[Apr. 6, 2023: Scott La Fee, University of California – San Diego]
Many diseases are associated with an imbalance or dysfunction of the gut microbiome. (CREDIT: Shutterstock)
Residing in the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human diseases, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel disease.
Many diseases are associated with an imbalance or dysfunction of the gut microbiome. Even in diseases that don’t involve the microbiome, the gut microflora provides an important entry point that can alter many physiological systems.
Modification to remedy, perhaps even cure, these conditions has generated substantial interest, leading to the development of live bacterial therapies (LBT). One idea behind LBTs is to engineer bacterial hosts, or frameworks, to produce therapeutics capable of repairing or restoring healthy microbial function and diversity.
Existing efforts have mainly focused on the use of probiotic bacterial strains from the Bacteroides or Lactobacillus or Escherichia coli families that have been used for decades in the laboratory. However, these efforts have largely failed because the artificial bacteria introduced into the gut usually do not survive what is basically a harsh environment.
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Failure to engraft or even survive in the gut necessitates frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in people taking probiotics, where these beneficial bacteria are unable to compete with the individual’s native microorganisms and largely disappear quickly.
“Lack of engraftment severely limits the use of LBTs for chronic diseases for curative purposes or to study specific functions of the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego. School of Medicine and gastroenterologist. at UC San Diego Health. “Published human trials using artificial LBTs have demonstrated safety, but have yet to demonstrate disease reversal. We believe this may be due to colonization issues.
In a proof-of-concept study, published in the online issue of CellZarrinpar and colleagues at the University of California, San Diego School of Medicine report overcoming this hurdle by using native bacteria in mice as a chassis to deliver transgenes capable of inducing persistent and potentially even curative therapeutic changes. in the gut and reverse pathological conditions.
Graphic abstract. (CREDIT: Administration of Gut Transgenes with Native E. coli Chassis Enables Persistent Physiological Changes – Cell)
Using this method, the group found it could provide long-term therapy in a mouse model of type 2 diabetes.
“In theory, native bacteria are already maximally adapted to the luminal environment,” Zarrinpar said. “Thus overcoming almost all obstacles to transplantation and making an ideal framework for therapeutic administration.”
Artistic representation of the concept of re-engineered native bacteria that serve as a framework for introducing therapeutic agents into the gut microbiome to treat or cure disease. (CREDIT: Thom Leach, Amoeba Studios)
In the study, the research team showed that they could take a strain of E. coli native to the host and engineer it to express transgenes that affect its physiology, such as blood sugar. The modified native bacteria were then reintroduced into the intestine of the mouse.
After just one treatment, Zarrinpar said the engineered native bacteria engrafted into the gut for the lifetime of the treated mice, retained their functionality, and induced an improved glycemic response for months. The researchers also demonstrated that similar bacterial engineering can be performed in native human E. coli.
Gut-native E. coli are genetically traceable and can serve as a chassis for transgene delivery. (CREDIT: Administration of Gut Transgenes with Native E. coli Chassis Enables Persistent Physiological Changes – Cell)
“This work is an exciting step in demonstrating that live bacterial therapies can be used to treat or possibly even cure chronic diseases,” said study first author Baylee Russell, now a graduate student at the University. from Harvard.
“In principle, live bacterial therapies can be a relatively non-invasive, low-risk and cost-effective option for the treatment of a number of diseases. It deserves further exploration. There is still a lot of work to be done, but it will be exciting to see this technology develop in the years to come. »
Native E. coli can be used to modify the luminal metabolome without measurable effects in the microbiome. (CREDIT: Administration of Gut Transgenes with Native E. coli Chassis Enables Persistent Physiological Changes – Cell)
Zarrinpar said the reluctance of some groups to use native, undomesticated bacteria rather than well-known laboratory strains is driven by the assumption that they are difficult to grow and modify, although the study authors note that recent studies have demonstrated that they can be changed more consistently using new methods.
“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 remains to be accomplished with other synthetic biology approaches,” said said Zarrinpar “That is, a functional manipulation of the gut luminal environment to create persistent physiological effects.”
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Note: The documents provided above by University of California – San Diego. Content may be edited for style and length.
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