Engineering the Microbiome to Cure Disease

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease. 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.

Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

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.

The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly.

The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. “Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell , Zarrinpar and colleagues at University of California San Diego School of Medicine report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.

Source: https://health.ucsd.edu/