Diarrheal Disease Protection May Literally Be within Spitting Distance

While it’s not typically desirable to think about saliva and diarrhea in the same context, a new study led by investigators at the Boston University School of Medicine (BUSM) may have just uncovered a role for a family of salivary peptides in defending the body against diarrheal disease. The research team identified a protein in saliva (histatin-5) that protects enterotoxigenic Escherichia coli (ETEC), which causes significant worldwide morbidity and mortality in young children and is the leading cause of traveler’s diarrhea.

Findings from the new study – published in the Journal of Infectious Diseases in an article entitled “A Role for Salivary Peptides in the Innate Defense Against Enterotoxigenic Escherichia coli” – may lead to the development of new preventive therapies for the disease.

Traveler’s diarrhea is an inconvenience to many in the U.S., but worldwide it can be deadly. It produces watery diarrhea, which can cause life-threatening dehydration in infants or other vulnerable populations in endemic countries. With more than one billion cases each year, hundreds of thousands of deaths can be attributed to this bacterial disease which is caused by ETEC, invading the small intestine using arm-like structures called pili.

The research team exposed miniature human small intestines that they were able to grow in a dish (organoids) to the bacteria ETEC in the presence and absence of the protein histatin-5. Amazingly, when the scientists examined the infected organoids under the microscope, significantly fewer bacteria were able to attach to the tissue in the presence of histatin-5.

“We found that the protein histatin-5 present in human saliva stiffens the pili of ETEC, preventing the bacteria from effectively adhering to the small intestine,” explained senior study investigator Esther Bullitt, Ph.D., associate professor of physiology and biophysics at BUSM. “If they can’t attach, they simply can’t cause disease.”

Prior to this study, it was not known that saliva could play such a significant role in protecting the body from gut infections. According to the researchers, this initial line of defense in the mouth likely explains why it takes such a large number of ETEC to infect a human. They also suggest that histatin-5 might be manufactured as a dissolvable powder and used to prevent traveler’s diarrhea in the future.

“…we show that the salivary peptide histatin-5 binds colonization factor antigen I pili, thereby blocking adhesion of ETEC to intestinal epithelial cells,” the authors wrote. “Mechanistically, we demonstrate that histatin-5 stiffens the typically dynamic pili, abolishing their ability to function as spring-like shock absorbers, thereby inhibiting colonization within the turbulent vortices of chyme in the gastrointestinal tract.”

The findings in this new study open the possibility that other salivary proteins might exist that protect against many other diseases, including infectious gastritis, food poisoning, or even pneumonia.

“We believe that our data represent the first example of a new paradigm in innate immunity: the contributions of salivary components to preventing infection,” Dr. Bullitt concluded. “This research opens an untapped avenue for prevention of enteric infectious diseases through the targeted use of naturally occurring components of saliva.”