From bench to bed and back again: phage therapy of childhood Escherichia coli diarrhea

Over the last 20 years, the Nestlé Research Center in Switzerland and the International Center for Diarrhoeal Diseases Research in Bangladesh have explored the efficacy of alternative biological agents for the treatment of diarrheal diseases. This paper reviews the work of this collaborative effort, particularly on Escherichia coli phage therapy (PT), and discusses the development of the project, starting with the isolation of T4-like coliphages from the stool of diarrhea patients, their pilot plant amplification and purification, and the constitution and testing of a cocktail of T4-like phages in mice. A series of phase I clinical trials has demonstrated the safety of PT. Oral phage given without protection survived gastric passage and was recovered in the feces. Oral T4 phage cocktail was then tested in parallel to a commercial phage product in a phase II randomized, placebo-controlled single-center trial in Bangladeshi children hospitalized with acute E. coli diarrhea. It was found that oral phage did not perform better than the current standard of care by oral rehydration/zinc treatment. Furthermore, fecal E. coli pathogen titers were low and mixed infections were found to be frequent. Microbiota analysis showed a correlation between diarrhea and increased levels of Streptococcus, which raises fundamental questions on the causative agent of diarrhea that may explain PT clinical failure.