A gut meta-interactome map reveals modulation of human immunity by microbiome effectors

Veronika Young , Bushra Dohai , Thomas Hitch , Patrick Hyden , Benjamin Weller , Niels van Heusden , Deeya Saha , Jaime Fernandez Macgregor , Sibusiso Maseko , Chung-Wen Lin , Mégane Boujeant , Sébastien Choteau , Franziska Ober , Patrick Schwehn , Simin Rothballer , Melina Altmann , Stefan Altmann , Alexandra Strobel , Michael Rothballer , Marie Tofaute , Matthias Heinig , Thomas Clavel , Jean-Claude Twizere , Renaud Vincentelli (1) , Marianne Boes , Daniel Krappmann , Claudia Falter , Thomas Rattei , Christine Brun (2, 3) , Andreas Zanzoni (2) , Pascal Falter-Braun

1 AFMB - Architecture et fonction des macromolécules biologiques
2 TAGC - Theories and Approaches of Genomic Complexity
3 CNRS - Centre National de la Recherche Scientifique

SUMMARY The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-κB signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohn’s disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

Domaines: Sciences du Vivant [q-bio]

Veronika Young, Bushra Dohai, Thomas Hitch, Patrick Hyden, Benjamin Weller, et al.. A gut meta-interactome map reveals modulation of human immunity by microbiome effectors. 2023. ⟨hal-04240263⟩