A host–microbiota interactome reveals extensive transkingdom connectivity

Nicole D. Sonnert, Connor E. Rosen, Andrew R. Ghazi, Eric A. Franzosa, Brianna Duncan-Lowey, Jaime A. González-Hernández, John D. Huck, Yi Yang, Yile Dai, Tyler A. Rice, Mytien T. Nguyen, Deguang Song, Yiyun Cao, Anjelica L. Martin, Agata A. Bielecka, Suzanne Fischer, Changhui Guan, Julia Oh, Curtis Huttenhower, Aaron M. Ring () and Noah W. Palm ()
Additional contact information
Nicole D. Sonnert: Yale School of Medicine
Connor E. Rosen: Yale School of Medicine
Andrew R. Ghazi: Harvard T. H. Chan School of Public Health
Eric A. Franzosa: Harvard T. H. Chan School of Public Health
Brianna Duncan-Lowey: Yale School of Medicine
Jaime A. González-Hernández: Yale School of Medicine
John D. Huck: Yale School of Medicine
Yi Yang: Yale School of Medicine
Yile Dai: Yale School of Medicine
Tyler A. Rice: Yale School of Medicine
Mytien T. Nguyen: Yale School of Medicine
Deguang Song: Yale School of Medicine
Yiyun Cao: Yale School of Medicine
Anjelica L. Martin: Yale School of Medicine
Agata A. Bielecka: Yale School of Medicine
Suzanne Fischer: Yale School of Medicine
Changhui Guan: The Jackson Laboratory for Genomic Medicine
Julia Oh: The Jackson Laboratory for Genomic Medicine
Curtis Huttenhower: Harvard T. H. Chan School of Public Health
Aaron M. Ring: Yale School of Medicine
Noah W. Palm: Yale School of Medicine

Nature, 2024, vol. 628, issue 8006, 171-179

Abstract: Abstract The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1–3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the ‘exoproteome’). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome–microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome–microbiome interactions. Using BASEHIT, we interrogated more than 1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host–microorganism interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic; for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host–microbiota interactions that may underlie causal effects of indigenous microorganisms on human health and disease.

Date: 2024
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DOI: 10.1038/s41586-024-07162-0

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