Gut bacteria-derived sphingolipids alter innate immune responses to oral cholera vaccine antigens

The degree of protection conferred after receiving an oral cholera vaccine (OCV) varies based on age, prior exposure to Vibrio cholerae, and unknown factors. Recent evidence suggests that the microbiota may mediate some of the unexplained differences in oral vaccine responses. Here, we use metagenomic sequencing of the fecal microbiota at the time of vaccination and relate microbial features to immune responses after OCV using a reference-independent gene-level method. We find that the presence of sphingolipid-producing bacteria is associated with the development of protective immune responses after OCV. We test these associations by stimulating human macrophages with Bacteroides xylanisolvens metabolites and find that sphingolipid-containing extracts increase innate immune responses to OCV antigens. Our findings demonstrate a new analytic method for translating metagenomic sequencing data into strain-specific results associated with a biological outcome, and in validating this tool, we identify that microbe-derived sphingolipids impact immune responses to OCV antigens.