Vitamin A Biosynthesis in Probiotic Bacteria
Vitamin A deficiency causes susceptibility—especially in children—to diarrhea-causing infections, some fatal. SRI worked to develop a probiotic that produces the vitamin, and which could be distributed inexpensively during clinic visits in the developing world.
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 engineered probiotic bacteria to biosynthesize 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 hypothesized 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 modified bacteria by incorporating enzymes that biosynthesize vitamin A from dimethylallyl diphosphate, a metabolic intermediate present in bacteria. SRI carefully assessed the stability of vitamin A production over time, as well as any toxicity to the bacteria that may result from vitamin A production.
SRI also worked to determine whether vitamin A produced by probiotic bacteria is capable of stimulating dendritic cells and other important immune cells. If successful, SRI researchers would 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.
Outcomes of this project were described in an article, β-Carotene Biosynthesis in Probiotic Bacteria, published in the Journal of Probiotics and Antimicrobial Proteins in March 2013.
This project was funded by a grant from the Bill & Melinda Gates Foundation through the Grand Challenges Explorations Initiative.