A distinct immunophenotype in children carrying the Blautia enterotype: The Generation R study

Objective: Studies in mouse models and human adults have shown that the intestinal microbiota composition can affect peripheral immune cells. We here examined whether the gut microbiota compositions affect B and T-cell subsets in children. Methods: The intestinal microbiota was characterized from stool samples of 344 10-year-old children from the Generation R Study by performing 16S rRNA sequencing. Bray-Curtis dissimilarity was used to cluster distinct microbiome compositions (enterotypes). B-cell and T-cell phenotypes were defined by 11-color-flow cytometry. Linear regression models with adjustment for lifestyle and child characteristics were performed to determine associations between enterotypes and immune cell numbers. Results: Three enterotypes with distinct microbiota composition were found, characterized by high abundance of Prevotella, Bacteroides and Blautia. Children with the Blautia enterotype had decreased numbers of plasmablasts, CD4⁺ central memory (Tcm) T cells and follicular T-helper cells (Tfh), while Th22 cells and CD4⁺ effector memory (Tem) T cells, CD27⁻IgA⁺ memory B cells and CD27⁻IgE⁺ memory B cells, were increased in these children. In addition, in children with the Blautia enterotype CD4⁺ Tcm cell numbers expressing the β7 integrin, which can pair with α4 to mediate intestinal homing were also lower, while CD4⁺β7⁺ Tem cell numbers were higher than in the other enterotypes. Conclusion: The Blautia enterotype showed features beneficial for human health. Enterotypes were associated with differences in memory B- and T-cell compartments. This study is unique in the detailed analysis of the B and T-cell compartment and the intestinal microbiome in a large generic pediatric cohort, enabling correction for child and maternal covariates. These outcomes could guide further studies about the impact of intestinal microbiome intervention, for instance through diet and microbiota metabolites such as short chain fatty acid production.