Applying the design-build-test paradigm in microbiome engineering
Graphical abstract
Introduction
Recent discoveries on the roles of the human gut microbiome in health and diseases have inspired novel means for prophylactic and therapeutic intervention against disease onset and progression. The engineering of human microbiome for health benefits and related applications could be observed across many disciplines in nanotechnology, chemistry, and biology. Nanoscale instruments are being fabricated to interface with human microbiome for real-time monitoring of health status, or for on-site protection against early disease onset [1]. Chemical microbiome modifiers, such as prebiotics, probiotics, and antibiotics, have long been prescribed by doctors for disease treatment [2]. With the advent of DNA sequencing and metabolomics tools allowing data analysis at higher resolution and throughput, interests to develop biological modifiers for in situ precision engineering of the human microbiome are increasingly gaining momentum [3, 4••, 5]. Synthetic biology envisages microbiome engineering as one of the grand frontiers of precision medicine. Genetic programs have been installed into single-species microbial communities to perform diagnostic and therapeutic operations, such as regulating glucose level in the blood, or detecting liver metastasis in urine [6, 7]. Alongside these developments, there is emerging global interest to expand the said conceptual frameworks for the development of synthetic cellular consortia that could enable targeted engineering of the human microbiome and deliver the corresponding health benefits [5]. The ‘design-build-test’ (DBT) cycle is an engineering paradigm that is widely practiced among engineering disciplines for the design of experiments and the rational optimization of technology. In this review, we aim to demonstrate how the DBT cycle can be strategically applied to expedite microbiome engineering efforts. To support this proposition, we herein assess the status of human gut microbiome engineering with a focus on three key aspects: design principles to engineer the human microbiome, methods to reassemble microbiome with desired functions, and analytical techniques to examine complex microbiome samples.
Section snippets
Design
Harnessing the design principles of natural microbiome represents a pioneering step for rational microbiome engineering. In this section, we review the current knowledge on fundamental design features of natural human gut microbiome, including the composition and dynamics, biogeography, and metabolic activity (Figure 1). Examples illustrating the application of these understanding to modify microbiome are presented.
Build
Current microbiome engineering methods aim to introduce specific perturbation to cause the intentional shift and transition of the human microbiota. Subsequently, the composition and metagenome of the re-assembled microbiota could be correlated with host physiology changes to identify and augment microbial functions that contribute to specific health conditions [4••]. Ongoing efforts to engineer the microbiome can be classified as either abiotic perturbation, including drug treatment and
Test
Possessing the capability to analyze complex microbial samples in high-throughput workflows is critical in advancing current knowledge and application in microbiome engineering. In this section, we survey the status of contemporary tools for microbiome testing and analysis, particularly on cutting-edge tools for transcriptomics, metagenomics, proteomics, and metabolomics (Figure 3).
Conclusion
In this review, we describe various aspects of the human microbiome and how modifications to the composition and functionality of the microbiome can result in implications to human health. Understanding these fundamental mechanisms allow us to formulate design principles and strategies to enable rational engineering and analysis of the human microbiome at multi-species community levels. Despite the rapid advancement of human microbiome knowledge, it is critical to acknowledge that the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Synthetic Biology Initiative of the National University of Singapore (DPRT/943/09/14), the Summit Research Program of the National University Health System (NUHSRO/2016/053/SRP/05), the Ministry of Defence of Singapore (MINDEF, RE2016-074), the Singapore Ministry of Education (MOE/2014/T2/2/128), the US Air Force (AOARD, FA2386-14-1-4060) and the U.S. Defense Threat Reduction Agency (DTRA, HDTRA1-13-0037).
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These authors contributed equally to this work.