Effector–host interactome map links type III secretion systems in healthy gut microbiomes to immune modulation

Pseudomonadota (formerly Proteobacteria) are prevalent in the commensal human gut microbiota, but also include many pathogens that rely on secretion systems to support pathogenicity by injecting proteins into host cells. Here we show that 80% of Pseudomonadota from healthy gut microbiomes also have intact type III secretion systems (T3SS). Candidate effectors predicted by machine learning display sequence and structural features that are distinct from those of pathogen effectors. Towards a systems-level functional understanding, we experimentally constructed a protein-protein meta-interactome map between human proteins and commensal effectors. Network analyses uncovered that effector-targeted neighbourhoods are enriched for genetic variation linked to microbiome-associated conditions, including autoimmune and metabolic diseases. Metagenomic analysis revealed effector enrichment in Crohn's disease but depletion in ulcerative colitis. Functionally, commensal effectors can translocate into human cells and modulate NF-κB signalling and cytokine secretion in vitro. Our findings indicate that T3SS contribute to microorganism-host cohabitation and that effector-host protein interactions may represent an underappreciated route by which commensal gut microbiota influences health.

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Publication Details

Journal
Nature Microbiology
Published
2026-01-26
DOI
https://doi.org/10.1038/s41564-025-02241-y
Citations
1
Primary Topic
Bioinformatics and Genomic Networks
Type
article
Field-Weighted Citation Impact
22.24
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article

Effector–host interactome map links type III secretion systems in healthy gut microbiomes to immune modulation

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1 citations
Nature Microbiology
Bioinformatics and Genomic Networks
22.24
article

Effector–host interactome map links type III secretion systems in healthy gut microbiomes to immune modulation

Patrick Hyden, Jérémie Perrin, Franziska Ober, Michael Rothballer, Rattei Thomas, Matthias Heinig, Deeya Saha, Sibusiso B. Maseko, Stefan Altmann, Sonja Rittchen, Simin Rothballer, Michael A. Calderwood, Sébastien A. Choteau, Daniel Krappmann, Claudia Falter, Daniel Kotlarz, Benjamin Weller, Patrick Schwehn, Bushra Dohai, Alexandra Strobel, Veronika Young, Marie J. Tofaute, Mégane Boujeant, Andreas Zanzoni, Niels S. van Heusden, Melina Altmann, Boes Marianne, Luisa Pletschacher, Jonas Bibus, Pascal Falter-Braun, Marc Vidal, Jean-Claude Twizere, Ye Min Tun, Chung-Wen Lin, Christine Brun, Jaime Fernandez-Macgregor, Luke Lambourne, Daan K. J. Pieren, Lou Bergogne, Hridi Halder, Renaud Vincentelli
article en
1 citations

Abstract

Pseudomonadota (formerly Proteobacteria) are prevalent in the commensal human gut microbiota, but also include many pathogens that rely on secretion systems to support pathogenicity by injecting proteins into host cells. Here we show that 80% of Pseudomonadota from healthy gut microbiomes also have intact type III secretion systems (T3SS). Candidate effectors predicted by machine learning display sequence and structural features that are distinct from those of pathogen effectors. Towards a systems-level functional understanding, we experimentally constructed a protein-protein meta-interactome map between human proteins and commensal effectors. Network analyses uncovered that effector-targeted neighbourhoods are enriched for genetic variation linked to microbiome-associated conditions, including autoimmune and metabolic diseases. Metagenomic analysis revealed effector enrichment in Crohn's disease but depletion in ulcerative colitis. Functionally, commensal effectors can translocate into human cells and modulate NF-κB signalling and cytokine secretion in vitro. Our findings indicate that T3SS contribute to microorganism-host cohabitation and that effector-host protein interactions may represent an underappreciated route by which commensal gut microbiota influences health.

Nature MicrobiologyVol. 11(2)
New York University Abu Dhabi (AE), Centre National de la Recherche Scientifique (FR), University of Vienna (AT), Harvard University (US), Inserm (FR), University of Liège (BE), Utrecht University (NL), Aix-Marseille Université (FR), Gembloux Agro-Bio Tech (BE), Center for Environmental Health (US), Helmholtz Zentrum München (DE), University Medical Center Utrecht (NL), M S Ramaiah University of Applied Sciences (IN), German Center for Pediatric and Adolescent Rheumatology (DE), Boston VA Research Institute (US), Dana-Farber Cancer Institute (US), Ec3 NetWorks (Austria) (AT), Living Systems (United States) (US), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), RWTH Aachen University (DE)
Openalex Percentile: Top 2%
Bioinformatics and Genomic Networks
22.24
DOIOpen Access PDFOpenAlex
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