Interplay between the gut microbiome and typhoid fever: insights from endemic countries and a controlled human infection model

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BACKGROUND: Typhoid fever is a systemic infection caused by Salmonella enterica serovar 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 of S. Typhi exposure. There is some evidence that bacteria producing short-chain fatty acids (SCFAs) may create an environment unfavourable to invasive Salmonella, but data from humans is limited. METHODS: To investigate the association between the 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 to S. Typhi but did not develop the disease, n = 97) and asymptomatic serosurvey participants with high Vi antibody titres (representing individuals who were exposed to S. 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. RESULTS: 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 the development of clinical infection upon exposure to S. Typhi and include the inflammation-associated species Prevotella copri clade A and Haemophilus 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 of S. Typhi had a higher abundance of a putative SCFA-metabolising MGC (q-value = 0.22). CONCLUSIONS: 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 to S. Typhi and other enteric infections. Video Abstract.

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