AI Insight
Researchers engineered a probiotic E. coli strain to detect stress hormones like norepinephrine and epinephrine by incorporating a two-component sensing system from pathogenic bacteria. They optimized this system through promoter redesign and identified specific amino acid residues critical for hormone recognition, then demonstrated its functionality by coupling hormone detection to the production of a therapeutic peptide that blocks stress signaling. This work shows that bacterial sensors for host stress hormones can be systematically reprogrammed to produce controllable biological outputs.
Why it matters
This technology could enable the development of "smart" probiotics that respond to physiological stress by delivering therapeutics directly in the gut, potentially treating stress-related gastrointestinal disorders or mental health conditions through the gut-brain axis. The engineering principles established here provide a foundation for creating programmable microbiome-based diagnostics and therapies.
Understand the Science
by Santosh Kumar Srivastava, Guo Wei Foo, Haosheng Shen, Yuanzhi He, Kwok Soon Wun, In Young Hwang, Michael S. Goodson, Nikhil Aggarwal, Matthew Wook Chang
Host stress is associated with elevated catecholamine neurohormones that influence gut physiology and host–microbe interactions, yet how bacterial systems detect and interpret these signals remains incompletely understood. Enteric pathogens exploit inter-kingdom adrenergic signaling to sense host-derived norepinephrine and epinephrine, but whether such pathways can be rationally rewired to produce predictable, programmable outputs has not been systematically explored. Here, we reconstitute adrenergic signaling in Escherichia coli Nissle 1917 by repurposing the enterohemorrhagic E. coli QseBC two-component system. Transcriptomic profiling revealed robust catecholamine-dependent activation of QseBC-regulated pathways in the engineered strain. Guided by these data, we redesigned a QseBC-responsive promoter through rational truncation, sigma-factor replacement, and optimization of QseBC expression, generating a synthetic promoter with enhanced sensitivity and dose-dependent responsiveness to stress hormones. Structure-guided mutagenesis of the QseC sensor kinase identified key residues required for catecholamine recognition, providing mechanistic insight into adrenergic hormone sensing. To demonstrate functional signal transduction beyond transcriptional reporting, we coupled the sensing module to a secretion cassette encoding a corticotropin-releasing factor (CRF) receptor antagonist as a model bioactive output and validated bioactivity in vitro. Together, this work elucidates principles governing bacterial stress hormone sensing and demonstrates how inter-kingdom signaling pathways can be engineered to yield programmable biological outputs.