing the local pH to 5.0 or less by producing lactic acid. Our observations demonstrate the unique capability of our SECM chemical probes for studying real-time metabolic interactions between two bacterial species, which would not otherwise be achievable in traditional assays.
Pyruvate oxidase (SpxB)-dependent HO production is under the control of carbon catabolite protein A (CcpA) in the oral species and Interestingly, both species react differently to the presence of the preferred carbohydrate source glucose. CcpA-dependent regulation of follows classical carbon catabolite repression. Conversely, expression in is not influenced by glucose but is repressed by CcpA. Here, we constructed strains expressing the heterologous versions of CcpA or the promoter region to learn if the distinct regulation of expression is transferable from to and vice versa. While cross-species binding of CcpA to the promoter is conserved, we were unable to swap the species-specific regulation. This suggests that a regulatory mechanism upstream of CcpA most likely is responsible for the observed difference in expression. Moreover, the overall ecological significance of differential regulation in the presence of various glucose concentrations was tested with additional oral streptococcus isolates and demonstrated that carbohydrate-dependent and carbohydrate-independent mechanisms exist to control expression of in the oral biofilm. Overall, our data demonstrate the unexpected finding that metabolic pathways between two closely related oral streptococcal species can be regulated differently despite an exceptionally high DNA sequence identity. Polymicrobial diseases are the result of interactions among the residential microbes, which can lead to a dysbiotic community. and are considered commensal species that are present in the healthy dental biofilm. Both species are able to produce significant amounts of HO via the enzymatic action of the pyruvate oxidase SpxB. HO is able to inhibit species associated with oral diseases. SpxB and its gene-regulatory elements present in both species are highly conserved. Nonetheless, a differential response to the presence of glucose was observed. Here, we investigate the mechanisms that lead to this differential response. Detailed knowledge of the regulatory mechanisms will aid in a better understanding of oral disease development and how to prevent dysbiosis.
Commensal and are pioneer oral biofilm colonizers. Characteristic for both is the SpxB-dependent production of HO, which is crucial for inhibiting competing biofilm members, especially the cariogenic species HO production is strongly affected by environmental conditions, but few mechanisms are known. Dental plaque pH is one of the key parameters dictating dental plaque ecology and ultimately oral health status. Therefore, the objective of the current study was to characterize the effects of environmental pH on HO production by and HO production was not found to be affected by moderate changes in environmental pH, whereas HO production declined markedly in response to lower pH. Further investigation into the pyruvate node, the central metabolic switch modulating HO or lactic acid production, revealed increased lactic acid levels for at pH 6. The bias for lactic acid production at pH 6 resulted in concomitant improvement in the survival of at low pH and seems to constitute part of the acid tolerance response of Differential responses to pH similarly affect other oral streptococcal species, suggesting that the observed results are part of a larger phenomenon linking environmental pH, central metabolism, and the capacity to produce antagonistic amounts of HO Oral biofilms are subject to frequent and dramatic changes in pH. and can compete with caries- and periodontitis-associated pathogens by generating HO Therefore, it is crucial to understand how and adapt to low pH and maintain their competitiveness under acid stress. The present study provides evidence that certain oral bacteria respond to environmental pH changes by tuning their metabolic output in favor of lactic acid production, to increase their acid survival, while others maintain their HO production at a constant level. The differential control of HO production provides important insights into the role of environmental conditions for growth competition of the oral flora.
The overall health of the oral cavity is dependent on proper homeostasis between health-associated bacterial colonizers and bacteria known to promote dental caries. is a health-associated commensal organism, a known early colonizer of the acquired tooth pellicle, and is naturally competent. We have shown that LytF, a competence-controlled murein hydrolase, is capable of inducing the release of extracellular DNA (eDNA) from oral bacteria. Precipitated LytF and purified LytF were used as treatments against planktonic cultures and biofilms. Larger amounts of eDNA were released from cultures treated with protein samples containing LytF. Additionally, LytF could affect biofilm formation and cellular morphology. Biofilm formation was significantly decreased in the-complemented strain, in which increased amounts of LytF are present. The same strain also exhibited cell morphology defects in both planktonic cultures and biofilms. Furthermore, the LytF cell morphology phenotype was reproducible in wild-type cells using purified LytF protein. In sum, our findings demonstrate that LytF can induce the release of eDNA from oral bacteria, and they suggest that, without proper regulation of LytF, cells display morphological abnormalities that contribute to biofilm malformation. In the context of the oral biofilm, LytF may play important roles as part of the competence and biofilm development programs, as well as increasing the availability of eDNA., a commensal organism in the oral cavity and one of the pioneer colonizers of the tooth surface, is associated with the overall health of the oral environment. Our laboratory showed previously that, under aerobic conditions, can produce HO to inhibit the growth of bacterial species that promote dental caries. This production of HO by also induces the release of eDNA, which is essential for proper biofilm formation. Under anaerobic conditions, does not produce HO but DNA is still released. Determining how releases DNA is thus essential to understand biofilm formation in the oral cavity.
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