Analyze And Regulate Quorum Sensing-based Communication Systems For Microbial Communities

Quorum Sensing(QS)is a microbial cell-cell communication process,which plays an important role in the communication system of both natural and synthetic microbial communities.This study integrates methods of chemical process system engineering,metabolic engineering,bioinformatics,synthetic biology and other disciplines to analyze and regulate QS-based microbial communication for natural and synthetic microbial communities.With respect to natural microbial communities,we first studied the QS communication systems of human gut microbiota,proposed a system workflow,summarized nine QS languages,and mined new QS modules with the help of machine learning.Furthermore,we develop the Quorum Sensing of Human Gut Microbes(QSHGM)database(http://www.qshgm.lbci.net/)including 28,567 redundancy removal entries,to bridge the gap between QS repositories and human gut microbiota.With the help of QSHGM,various communication-based microbial interactions can be searched and a QS communication network(QSCN)is further constructed and analysed for 818 human gut microbes.It is one of the human gut knowledge maps to guide the QS interference(QSI),visualize the social network of gut microbiota,predict the QS interactions among different microbes,and design the synthetic microbial consortia for metabolic engineering,along with developing novel treatments for gut imbalances and disorders.To expand QSI molecules,we developed a similarity assessment algorithm based on ligand structure and a verification process based on docking calculation to mine new QSI molecules(QSIMs)from existing small molecule libraries and establish the corresponding database(http://qsidb.lbci.net/),including 633 reported QSIMs and73073 expanded QSIMs.We also evaluated their functional similarity to obtain a broader spectrum of QSI molecules as potential next generation antibiotics.Furthermore,we also developed a workflow to study the QS-based complex interactions between different drugs and microbes,and established the corresponding database(http://www.qsdmd.lbci.net/)and networks for more than 8,000 drugs,163 microbes,and 42 common diseases.We also proposed a drug-receptor-microbialdisease framework to advance understanding of personalized and precision medicine.With regard to synthetic microbial consortia,we followed the two-layer network control principle based on metabolic interaction and communication regulation of natural microbial community to design,optimize and construct the synthetic two-strain system.We first proposed that different QS control strategies(synchronized lysis circuit and metabolic toggle switch)can be integrated to regulate different strains in cocultivation dynamically,and developed a new co-culture fermentation system with both metabolic interaction and communication regulation.Taking the production of isopropanol and salidroside as case studies,we have mathematically modeled a comprehensive set of QS-regulated cocultivation schemes and constructed experimental combinations of QS devices,respectively,to evaluate their feasibility and optimality for regulating growth competition and corporative production.Results showed that the yield of salidroside could reach 1.18 g/L by shaking flask fermentation,which was more than 9 times that of the control case,and 75.97% higher than that reported by the previous research.Furthermore,we further analyzed the influence of QS crosstalk on the metabolic production of specific QS-based cocultivations,clarified the influence mechanism of the internal function and stability of two-strain system,and realized the dynamic metabolic regulation of microbial community.Note that the yield of isopropanol with QS crosstalk system can be increased by 144.75% compared with previous work.To sum up,with the help of multidisciplinary cross,starting from QS-based communication of human gut microbes,we have explored a variety of QSI active molecules,sorted out the QS-based associations between microbes and drugs,proposed the important knowledge map for gut microbiota intervention,developed a variety of potential strategies for the treatment of gut imbalance,analyzed the basic principle of two-layer network control theory,designed(and constructed)a synthetic two-strain system based on this rationality,and completed the verification of the two-strain consortia on synthetic biology level with specific metabolic productions,which has certain guiding significance for the development of synthetic ecology and wider applications of diverse microbial communities.