Cancer and type 2 diabetes could be reversed with transgenes in the gut

Many diseases are associated with an imbalance or dysfunction of the gut microbiome. (CREDIT: Shutterstock)

The human gut is home to trillions of bacteria and other microorganisms that can contribute to 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 non-microbiome related diseases, the gut microflora provides an important access point to modify many physiological systems.

Modification to treat, perhaps even treat, these conditions has generated significant interest, leading to the development of live bacterial therapeutics (LBTs). One of the ideas behind LBT is to create bacterial hosts or chassis to produce therapeutics capable of restoring 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, which have been used in the laboratory for decades. However, these efforts have largely failed because engineered bacteria introduced into the gut usually do not survive in a fundamentally hostile environment.

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Failure to establish or even survive in the gut necessitates frequent reintroduction of these bacterial strains and often results in intermittent effects or no effect at all. This phenomenon is perhaps most noticeable in people taking probiotics, where these beneficial bacteria cannot compete with the human native microorganisms and are largely eliminated quickly.

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

In a proof-of-concept study published in the online edition of Cell, Zarrinpar and colleagues at UC San Diego School of Medicine report overcoming this hurdle by using native bacteria in mice as the basis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the intestine and reversal of pathological conditions.

Graphic abstraction. (CREDIT: Transgene delivery to the gut with native E. coli chassis provides lasting physiological changes – The Cell)

Using this method, the group found it could provide long-term therapy in a mouse model of type 2 diabetes.

“Theoretically, local bacteria are already maximally adapted to the translucent environment,” Zarrinpar said. “Thus bypassing almost all barriers to graft engraftment and making them an ideal basis for therapeutic delivery.”

An artist’s representation of the concept of reconstructed native bacteria that serve as a chassis for introducing therapeutic agents into the gut microbiome to treat or treat disease. (LETTER: Tom Leach, Amoeba Studios)

Through the study, the research team showed that they could take a strain of E. coli that is 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 re-introduced into the mouse intestine.

After a single treatment, the modified local bacteria established themselves throughout the entire gut throughout the life of the treated mice, retained functionality, and elicited an improved response to blood glucose levels for several months, Zarrinpar said. The researchers also demonstrated that similar bacterial engineering could be implemented in natural human E. coli.

The native E. coli is genetically malleable and can serve as a basis for transgene delivery. (CREDIT: Transgene delivery to the gut with native E. coli chassis provides lasting physiological changes – The Cell)

“This work is an exciting step in demonstrating that live bacterial therapeutics can be used to treat or possibly even treat chronic disease,” said study first author Bailey Russell, now a graduate student at Harvard University.

“In principle, live bacterial therapeutics could be a relatively non-invasive, low-risk, and cost-effective treatment option for a range of diseases. This is worthy of further study. There is still a lot of work to be done, but it will be interesting to see how this technology expands in the coming years.”

Native E. coli can be used to alter the luminal metabolome without tangible effects in the microbiome. (CREDIT: Transgene delivery to the gut with native E. coli chassis provides lasting physiological changes – The Cell)

Zarrinpar said the reluctance of some groups to use untamed native bacteria rather than well-known laboratory strains is due to the assumption that they are difficult to culture and modify, although the study authors note that recent studies have demonstrated that they can be modified more consistently using newer strains. . methods.

“None of the individual steps we have used or described are particularly complex, but combined they are novel. Together, they clearly demonstrate that we can achieve what is yet to be achieved with other synthetic biology approaches,” said Zarrinpar. “That is, the functional manipulation of the intestinal lumen environment to create persistent physiological effects.”

To learn more about science and technology, visit our New Discoveries section at The bright side of the news.

Note. Materials provided by the University of California, San Diego. Content can be edited for style and length.

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