Synthetic Biology and the Gut Microbiome

Abstract

The gut microbiome plays a crucial role in maintaining human health. Functions performed by gastrointestinal microbes range from regulating metabolism to modulating immune and nervous system development. Scientists have attempted to exploit this importance through the development of engineered probiotics that are capable of producing and delivering small molecule therapeutics within the gut. However, existing synthetic probiotics are simplistic and fail to replicate the complexity and adaptability of native homeostatic mechanisms. In this review, the ways in which the tools and approaches of synthetic biology have been applied to improve the efficacy of therapeutic probiotics, and the ways in which they might be applied in the future is discussed. Simple devices, such as a bistable switches and integrase memory arrays, have been successfully implemented in the mammalian gut, and models for targeted delivery in this environment have also been developed. In the future, it will be necessary to introduce concepts such as logic-gating and biocontainment mechanisms into synthetic probiotics, as well as to expand the collection of relevant biosensors. Ideally, this will bring us closer to a reality in which engineered therapeutic microbes will be able to accurately diagnose and effectively respond to a variety of disease states.

Keywords: biosensors; engineered microbes; engineered probiotics; microbiome therapeutics.

Figure 1

Overview of the ways in which the gut microbiome influences the human body. The microbiota is known to have a profound effect on the gastrointestinal, immune, and neuroendocrine systems.

Figure 2

Synthetic biology "devices" applied in the (simulated or otherwise) environment of the mammalian gut, and expected behavior of reporter genes when tested (blue shading signifies addition of inducer). C) was conducted in mouse GI tract explants, while A) and B) were successfully tested in a living mouse model. A) An aTC-triggered variation on the lambda cI/cro bistable switch, in which one of two stable states is maintained over time unless the other state is deliberately triggered. B) A serine integrase-based memory array, consisting of multiple recognition sites which are successively inverted when integrase expression is induced through the presence of rhamnose. C) A nitric oxide-sensing recombinase-based switch which inverts a promoter when activated, switching from production of YFP to CFP.

Figure 3

Comparison of existing therapeutic probiotics with proposed future model. a) Existing therapeutic probiotics are either constitutive or respond to a single-molecule input to produce a single-molecule therapeutic. b) Ideally, in the future, we would like engineered probiotics to 1) integrate a variety of different types of information 2) diagnose a disease state based on that information 3) output a therapeutic program of multiple genes if the body is in a disease state.