Prevalent Gut Phages Encode Modular Adhesins Mediating Epithelial Binding and Endoplasmic Reticulum Trafficking

Apjok, Gábor and Sári, Tóbiás and Méhi, Orsolya and Asbóth, András and Barna, Lilla and Sala, Dóra and Gróf, Ilona and Vásárhelyi, Bálint Márk and Juhász, Szilvia and Pál, Csaba and Horváth, Péter and Migh, Ede and Schneider, György and Hill, Colin and Deli, Mária and Shkoporov, Andrey and Kintses, Bálint (2026) Prevalent Gut Phages Encode Modular Adhesins Mediating Epithelial Binding and Endoplasmic Reticulum Trafficking. NATURE COMMUNICATIONS, 17. No. 6191. ISSN 2041-1723

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Abstract

Bacteriophages are crucial components of the human microbiome and hold promise as therapeutic agents. Yet, their physical interactions with mammalian cells remain poorly understood. Here, we developed a high-throughput platform to identify phages that adhere to epithelial layers and the proteins that mediate this interaction. The identified phages encode immunoglobulin (Ig)- like domain-containing proteins that, when displayed on a non-adherent phage, confer epithelial binding and internalization in vitro, and increased phage retention in the mouse gut in vivo. Phages encoding these adhesins are among the most abundant and prevalent human gut phages, including crAsslike phages and myoviruses closely related to the recently proposed Flandersviridae family. Domain sequence variation alters epithelial interaction profiles, and internalized phages traffic to the endoplasmic reticulum through the Golgi apparatus, suggesting access to non-degradative internalization pathways. These findings reveal widespread phage-human interactions in the human viral community, with potential impacts on health and implications for next-generation phage therapeutics.

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