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Oral, Ultra-long-acting GLP-1-based Therapy
with Enhanced Patient Compliance via Gut Probiotic
· In 2022, 1 in 8 people in the world were living with obesity.
· Worldwide adult obesity has more
than doubled since 1990.
· The rise is particularly rapid in low-
and middle-income countries.
The global situation regarding
obesity and diabetes is severe.
Glucagon-like
peptide-1 (GLP-1)
is a hormone secreted by the intestines.
Its main functions include:
by engineering
the probiotic bacterium
Escherichia coli Nissle 1917
Dual-input signals induce efficient synthesis and secretion of GLP-1
Stability modification is performed on GLP-1 to extend its in vivo circulation time
A suicide switch is designed to ensure biosafety
Hydrogel is used as a carrier to achieve targeted delivery and controlled release
The AAF sensing module consists of two main genetic circuits:
1. An AND-gate sensing circuit：Spatiotemporal regulation of GLP-1 synthesis via activation of both PCA induction AND successful intestinal colonization.
2. An Amplification & Feedback circuit: Amplifying the AND-gate signal to combat enzymatic and transmembrane losses of GLP-1 in the gut, while dynamically adjusting output to host diet for optimal bacterial fitness.
To address the short plasma half-life (~2 minutes) of native GLP-1(7-36), we employed a combined computational and experimental strategy. Our workflow leveraged molecular docking and dynamics simulations to guide the rational design of the GLP-1Z variant and select optimal sites for non-canonical amino acid incorporation, followed by experimental validation of stability and activity.
We have constructed a dual-input OR-gate suicide circuit that responds to both active arabinose administration and passive temperature sensing. Through precision repressor tuning and promoter engineering, the system enables programmable control of bacterial survival by leveraging the tightly regulated CcdB/CcdA toxin–antitoxin system.
Our hardware platform features a hydrogel-based strategy for viable probiotic intestinal delivery and enhanced gut colonization, coupled with an in vitro turbidostat that simulates in vivo gut microbiota population dynamics to bridge experimental and physiological conditions, facilitating the overall development of oral bacterial agents.