Interplay Between the Gut Microbiome and Typhoid Fever: Insights from Endemic Countries and a Controlled Human Infection Model

Abstract

AbstractTyphoid fever is a systemic infection caused bySalmonella entericaserovar Typhi (S.Typhi) bacteria invading through the gut lumen. Transmission occurs through ingestion of contaminated food and water, particularly in settings with poor water, sanitation and hygiene infrastructure, resulting in over 10 million illnesses annually. It is well established that vaccines and natural infections can stimulate protective immunity againstS.Typhi. As the pathogen invades through the gastrointestinal tract, it is plausible that the gut microbiome may also influence the outcome ofS. Typhi exposure. There is some evidence that bacteria producing short-chain fatty acids (SCFAs) may create an environment unfavourable to invasiveSalmonella,but data from humans is very limited.To investigate the association between gut microbiome and typhoid fever, we analysed samples collected from three all-age cohorts recruited in a prospective surveillance study conducted in parallel in three settings where typhoid fever is endemic (Dhaka, Bangladesh; Blantyre, Malawi; and Kathmandu, Nepal). Cohorts consisted of acute typhoid fever patients (n=92), asymptomatic household contacts of typhoid fever patients (representing individuals who were likely exposed toS. Typhi but did not develop disease, n=97), and asymptomatic serosurvey participants with high Vi antibody titres (representing individuals who were exposed toS. Typhi and may be carriers, n=69). The stool microbiomes of each cohort were characterised using shotgun metagenomics, and bacterial composition and diversity were compared.We identified four bacterial species and 28 metabolic gene clusters (MGCs) that were significantly lower in abundance in typhoid fever patients compared with household contacts (i.e. probably exposed), in two of the three host populations (Bangladesh and Malawi). These may represent taxa that provide protection against development of clinical infection upon exposure toS. Typhi, and include the inflammation-associated speciesPrevotella copriclade A andHaemophilus parainfluenzae, and seven MGCs involved in SCFA metabolism. The putative protection provided by SCFA metabolism was supported by data from a controlled human infection model conducted in a UK population, in which participants who did not develop typhoid fever following ingestion ofS. Typhi had significantly higher abundance of a putative SCFA-metabolising MGC (q-value = 0.22).This study identified the same associations between taxonomic and functional microbiota characteristics and non-susceptibility to typhoid fever across multiple cohorts. Future research should explore the potential functional role of SCFAs and inflammation-associated bacteria in resistance toS.Typhi and other enteric infections.