Prevalent gut phages encode modular adhesins mediating epithelial binding and endoplasmic reticulum trafficking
- Gábor Apjok
- Tóbiás Sári
- Orsolya Méhi
- András Asbóth
- Lilla Barna
- Dóra Sala
- Ilona Gróf
- Bálint Márk Vásárhelyi
- Szilvia Juhász
- Csaba Pál
- Peter Horvath
- Ede Migh
- György Schneider
- Colin Hill
- Mária Deli
- Andrey Shkoporov
- Bálint Kintses
2026-06-03
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 crAss-like 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.