Bacteria with Recording Function Capture Gut Health Status

Our intestine is residence to plenty of bacteria, which help us digest food. However, just what do the microorganisms do inside the body? Which enzymes do they create, and when? And how do the bacteria metabolize health-promoting foods that aid us in minimizing disease?

To obtain replies to such matters, researchers at the Department of Biosystems Science and Engineering at ETH Zurich in Basel changed bacteria to operate as information loggers for data on gene tasks. Along with scientists from University Hospital of Bern and the University of Bern, they have currently examined these bacteria in mice. This is a vital step toward utilizing sensor bacteria in medicine in the future for applications such as diagnosing malnutrition and comprehending which diets are better for a person.

Immune system turns into data logger

The information logger function was developed over the past few years by scientists guided by Randall Platt, Professor of Biological Engineering at ETH Zurich. To perform this, they used the CRISPR-Cas mechanism, a kind of immune system that generally exists in many bacterial species.

If viruses strike the bacteria, they can embody snippets of the viral DNA or RNA in a section of their genome named the CRISPR array. This allows the bacteria not to forget viruses with which they have had contact, enabling them to fight off a future viral assault faster.

To use this mechanism as an information logger, the scientists did not worry themselves with DNA snippets of viral interlopers. However, they concentrated on another thing: the mechanism can be utilized such that the bacteria integrate snippets of their messenger RNA (mRNA) into the CRISPR array. mRNA molecules are the figure that cells utilize to fabricate proteins. mRNA snippets can reveal which genes are being utilized to develop proteins for carrying out cellular functionalities.

To make the method efficient, the scientists inserted the CRISPR array of the bacterial species Fusicatenibacter saccharivorans in a strain of the intestinal bacterium Escherichia coli, which is considered secure in people and available as a probiotic. The transition involved the plan of an enzyme called reverse transcriptase, which can transcribe RNA into DNA. This enzyme also transcribes the data in the mRNA into DNA form, which, together with associating with CRISPR-associated proteins, is necessary for including the DNA snippet into the CRISPR array.

Obtaining data without disturbing the body

After that, scientists from University Hospital of Bern and the University of Bern, led by Andrew Macpherson, administrated these modified gut bacteria to mice in the laboratory. They gathered fecal specimens from the animals and segregated the bacterial DNA, which they then evaluated using high-throughput DNA sequencing.

With a subsequent bioinformatic assessment, carried out and assessed in collaboration, they managed to work through the mass of data and rebuild the genetic data of the mRNA snippets. This allowed the researchers to determine by noninvasive means how the intestine bacteria usually produced a given mRNA molecule during their time in the body and which genes are active.

“This new technique allows us to acquire data straight from the gut, without needing to interrupt intestinal functionalities,” states Andrew Macpherson, Professor and Director of Gastroenterology at University Hospital Bern. As such, the technique has significant benefits over endoscopies, which can be unpleasant for individuals and usually includes disturbing gut function, as the bowels need to be empty for the assessment.

Establishing dietary status

“Bacteria are so great at registering environmental conditions and adjusting their metabolism to new conditions such as dietary modifications,” Macpherson claims. In tests with mice that were given different foods, the researchers can demonstrate how the bacteria adjusted their metabolism to the particular nutrient supply. A report of the results has been released in the latest issue of the journal Science.

The researchers want to expand the procedure to ensure that someday they can research human patients to see how diet plan influences the gut ecosystem and how this affects health. In the future, they hope to utilize the method to determine the dietary status of kids or grownups. Armed with this data, doctors will have the ability to diagnose malnutrition or decide whether a person requires nutritional supplements.

Furthermore, scientists could acknowledge inflammatory reactions in the intestine. The researchers conducted the sensor bacteria in mice with intestinal inflammation as well as in healthy mice. In this mean, they could define the specific mRNA profile of intestine bacteria that change to inflammation mode.

Differentiating distinct bacteria

The present research released in the journal Science involves a scientific advancement that permits the scientists to differentiate two strains of bacteria from each other based upon individual genetic “barcodes.” In the future, this will make it achievable to study the function of gene mutations in lab animals in bacteria.

This will let scientists compare the mRNA profile of distinct bacteria, such as normal contrasted to mutant bacteria. Thanks to the molecular data logger, it is conceivable for the first time to define this profile as they pass through the gut, not just when the bacteria get to the feces, to make sure that the information shows what was taking place when the bacteria were still staying in the intestine.

An additional conceivable opportunity would be to establish further the system to differentiate RNA profiles of bacteria in the small and large intestine. Additionally, the data logger function could be incorporated into other types of bacteria. This would open the door to applications in environmental supervision. An evaluation of soil bacteria from a crop field, for instance, would determine whether herbicides had been used.

Secure application possible

The scientists have filed patent applications for the procedure itself and the particular RNA profiles that are signatures of particular nutritional molecules and signs of intestinal health.

Before the sensor bacteria can be utilized outside the laboratory– involving human patients– the scientists still have to clarify numerous safety and lawful concerns, as the bacteria have been genetically customized.

“In principle, there are means of utilizing live genetically engineered microorganisms as diagnostic or therapeutic agents in medicine, provided that certain conditions are met,” Platt describes. It is feasible, for instance, to modify the sensor bacteria to ensure that they require specific nutrients and consequently can survive only inside a person’s intestine.

Right after these specific bacteria leave the gut, they will die. Incorporating appropriate security mechanisms is the next step toward applying the technique in medicine.

This study work was supported by ERC Grants rewarded to Randall Platt and Andrew Macpherson and by a grant from the Botnar Research Center for Child Health.The mice studies were carried out at the Clean Mouse Facility at the University of Bern, which the Genaxen research foundation supports.

Reference: Florian Schmidt, Jakob Zimmermann, Tanmay Tanna, Rick Farouni, Tyrrell Conway, Andrew J. Macpherson, Randall J. Platt. Noninvasive assessment of gut function using transcriptional recording sentinel cells. Science, 2022; 376 (6594) DOI: 10.1126/science.abm6038

Provided by ETH Zurich.