Diarrheal diseases, such as those caused by infection with Escherichia coli or rotavirus, kill nearly two million children every year. Deficient mucosal immunity is a significant contributor to children's susceptibility to diarrheal diseases, largely due to widespread pediatric vitamin A deficiency. Because only half of malnourished children receive necessary vitamin supplementation, innovative approaches are needed to increase coverage, restore functional gut immunity, and reduce mortality associated with diarrheal diseases.
As an alternative approach for delivering vitamin A in resource-poor settings, SRI is engineering probiotic bacteria to biosynthesize vitamin A or beta-carotene, the metabolic precursor of vitamin A. Probiotic therapies have been shown to stimulate gut immunity and reduce diarrhea. Live probiotics activate key immune cells, called dendritic cells, in the gut and broadly promote immunity to enteric infections.
SRI researchers hypothesize that vitamin A-producing live probiotic bacteria will act as a dual-use therapy to combat vitamin deficiency while delivering the vitamin directly to relevant immune-related tissues in the intestine, stimulating gut immunity and reducing the incidence and duration of diarrheal disease.
To generate vitamin-producing strains, SRI is modifying bacteria by incorporating enzymes that biosynthesize vitamin A from dimethylallyl diphosphate, a metabolic intermediate present in bacteria. SRI is carefully assessing the stability of vitamin A production over time, as well as any toxicity to the bacteria that may result from vitamin A production.
SRI is also determining whether vitamin A produced by probiotic bacteria is capable of stimulating dendritic cells and other important immune cells. If successful, SRI researchers will then assess the beneficial effects of this novel therapy in models of diarrheal disease and in humans. The ultimate goal is to create a new therapy that can be prepared and disseminated locally and at a low cost.
This project was funded by a grant from the Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative.
