Engineering bacterial thiosulfate and tetrathionate sensors for detecting gut inflammation

Abstract

There is a groundswell of interest in using genetically engineered sensor bacteria to study gut microbiota pathways, and diagnose or treat associated diseases. Here, we computationally identify the first biological thiosulfate sensor and an improved tetrathionate sensor, both two‐component systems from marine Shewanella species, and validate them in laboratory Escherichia coli. Then, we port these sensors into a gut‐adapted probiotic E. coli strain, and develop a method based upon oral gavage and flow cytometry of colon and fecal samples to demonstrate that colon inflammation (colitis) activates the thiosulfate sensor in mice harboring native gut microbiota. Our thiosulfate sensor may have applications in bacterial diagnostics or therapeutics. Finally, our approach can be replicated for a wide range of bacterial sensors and should thus enable a new class of minimally invasive studies of gut microbiota pathways.

Multiplexed biosensors for precision bacteria tropism in vivo

“…An emerging focus in synthetic biology engineers microbes to integrate within specific niches in nature, artificial infrastructure and the human body (4)(5)(6)(7)(8)(9)(10)(11). Since genetic programming of bacteria enables them to sense and respond to physiological conditions in situ, this approach is poised to change existing paradigms for diagnosing and treating diseases such as inflammation (12,13), infection (14,15), and cancer (16)(17)(18). An essential element of this approach requires the precise regulation of microbial growth at disease sites, since uncontrolled bacterial replication can lead to severe side effects including tissue damage and septic shock (19,20).…”

Quantitative and synthetic biology approaches to combat bacterial pathogens

“…A model chemical (andhydrotetracycline) is used in this study but the design can be adapted to sense biomarkers of interest, including those associated with bacterial infections [48]. Along the same line, another study demonstrated the engineering of a probiotic strain of E. coli (Nissle 1917) to sense thiosulfate and tetrathionate, which are associated with a gut inflammation mouse model infected by Salmonella typhimurium [49,50]. Such whole-cell sensors have the potential of being used for continuous monitoring of host environments for biomarkers associated with bacterial infections.…”

Going with the flow

“…Recently, researchers from Rice University and Baylor University in Texas took advantage of this idea to engineer a novel strain of bacteria that could report on the intracellular levels of two key metabolites in a mouse model of colitis (1). Even though mounting data show mammalian gut function is regulated through cross-talk between host cells and resident bacteria, deciphering this cross-talk and the signaling molecules involved has proven to be quite a challenge.…”

Synthetic gene circuits enable systems-level biosensor discovery at the host-microbe interface

“…Environment-and disease-responsive functions, which could minimize both the metabolic burden of engineered systems on the bacteria and off-target effects on the patient, offer exciting prospects for clinical applications. To this end, recent in vivo approaches have developed sensors responding to inflammation (3,4), intestinal bleeding (5), and pathogen quorum-sensing systems (6,7). However, the construction of disease-responsive circuits in bacteria has been hindered by the limited number of characterized bacterial systems that can be reliably employed as sensors.…”

A synthetic bacterial information transfer system functions in the mammalian gut

“…This synthetic biology approach has shown progress in several ways thus far. First, engineered bacterial sensors can successfully detect their target molecules in the gut, such as orally administered anhydrotetracycline (ATC) and gut inflammatory markers, thiosulfate and tetrathionate (Daeffler, et al, 2017;Kotula et al, 2014;Riglar et al, 2017). Second, engineered bacteria with information recording systems using genetic switches can report on the state of the gut through fecal sample analysis (Kotula et al, 2014;Slauch et al, 2000;Mimee et al, 2016).…”