The Influence of the gut microbiome on BCG-induced trained immunity

The bacillus Calmette-Guerin (BCG) vaccine protects against tuberculosis and heterologous infections, but elicits high interindividual variation in specific and nonspecific (trained) immune responses. As the gut microbiome might mediate this variability, stool and blood were collected from 321 healthy adults before BCG vaccination, followed by blood sampling two weeks and three months afterwards. Metagenomics based on de novo genome assemble revealed 43 taxa associated with increased cytokine production upon ex vivo blood restimulation by Mycobacterium tuberculosis and Staphylococcus aureus. Trained responses negatively correlated with Roseburia, while specific responses associated positively with Ruminococcus and Eggerthella Ienta. The immunomodulatory taxa identified also had the strongest effects on circulating metaboloties, with Roseburia predominantly affecting phenylalanine metabolism. This was corroborated by abundances of relevant enzymes, suggesting alternate phenylalanine metabolism modules are activated in a Roseburia species-dependent manner. These findings reveal microbes and their products that may alter BCG-induced specific and trained immune responses.