Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota

• Published in: Nature medicine Vol. 27; no. 8; pp. 1442 - 1450
• Main Authors: Vogl, Thomas, Klompus, Shelley, Leviatan, Sigal, Kalka, Iris N., Weinberger, Adina, Wijmenga, Cisca, Fu, Jingyuan, Zhernakova, Alexandra, Weersma, Rinse K., Segal, Eran
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2021; Nature Publishing Group
• Subjects: 631/1647/2163; 631/1647/514/2254; 631/1647/664/2089; 631/250/2152/2153/1291; 631/326/2565/2134; Abundance; Analysis; Antibodies; Antibody diversity; Antigens; B-cell receptor; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemical properties; Deoxyribonucleic acid; DNA; DNA sequencing; Epitopes; Immune response; Immunoprecipitation; Infectious Diseases; Intestinal microflora; Lymphocytes B; Metabolic Diseases; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Molecular Medicine; Neurosciences; Phages; Physiological aspects; Probiotics; Species composition; Netherlands
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01409-3

Serum antibodies can recognize both pathogens and commensal gut microbiota. However, our current understanding of antibody repertoires is largely based on DNA sequencing of the corresponding B-cell receptor genes, and actual bacterial antigen targets remain incompletely characterized. Here we have profiled the serum antibody responses of 997 healthy individuals against 244,000 rationally selected peptide antigens derived from gut microbiota and pathogenic and probiotic bacteria. Leveraging phage immunoprecipitation sequencing (PhIP-Seq) based on phage-displayed synthetic oligo libraries, we detect a wide breadth of individual-specific as well as shared antibody responses against microbiota that associate with age and gender. We also demonstrate that these antibody epitope repertoires are more longitudinally stable than gut microbiome species abundances. Serum samples of more than 200 individuals collected five years apart could be accurately matched and could serve as an immunologic fingerprint. Overall, our results suggest that systemic antibody responses provide a non-redundant layer of information about microbiota beyond gut microbial species composition. Phage immunoprecipitation sequencing illustrates the wide breadth of systemic microbiota-specific antibody responses, which are more longitudinally stable than gut microbiome species abundances in a cohort of healthy individuals.