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Background   Salmonella  Typhi and  Salmonella  Paratyphi A are the agents of enteric (typhoid) fever; both can establish chronic carriage in the gallbladder. Chronic  Salmonella  carriers are typically asymptomatic, intermittently shedding bacteria in the feces, and contributing to disease transmission. Detecting chronic carriers is of public health relevance in areas where enteric fever is endemic, but there are no routinely used methods for prospectively identifying those carrying  Salmonella  in their gallbladder.    Methodology/Principal findings  Here we aimed to identify biomarkers of  Salmonella  carriage using metabolite profiling. We performed metabolite profiling on plasma from Nepali patients undergoing cholecystectomy with confirmed  S . Typhi or  S . Paratyphi A gallbladder carriage (and non-carriage controls) using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) and supervised pattern recognition modeling. We were able to significantly discriminate  Salmonella  carriage samples from non-carriage control samples. We were also able to detect differential signatures between  S . Typhi and  S . Paratyphi A carriers. We additionally compared carriage metabolite profiles with profiles generated during acute infection; these data revealed substantial heterogeneity between metabolites associated with acute enteric fever and chronic carriage. Lastly, we found that  Salmonella  carriers could be significantly distinguished from non-carriage controls using only five metabolites, indicating the potential of these metabolites as diagnostic markers for detecting chronic  Salmonella  carriers.    Conclusions/Significance  Our novel approach has highlighted the potential of using metabolomics to search for diagnostic markers of chronic  Salmonella  carriage. We suggest further epidemiological investigations of these potential biomarkers in alternative endemic enteric fever settings.

Diagnostic metabolite biomarkers of chronic typhoid carriage