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

Abstract

SUMMARYThe 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.

Lineage-specific microbial protein prediction enables large-scale exploration of protein ecology within the human gut

“…Studying the ecology of proteins, rather than species, can provide insights into the ecological importance of protein-bearing species and the ecological pressures that drive protein evolution 17 . In the context of the human gut microbiome, species-independent functional studies have provided insights into the association of bile acid and sulphur metabolic genes with colorectal cancer 18 , and type 3 secretion system effectors with human health conditions 19,20 .…”