Interplay Between the Gut Microbiome and Typhoid Fever: Insights from Endemic Countries and a Controlled Human Infection Model
Authors: Ashton Philip M. , Mageiros Leonardos , Meiring James E. , Chirambo Angeziwa Chunga , Khanam Farhana , Dongol Sabina , Banda Happy , Karkey Abhilasha , Llanes Lorena Preciado , Thomaides-Brears Helena , Gibani Malick , Rajib Nazmul Hasan , Rahman Nazia , Biswas Prasanta Kumar , Bhuiyan Md Amirul Islam , Kay Sally , Auger Kate , Seret Olivier , Thomson Nicholas R. , Pollard Andrew J , Baker Stephen , Basnyat Buddha , Clemens John D. , Dolecek Christiane , Dunstan Sarah J. , Dougan Gordon , Heyderman Robert S. , Pitzer Virginia E. , Qadri Firdausi , Gordon Melita A. , Holt Kathryn E. , Darton Thomas C. ,   STRATAA Study Group
Published: September 2024

AbstractTyphoid fever is a systemic infection caused bySalmonella entericaserovar Typhi (S.Typhi) invasion from the gut lumen. Transmission between people occurs through ingestion of contaminated food and water, particularly in settings with poor water and sanitation infrastructure, resulting in over 10 million illnesses annually. As the pathogen invades via the gastrointestinal tract, it is plausible that the gut microbiome may 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 limited.To investigate the association between gut microbiome and typhoid fever, we analysed samples collected from three all-age cohorts enrolled in a prospective surveillance study conducted across 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 diversity, composition, and function were compared.We identified 4 bacterial species that were significantly lower in abundance in typhoid fever patients compared with household contacts (i.e. probably exposed), in two of the three participant populations (Bangladesh and Malawi). These bacteria 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. Our functional analysis identified 28 specific metabolic gene clusters (MGCs) negatively associated with typhoid fever in Bangladesh and Malawi, including seven MGCs involved in SCFA metabolism. The putative protection provided by microbiome 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 higher abundance of a putative SCFA-metabolising MGC (q-value = 0.22).This study identified the same protective associations between taxonomic and functional microbiota characteristics and non-susceptibility to typhoid fever across multiple human populations. Future research should explore the potential functional role of SCFAs and inflammation-associated bacteria in resistance toS.Typhi and other enteric infections.