Type I diabetes (T1D) is a chronic disease characterized by the destruction of the insulin-producing pancreatic beta cells with early onset, such as childhood and adolescence. Despite the tremendous efforts and investments to cure or improve therapies for T1D, optimal solution of this disease has not been discovered. Therefore, the individuals with T1D still require lifetime treatment with insulin injection to control blood glucose. The goal of our project is to establish an alternative insulin delivery system for T1D patients.

Theoretically, the deep skin area has been thought to be sterile with no living organisms. However, a study discovered non-pathogenic bacteria that reside adjacent to the vasculature deep in the skin. We propose to engineer these skin bacteria to serve as surrogates of pancreatic beta cells for controlling blood glucose levels in T1D. The engineered bacteria should be able to (1) produce and secrete insulin as needed, (2) detect and rapidly respond to blood glucose levels, and (3) evade host immune attacks. For safety concerns, the engineered skin bacteria can be also equipped with a kill switch that allows for easy elimination of the bacteria from a treated patient if needed.

Using previous DRC and other funding, our team has demonstrated that an engineered strain of the main deep-skin bacteria, Staphylococcus epidermidis, can produce and secrete a single-chain insulin analog that can increase glucose uptake. We also have confirmed that our engineered strains provided on the skin surface with Cetaphil cream move into the deep skin layers. So far, tests of this insulin-producing bacterium in mice have not lowered mouse blood glucose levels. We hypothesize that our engineered S. epidermidis strains are not producing enough insulin analog to alter murine blood glucose. In addition, engineered bacterial strains would need to compete with the native deep-skin bacteria for space and resources, possibly reducing their activities as insulin producing cells.

The novelty of my project is to directly engineer native skin bacteria in vivo using bacteriophages, or phages, which are viruses that specifically infect bacteria. Using a cocktail of phages, multiple subgroups of skin bacteria can be targeted to amplify the insulin signal. The expected outcome is a more robust expression of insulin in response to high glucose conditions.

Phages have been used as an additional therapeutic option for infectious diseases that cannot be treated with antibiotics due to multidrug resistant bacteria. This is called bacteriophage therapy. Our study is going to expand the extent of the bacteriophage therapy. Success of the phage-mediated engineering of the skin microbiotas could be an avenue to better blood glucose control than with current insulin therapy and improve the health of those individuals who suffer from T1D.