Microbiome engineering: Curing disease by bacterial therapeutics?

05 Aug 2022 --- A team of scientists are unraveling how native bacteria may be harnessed to induce persistent and potentially even curative therapeutic changes in the gut. In a proof-of-concept study, the researchers found they could provide long-term therapy for type 2 diabetes in a mouse model.

“This work is an exciting step in demonstrating that live bacterial therapeutics can be used for treating or possibly even curing chronic conditions,” says the study’s first author Baylee Russell, graduate student at Harvard University.

“In principle, live bacterial therapeutics may be a relatively non-invasive, low risk and cost-effective option for treating a number of diseases. It is worthy of additional exploration. There’s still a lot of work that needs to be done, but it will be exciting to see this technology expand in the years ahead.”

The “blackbox” of nutrition
Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don’t involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems, according to the study published in Cell.

Across research developments this year, there has been growing interest in modifying the gut in order to remedy or even cure conditions such as obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease. The interest has led to the development of live bacterial therapeutics (LBTs). 

The idea is to engineer bacterial hosts to produce therapeutics so they can repair or restore healthy microbial function and diversity. 

Scientists have pegged the gut microbiome as the “black box” of nutrition research as diet-microbiome interactions are anticipated to contribute to the foundation of dietary physiological effects.

The gut microbiome is eyed for an array of health benefits, with the gut-brain axis garnering increased interest.Disappearing probiotic impact?
Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment.

As a result, the bacterial strains have to often be re-administered, which often produces inconsistent effects or no effect at all, according to the researchers.

According to the study, the phenomenon is most apparent in individuals who take probiotics, where beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly. 

Overcoming hurdles
Attempting to work around the challenges, the researchers employed native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent – and potentially even curative therapeutic – changes in the gut.

“In theory, native bacteria are already maximally adapted to the luminal environment, thereby bypassing nearly all the barriers to engraftment and making them an ideal chassis for therapeutic delivery,” explains Zarrinpar.

In the study, the research team showed they can take a strain of E. coli native to the host and engineer it to express transgenes that affect its physiology, such as blood glucose levels. The modified native bacteria were then reintroduced into the mouse’s gut.

Zarrinpar notes that after a single treatment, the engineered native bacteria engrafted throughout the gut for the lifetime of the treated mice, retained functionality and induced improved blood glucose response for months. The researchers also demonstrated that similar bacterial engineering can be done in human native E. coli. 

“None of the individual steps we used or described are particularly difficult, but in combination, they are novel. Together, they clearly demonstrate that we can accomplish what has yet to be achieved with other synthetic biology approaches,” highlights Zarrinpar. 

“That is, functional manipulation of the luminal gut environment to create persistent physiological effects.”

By Andria Kades