Deciphering host-oral microbiome interactions and mechanisms for prevention of dysbiosis and antimicrobial resistance

宿主-微生物组相互作用在决定健康和疾病状态中起关键作用。通过破译宿主和微生物群中复杂的信号，我们将推进维持健康和预防生态失调的知识。微生物组对宿主健康的重要性导致了新的治疗方法的出现，这些方法集中在对宿主微生物组的规定操作上，通过减少有害类群或恢复缺失的有益类群及其发挥的功能作用。丰富多样的微生物群对宿主生物是必要的，因为它有助于重要生理过程的顺利发育和运作。我们将重点关注口腔微生物群及其维持口腔粘膜屏障的作用。减少生物体的全身易位和随后的感染对全身健康的破坏。这在免疫系统受损的个体中尤其成问题，强调了了解工作中的潜在生物学机制的重要性。口腔由附着在被称为生物膜的表面上的微生物组成。这些都是高度调节的，与有机体之间复杂的相互依赖关系，以适应更广泛环境的变化。这些生物膜对健康至关重要，具有多种功能，例如有助于维持粘膜屏障，防止促病物种的入侵。共培养允许研究细胞-细胞相互作用，更接近地模拟复杂的组织结构（如人类细胞-生物膜）。许多研究正在推进对微生物组作为治疗剂的作用及其对人类健康的重要性的认识。目的：WP1：促进目前对口腔微生物组在健康和生态失调中的分类和功能概况的了解，并筛选口腔微生物组所携带的AMR基因。了解微生物组在人类健康中的作用依赖于详细的特征。微生物组的组成是复杂的，由高度多样化的群落组成，其中许多微生物尚未培养。我们将使用我们之前的数据集（宏基因组和元转录组），并辅以公开可用的数据（包括相关的宿主细胞数据）来总结在健康人群和龋齿、牙龈炎和牙周炎患者口腔微生物组中观察到的分类、功能和抵抗组谱。WP2：构建和表征口腔上皮细胞共培养生物膜。使用我们已经建立的方法，我们将收集健康志愿者的口腔生物膜样本，并将其与口腔上皮细胞系共培养。为了建立一种典型的龋齿、牙龈炎或牙周炎的生态失调状态，我们将在诱发疾病的培养基中培养样品。我们将测量确定的治疗策略的效果，以恢复生态失调/恢复健康的微生物谱。这为探索GSK产品提供了潜力，例如口腔保健产品的活性成分或其他益生菌或抗生素。微生物生物膜和治疗剂对人类上皮细胞系基因表达的影响将被监测，以了解从微生物组转移观察到的免疫反应变化。我们将与格拉斯哥的同事密切合作，帮助解释转录组学工作中的人类细胞表达数据。目的：设计用于口腔健康和预防生态失调的硅管道模型。通过调查细胞-微生物相互作用从WP2中产生的数据将产生高度相关的信息，这些信息与WP1中收集的数据相补充，将有助于使用机器学习方法设计强大的计算机口腔健康和疾病建模和预测。我们的目标是开发的工具提供一种快速筛选方法，可以在未来用于全面筛选大量化合物，药物和代谢物，以确定有前途的药物

Host-microbiome interactions play a key role in determining health and disease status. By deciphering the intricate signals within host and microbiome profiles we will advance knowledge for maintaining health and preventing dysbiosis. The significance of the microbiome on host health has led to the emergence of new therapeutic approaches focused on the prescribed manipulation of the host microbiome, either by decreasing harmful taxa or reinstating missing beneficial taxa and the functional roles they perform.A rich and diverse microbiome is necessary for host organisms, as it contributes to the smooth development and functioning of important physiological processes. We will focus on the oral microbiota and its role maintaining the oral mucosal barrier. Reducing the portals for systemic translocation of organisms and disruption to systemic health from ensuing infections. This is particularly problematic in individuals whose immune system is compromised, highlighting the importance of understanding the underlying biological mechanisms at work.The oral cavity comprises microbes that attach to surfaces in communities called biofilms. These are highly regulated with complex interdependency of organisms that adapt to changes in the wider environment. These biofilms are essential to health with multiple functions e.g. contributing to the maintenance of mucosa barrier that prevents invasion of disease-promoting species. Co-cultures allow for the study of cell-cell interactions that more closely mimic complex tissue structures (e.g. human cells-biofilm). Many studies are advancing understanding of the role of the microbiome as a therapeutic agent and its significance in human health.Aims:WP1:To advance current understanding of the taxonomic and functional profiles of the oral microbiome in health and in dysbiosis, and screen for AMR genes harboured by the oral microbiome.Understanding the role of the microbiome in human health relies on detailed characterisation. The microbiome composition is complex, comprised of highly diverse communities with many micro-organisms not yet culturable. We will use our previous dataset (both metagenomic and meta-transcriptomic), supplemented with publicly available data (including associated host cell data) to summarise the taxonomical, functional and resistome profiles observed in oral microbiomes in health and in caries, gingivitis and periodontitis.WP2:To construct and characterise co-cultured biofilms with oral epithelia cells.1. Using our established methods, we will collect oral biofilm samples from healthy volunteers and incubate them in co-culture with an oral epithelial cell line. To establish a dysbiosis state, typical of either caries, gingivitis or periodontitis we will incubate samples in the presence of disease-inducing media.2. We will measure the effect of defined therapeutic strategies to revert dysbiosis/ restore healthy microbial profiles. This offers potential to explore GSK products e.g. active components of oral health products or other pre/probiotics, or antibiotics.3. The effect of the microbial biofilms and therapeutic agents on human epithelial cell line gene expression will be monitored to understand the immune response changes observed from shifting microbiomes. We will work closely with our Glasgow colleagues, to help interpret human cell expression data from transcriptomic work.WP3:To design in silico pipelines for oral health and prevention of dysbiosis modelling.Data generated from WP2 from surveying cell-microbe interactions will produce highly relevant information, which supplemented with those gathered in WP1 will help the design of robust in-silico oral health and disease modelling and predictions using a machine learning approach. We aim for the developed tool to provide a rapid screening methodology that can be used in the future to comprehensively screen for large panels of compounds, drugs, and metabolites to identify the promising ones for