Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, affect millions of people worldwide. They’re driven by a mix of genetic and environmental factors that cause chronic inflammation in the gut.
Diagnosing IBD today typically involves endoscopies and colonoscopies. These procedures are invasive, expensive, and frequently uncomfortable. As a result, diagnosis and treatment are often delayed, especially when symptoms are vague or intermittent.
Scientists have been exploring engineered probiotics as an alternative diagnostic treatment. These live bacteria can live temporarily in the gastrointestinal (GI) tract and sense specific chemical signals linked to inflammation. However, up to now, most have relied on fluorescent, glowing, or colour-changing outputs, which have several limitations.
Fluorescent and bioluminescent signals don’t penetrate tissue well, making them hard to detect outside of the body. Colorimetric methods require stool sample analysis and lab equipment. Some systems use ingestible electronics, like wireless "smart pills", but those are bulky, expensive, and still don’t offer the necessary resolution.
Repurposing Ultrasound
Ultrasound is already widely used in hospitals to image tissues. It’s safe, relatively cheap, and capable of detecting small structures deep in the body. But so far, it hasn’t been successfully paired with probiotic biosensors.
In this study, researchers combined a clinically approved probiotic strain (E. coli Nissle 1917) with genetic circuits that sense gut inflammation and produce microscopic gas-filled protein structures called gas vesicles. These gas vesicles scatter sound waves and appear clearly on an ultrasound scan.
Their idea is simple: a patient ingests the probiotic, lets it colonise the gut temporarily, and then the abdomen is scanned the next day to check for inflammation, without requiring an endoscopy or colonoscopy.
Built To Detect Specific Biomarkers
The scientists engineered the bacteria to detect two chemical markers linked to gut inflammation: tetrathionate and thiosulfate. When they detect either molecule, they activate an "acoustic reporter" that produces gas vesicles, creating contrast on an ultrasound image.
To do this, the team used two-component systems (TCSs), biological sensing circuits from bacteria that can detect environmental cues. These systems were linked to an acoustic reporter gene (ARG) known as bARGSer, derived from the Serratia species.
Two versions of the sensor were created, thsSR-bARGSer for thiosulfate, and ttrSR-bARGSer for tetrathionate. Each was placed on a plasmid with stabilizing components to ensure it functioned reliably in the gut environment.
The researchers then fine-tuned both sensors using targeted mutations. One variant, called thsS(t3)R-bARGSer, had six mutations and produced over 10 times more signal at body temperature in the presence of thiosulfate. Another, ttrSR(m13)-bARGSer, improved opacity by 1.5 times for tetrathionate detection.
The sensors produced strong, biomarker-specific signals when tested with ultrasound imaging techniques like BURST and xAM. The thiosulfate adapted sensor showed a 51-fold increase, while the tetrathionate version achieved a 41-fold increase, well beyond previous biosensor capabilities.
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Making The Sensors Even Smarter
To push the sensitivity further, the team integrated a recombinase-based genetic switch. The switch acts like a biological amplifier: once triggered, it locks in the gas vesicle signal even at low biomarker levels.
The upgraded strain, thsS(t3)R-Bxb1_P7-bARGSer, produced a much stronger signal at 100?μM thiosulfate, 2.5 times larger than its original version and requiring less biomarker to be activated. Similar improvements were seen in the tetrathionate sensor with the same recombinase-based genetic switch.
To validate the system in vivo, researchers used a mouse model of gut inflammation. Mice were treated with streptomycin, which disrupts gut bacteria and causes inflammation, resulting in higher thiosulfate levels. Controls were treated with chloramphenicol, which does not induce inflammation.
They administered the probiotic biosensors orally. Once inside the gut, the live bacteria responded to the inflammation-linked biomarkers and produced gas vesicles that were clearly visible on ultrasound scans.
Easier, Cheaper IBD Monitoring
This work could be a significant step toward making gut diagnostics simpler and more accessible. Instead of invasive procedures or specialized imaging equipment, a patient could someday swallow a probiotic capsule and receive a standard ultrasound scan to detect signs of IBD.
While still in early stages, the method could reduce healthcare costs, improve patient comfort, and be a quicker, easier way to monitor chronic gut conditions.
Journal Reference
Buss, M. T., Zhu, L., Kwon, J. H., Tabor, J. J., Shapiro, M. G. (2025). Probiotic acoustic biosensors for noninvasive imaging of gut inflammation. Nature Communications, 16(1), 1-15. DOI: 10.1038/s41467-025-62569-1, https://www.nature.com/articles/s41467-025-62569-1
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