biostudies-literatureChac DNICHD NIH HHSNIAID NIH HHSFIC NIH HHSNIGMS NIH HHSDivision of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)638https://www.ebi.ac.uk/biostudies/studies/S-EPMC12816596biostudies-literatureUnknown17(1)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.Nature communicationsGut bacteria-derived sphingolipids alter innate immune responses to oral cholera vaccine antigens.PMC12816596D43 TW005572R01 AI136979R01 AI103055R35 GM133420R01 AI106878T32 HD007233K08 AI123494T32HD007233R01 AI099243R01 106878K43 TW010362R01 AI AI136979Markiewicz SMXu LLaRocque RCQadri FBhuiyan TRAkter AMinot SSChowdhury FHarris JBKhan AIKarmakar PCBanna HAChac DDash PPruitt ELRice ARyan ETHeller FJKaisar MHDumayas MGWeil AAfalseGut 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.2025-01-01T00:00:00Z2025 Dec2026-06-06T17:49:16.898Z2026-06-03T03:10:49.354ZS-EPMC128165964138801910.1038/s41467-025-67388-y