Why are so many enteric pathogen infections asymptomatic? Pathogen and gut microbiome characteristics associated with diarrhea symptoms and carriage of diarrheagenic in northern Ecuador.

A high proportion of enteric infections, including those caused by diarrheagenic (DEC), are asymptomatic for diarrhea. The factors responsible for the development of diarrhea symptoms, or lack thereof, remain unclear. Here, we used DEC isolate genome and whole stool microbiome data from a case-control study of diarrhea in Ecuador to examine factors associated with diarrhea symptoms accompanying DEC carriage. We investigated i) pathogen abundance, ii) gut microbiome characteristics, and iii) strain-level pathogen characteristics from DEC infections with diarrhea symptoms (symptomatic infections) and without diarrhea symptoms (asymptomatic infections). We also included data from individuals with and without diarrhea who were not infected with DEC (uninfected cases and controls). i) relative abundance in the gut microbiome was highly variable, but higher on-average in individuals with symptomatic compared to asymptomatic DEC infections. Similarly, the number and relative abundances of virulence genes in the gut were higher in symptomatic than asymptomatic DEC infections. ii) Measures of microbiome diversity were similar regardless of diarrhea symptoms or DEC carriage. Proteobacterial families that have been described as pathobionts were enriched in symptomatic infections and uninfected cases, whereas potentially beneficial taxa, including the and , were more abundant in individuals without diarrhea. An analysis of high-level gene functions recovered in metagenomes revealed that genes that were differentially abundant by diarrhea and DEC infection status were more abundant in symptomatic than asymptomatic DEC infections. iii) DEC isolates from symptomatic versus asymptomatic individuals showed no significant differences in virulence or accessory gene content, and there was no phylogenetic signal associated with diarrhea symptoms. Together, these data suggest signals that distinguish symptomatic from asymptomatic DEC infections. In particular, the abundance of , the virulence gene content of the gut microbiome, and the taxa present in the gut microbiome have an apparent role.