Programmable bacterial biosensors for gut metabolites monitoring – SENSIGUT

SensiGut: Programmable bacterial biosensors for gut metabolites monitoring.

Increasing evidence describes how gut microbiota influences human physiology. The emerging picture suggests that the interplay between the human genome and the microbiome is continuously regulating metabolic pathways and host response, which can influence the pathogenesis of chronic inflammatory diseases. Inflammatory bowel disease (IBD) has recently emerged as a public health challenge worldwide. The imbalance of key microbiome-derived metabolites is implicated in the pathogenesis of IBD. Routine monitoring of these IBD metabolite signatures in patients' samples might improve their temporal mapping for predicting disease course. However, current metabolomics techniques are impractical and expensive for daily routine monitoring. Therefore, new methods are needed to support fast, field-deployable, and cost-effective monitoring of metabolites in clinical samples.

Here I aim to develop programmable whole-cell biosensors detecting metabolic biomarkers of IBD in clinical samples. Living cells perform parallel processing of various environmental signals and self-replicate, and are thus an attractive option to engineer affordable sensing devices. Here, I will develop an optimized bacterial biosensor chassis for operation in fecal samples and deliver a collection of reliable biosensors for IBD metabolite signatures. By applying my expertise: in synthetic biology, metabolic engineering, logic devices, and multicellular systems, I will deliver biosensors performing multiplexing logic for multiple and expanded metabolite detection in fecal samples. Their suitability to perform metabolic profiling will be evaluated in a clinical context using human samples from an established biobank in collaboration with Celine Deraison at IRSD, Toulouse, and clinicians at CHU Montpellier. The biosensor’s reliability will be tested by comparing the endogenous metabolites detected with metabolic analysis. This work will provide a solid tool for large-scale and daily metabolite monitoring in human samples, supporting new strategies for disease flares prevention and treatment. Ultimately, these sensors could be used by the patients themselves.

These biosensors could support a wide number of epidemiological studies, such as in different populations, and ethnic groups for which differences in microbiota composition have been described. This strategy will have a valuable impact on IBD disease monitoring as well as on synthetic biology, microbiome research, epidemiology, and health-focused fields in the social sciences. These biosensors could be then re-applied to other pathologies, providing new, field-deployable metabolite monitoring and contributing to a deeper understanding of the complex chemical cross-talk between the gut microbiota and humans, relevant for many diseases. In the future, these biosensors will support the engineering of therapeutic bacteria designed to sense and respond to these metabolites and reduce inflammation in situ.