Engineered probiotics a gutsy new field

CAPE TOWN – Bacteria mostly have a bad reputation for causing disease, so the idea of drinking a few billion bacteria every day for your health might seem a bit hard to “swallow!”

However, substantial scientific evidence is indicating that bacteria can be used to treat and prevent many illnesses. Therefore, millions of people all over the world are taking capsules of probiotics on a daily basis with the goal of improving their digestion and health. Probiotics are live bacteria and yeasts that are often recommended for gastrointestinal problems, for treating, amongst others, the development of allergies and eczema in children, treating and preventing vaginal and urinary tract infections in women, and delaying the recurrence of bladder cancer.

Probiotics are particularly helpful to maintain gut health and are often recommended to assist with digestive problems such as infectious diarrhoea, lactose intolerance, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, H. pylori (the cause of ulcers), digestive tract infection caused by Clostridium difficile (a bacteria causing diarrhoea), and pouchitis (a possible side effect of colon removal surgery).

Would it not be wonderful if the bacteria in your daily probiotic could timeously detect diseases in your intestines and inform you when something is wrong? Well, this wish may soon come true. In a recent paper published in the academic journal mSystems, researchers from the Wyss Institute at Harvard University and the Harvard Medical School described how they created an effective, non-invasive way to quickly identify new bacterial biosensors that can recognize and report the presence of various triggers in the gut indicating the onset of disease. This significant discovery sets the stage for a new frontier of digestive health monitoring and treatment.

Currently the understanding of how the human gut microbiome behaves is still in its early stages. The gut microbiome entails the collective genome of microbes inhabiting the gut including bacteria, archaea (single-celled organisms), protists (diverse eukaryotic, predominantly unicellular microscopic organisms), viruses, and fungi.

The lack of understanding has hindered research in the use of bacteria as biosensors. However, the research of the Harvard University team have succeeded to identify genetic elements in bacteria that respond to different signals in the gut, which allow them to detect and even treat diseases over a period of time.

The research builds on work previously done by the Wyss Institute that created a genetic circuit consisting of a “memory element” derived from a virus and a synthetic “trigger element.” Together these two can detect and record the presence of a specific stimulus. In the original experiment the researchers used a deactivated version of the antibiotic tetracycline as stimulus.

The genetic circuit was integrated into the genomes of Escherichia coli (better known as E. coli) bacteria, which were introduced into mice. The mice were then given the antibiotic tetracycline, which immediately caused the trigger element in the bacterial circuit to activate the memory element. It literally flipped like a switch and remained “on” for up to a week so that the bacteria “remembered” the presence of the tetracycline. The “on” signal was then easily read by analyzing the animals’ excrement, which is a totally non-invasive procedure.

Following the success of the experiment, the research team next demonstrated that the circuit could be modified to detect and report a naturally occurring molecule (tetrathionate) that indicates the presence of inflammation in the intestine of mice for up to six months after introduction into the animals. The experiment thus confirmed that the constructed diagnostic and therapeutic circuits could be used to monitor signals that would be useful in the diagnosis and treatment of disease in the gut over a longer period of time, such as inflammation and intestinal bleeding.

However, the researchers have in their bacteria-based diagnostic method identified only one molecule and condition. They thus started to test several potential trigger elements that could be indications of diseases in the intestines of mice by using a library of different strains of E. coli.

The researchers repeated the experiment numerous times to determine if any of the trigger elements were activated by substances in the mice’s intestines and could serve as sensors of gut-specific signals. Eventually they succeeded in successfully recording the presence of inflammatory biomolecules in the mouse gut that could thus serve as a living monitor of gastrointestinal health. Based on the triggering effect of the E. coli bacteria, the researchers were able to clearly distinguish between mice with intestinal inflammation and those mice that had a healthy gut.

The bacterial genome is much simpler than the human or animal genome, and is generally composed of only a single, circular chromosome. However, there is still much we do not know about the function and regulation of bacterial genomes. This is why the method of the Harvard researchers is such a breakthrough, since it allows for the use of biosensors that already exists in nature instead of the almost impossible task of designing it.

The scientists of the Wyss Institute under the leadership of Dr Alexander Naydich took advantage of the amazing genetic diversity of the microbiome to develop a solution for the detection of diseases in the intestines through the use of bacteria such as E. coli.

The system were further refined to include the ability to record signals that occur either chronically or momentarily in the gut, as well as adjustable sensitivity that allowed for the fine-tuning of bacterial biosensors to detect specific conditions within the gut over an extended period of time. The team of researchers was thus able to improve the technology from a tool that tests for one condition or disease to a tool that can test for multiple diseases in the gut concurrently.

The tool is thus not only useful for the identification of new potential biosensors and diseases, but could in the future be developed into a probiotic-like capsule containing complex collections of bacteria that sense and record several signals simultaneously, allowing clinicians to “fingerprint” a disease and thus have a much greater confidence in making a diagnosis.

The constant progress made by the team of the well-known Harvard University Silver Lab with regard to the development of living cellular devices based on the genetic reengineering of the microbiome, represents an entirely new approach to affordable low-cost diagnostics and therapeutics in the medical world.

Since the gut is a largely obscure and inaccessible environment, the use of live, engineered probiotics to detect and respond to disease signals in a living person represents a new frontier in the management of gut diseases.

This approach of the Harvard researchers of introducing engineering circuits into intestinal bacteria to sense, record and respond to signals could in future be a valuable tool for medical professionals in the diagnosis, treatment and prevention of gastrointestinal and other diseases. In recent times a range of studies have engineered bacteria to serve as potential treatments for inflammation, metabolic disease, cancer, and infection. This approach is not only cost-effective, but also non-invasive, since invasive sampling through an expensive colonoscopy and biopsy is not necessary.

Engineered probiotics also show promise as a novel mechanism for drug delivery. It has the potential to radically transform how we interact with and control biological systems, including our own bodies.

It seems that it is quite possible that the doctor would in future be able to say: “Take two E. coli capsules immediately and call me in the morning if you do not feel better.”

Professor Louis C H Fourie is a futurist and technology strategist.


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