Prevalent Gut Phages Use Adhesins to Bind Human Cells and Enhance Persistence in the Intestine

Bacteriophages are increasingly recognized as key members of the human microbiome, yet their interactions with human cells remain poorly understood. While phages are traditionally viewed as viruses that exclusively infect bacteria, new research suggests that many gut phages can directly interact with epithelial tissues lining the intestine. A recent study has uncovered a widespread mechanism that enables common gut phages to attach to epithelial surfaces, enter host cells, and persist longer within the gastrointestinal tract. These findings reveal an unexpected level of communication between phages and the human body and may have important implications for both microbiome biology and future phage-based therapeutics.

© The Phage Therapy

To identify phages capable of interacting with human tissues, researchers developed a high-throughput screening platform using viral communities isolated from the feces of healthy and dysbiotic individuals. By exposing these diverse phage populations to human intestinal epithelial cell lines and tracking which viruses remained attached after extensive washing, the team identified a subset of phages that consistently adhered to epithelial surfaces. Genomic analysis revealed that these adherent phages frequently encoded proteins containing immunoglobulin-like domains, particularly BACON and PKD domains, which appeared to function as molecular adhesins mediating contact with host tissues.

The study demonstrated that these adhesins are not rare features restricted to a few unusual viruses. Instead, they are commonly found among some of the most abundant phages in the human gut, including members of the highly prevalent Crassvirales group and phages closely related to the proposed Flandersviridae family. Many of these viruses encode multiple adhesin modules arranged in different combinations, suggesting that they have evolved sophisticated mechanisms for interacting with mucus layers and epithelial surfaces throughout the gastrointestinal tract.

To verify the role of these proteins, researchers engineered the Escherichia coli phage K1F, a virus that normally exhibits minimal interaction with epithelial cells. By displaying adhesin proteins identified from adherent gut phages on the surface of K1F particles, they created recombinant phages with dramatically enhanced abilities to bind and enter human epithelial cells. The modified phages showed significantly greater uptake across several cell types, including intestinal and lung epithelial cells, confirming that these immunoglobulin-like proteins are sufficient to confer epithelial interaction capabilities.

Interestingly, the strength of these interactions varied depending on the adhesin architecture. Some engineered phages demonstrated particularly strong uptake in mucus-producing epithelial cells, suggesting that specific adhesin combinations influence recognition of mucosal components. Experiments disrupting mucus structure or removing glycocalyx-associated molecules significantly reduced phage uptake, indicating that these surface features serve as important binding targets. Even small sequence differences within closely related adhesins altered epithelial interaction patterns, highlighting the remarkable specificity of these phage-host relationships.

The researchers then explored whether these interactions influence phage behavior in living organisms. Mice were orally administered wild-type and engineered phages, and viral shedding was monitored over time. Phages displaying adhesins persisted significantly longer within the gastrointestinal tract than the non-adherent control phage. The results suggest that adhesion to mucus and epithelial surfaces enhances phage retention in the gut, potentially increasing opportunities for encounters with bacterial hosts and improving long-term persistence within the microbiome.

Further analyses revealed that phages carrying these adhesins are not only widespread but also disproportionately abundant and prevalent across human populations. Examination of large virome datasets containing tens of thousands of viral genomes showed that phages encoding BACON, PKD, or related immunoglobulin-like domains are consistently enriched among the most abundant and commonly detected gut phages. Their prevalence was particularly high in mucosal body sites, supporting the idea that adhesion provides a major ecological advantage within mucus-rich environments.

The study also found evidence linking these phages to gut health. Adhesin-encoding phages were more abundant in healthy individuals than in patients with inflammatory bowel disease, suggesting that they may be associated with intact mucosal ecosystems. Although the findings do not imply a direct protective role, they indicate that these phages are characteristic components of stable and healthy gut microbial communities.

Perhaps most surprisingly, intracellular trafficking experiments revealed that internalized phages do not simply end up in degradative lysosomes. Instead, many accumulated within the Golgi apparatus and endoplasmic reticulum after entering epithelial cells. This pattern suggests that phages may exploit non-degradative intracellular pathways, potentially allowing them to persist inside host cells for extended periods. Such trafficking routes resemble those used by certain bacterial toxins and animal viruses, raising intriguing questions about the broader biological consequences of phage entry into mammalian tissues.

Together, these findings challenge the traditional view that bacteriophages interact only with bacteria. Instead, they reveal that many dominant gut phages possess specialized adhesins that facilitate direct engagement with epithelial surfaces, promote persistence in the gastrointestinal tract, and enable intracellular trafficking within mammalian cells. Beyond advancing our understanding of phage ecology, these discoveries may eventually support the development of engineered phages capable of targeted tissue delivery, enhanced retention, or novel therapeutic applications in human medicine.

Source: Apjok G., Sári T., Méhi O. et al. Prevalent gut phages encode modular adhesins mediating epithelial binding and endoplasmic reticulum trafficking (Nature Communications, 2026). DOI : https://www.nature.com/articles/s41467-026-74031-x