Ami Bhatt Links Gut Phages, Hospital Superbugs and Recombinases for In Vivo CAR-T Engineering
Ami Bhatt’s research at Stanford connects three problems that are usually studied separately: the origin of bloodstream infections in immunocompromised patients, rapid genome evolution in hospital-adapted bacteria, and the use of microbial recombinases to engineer human cells.
In a September 2026 episode of Stanford Medicine’s The Future of Medicine, Bhatt described how her group studies microbial communities as evolving genomic systems rather than static lists of bacterial species. The laboratory focuses particularly on mobile genetic elements, including transposable elements and bacteriophages, because these sequences can alter bacterial genomes over clinically relevant timescales.
One major application is hematopoietic cell transplantation. These patients receive combinations of chemotherapy, immunosuppressive drugs and broad-spectrum antibiotics that can disrupt the intestinal microbiota and impair epithelial barrier function. Bhatt describes work performed with Andrew Rezvani, David Miklos and colleagues in which approximately 40% of bloodstream infections in a Stanford bone marrow transplant population could be traced to organisms already present in the patients’ intestinal microbiomes.
The result supports a model in which some bloodstream infections arise through expansion and translocation of endogenous gut organisms rather than exclusively through acquisition of an external pathogen. Facultative anaerobes such as Escherichia coli and Enterococcus faecium are particularly relevant because they can proliferate in the intestinal environment while also remaining capable of growth after entering oxygenated tissues or blood.
Bhatt’s group has also investigated why E. faecium has become such a successful healthcare-associated pathogen. A 2026 Nature study analysed 19,485 high-contiguity genomes from major hospital-associated bacterial pathogens and found E. faecium to be the most enriched in insertion sequences among the organisms examined. The genome was particularly dominated by replicative ISL3-family transposable elements, which have expanded in clinical E. faecium lineages over approximately the past three decades.
The investigators combined population-scale genome analysis with long-read sequencing of bloodstream isolates and longitudinal metagenomic data from hematopoietic cell transplantation recipients. In 28 stool samples from 12 patients, they detected insertion-sequence-mediated genome changes occurring within hosts during treatment.
One experimentally characterized event involved an ISL3 insertion upstream of the folT folate transporter. The insertion generated a strong hybrid promoter, increased folT transcription and improved relative bacterial fitness under folate-limited conditions. The authors propose that enhanced folate scavenging could contribute to E. faecium expansion when the surrounding intestinal microbiome has collapsed, a state frequently observed in critically ill and transplant patients.
This provides a mechanistic example of how a transposable element can produce a selectable phenotype without requiring the gradual accumulation of conventional point mutations. Repeated transposition can alter promoters, gene dosage, genome architecture or coding sequences, creating substantial phenotypic diversity within rapidly replicating bacterial populations.
Bhatt’s Stanford interview then extends the mobile-genetic-element concept to bacteriophages.
Many phages in the intestinal microbiome are temperate rather than obligatorily lytic. They can integrate their genomes into bacterial chromosomes and persist as prophages. Site-specific integration requires enzymes able to recognize defined attachment sequences in the phage and bacterial genomes and catalyse recombination without randomly fragmenting the chromosome.
Large serine recombinases are one class of these enzymes. They catalyse directional recombination between short attachment sites and are found in mobile genetic elements including bacteriophages, integrative elements and other bacterial genomic islands.
A collaboration involving Matthew Durrant, Alison Fanton, Josh Tycko, Michael Bassik, Lacramioara Bintu, Ami Bhatt, Patrick Hsu and colleagues developed a computational strategy to identify LSRs and predict their corresponding attachment sites directly from microbial genomic data. The approach increased the known diversity of LSRs by more than 100-fold.
More than 60 candidate enzymes were experimentally characterized in human cells. The best-performing systems achieved 40–75% genomic integration efficiencies for DNA cargos larger than 7 kb and up to seven-fold higher recombination than the commonly used Bxb1 recombinase in the assays reported. The study also demonstrated direct genomic targeting by some enzymes and integration without exposing the double-stranded DNA breaks required by many nuclease-dependent editing approaches.
These properties are relevant because therapeutic genome engineering often requires insertion rather than deletion or small-sequence correction. Large genetic cargos may contain full coding sequences, regulatory elements or synthetic receptors whose size exceeds what is convenient for many conventional editing strategies.
LSRs are mechanistically attractive because recombination does not depend on endogenous homology-directed DNA repair. Instead, the recombinase recognizes defined attachment sequences, cleaves both DNA substrates, exchanges strands and religates them in a coordinated reaction. The specificity is determined largely by the cognate recombinase–attachment-site pair.
The Stanford work subsequently contributed to the creation of Stylus Medicine, founded by Bhatt, Bassik, Bintu and Patrick Hsu. The company emerged from stealth in 2025 with an $85 million Series A financing and is developing engineered recombinases coupled to lipid nanoparticle delivery for in vivo genetic medicines.
According to Stanford SPARK, the platform is being developed for targeted, sequence-specific integration of large therapeutic DNA payloads. Its initial therapeutic direction is in vivo CAR-T engineering, where the aim is to deliver the recombinase system and CAR genetic payload directly to immune cells inside the patient rather than isolating, engineering and expanding T cells ex vivo.
Conventional autologous CAR-T manufacturing requires leukapheresis, ex vivo T-cell activation, genetic modification, cell expansion, quality-control testing and reinfusion. In vivo engineering attempts to collapse several of these manufacturing steps into a directly administered genetic medicine.
Bhatt describes the proposed system as combining a recombinase, CAR-encoding DNA and targeted lipid nanoparticle delivery. The large-cargo capacity is relevant because CAR constructs can require several functional elements, while site-specific insertion could in principle provide more controlled genomic placement than random integrating vectors.
The technology remains preclinical. Stanford reported in 2025 that Stylus was continuing preclinical development and had presented its recombinase-engineering and in vivo CAR-T platform at the American Society of Gene & Cell Therapy annual meeting. There is no clinical evidence in the Stanford material demonstrating that this recombinase platform has yet generated CAR-T cells therapeutically in human patients.
The distinction between this work and conventional phage therapy is important. Stylus is not using intact bacteriophages to treat cancer. It is exploiting enzymes identified from the biology of phages and other mobile genetic elements as genome-engineering tools.
Bhatt nevertheless also discusses conventional therapeutic phages. She notes that lytic phage cocktails have been used experimentally against infections resistant to available antibiotics, while temperate phages are relevant as sources of molecular machinery because their genomes must integrate into bacterial chromosomes with high sequence specificity.
Her laboratory’s work on the gut virome provides another example of this emphasis on phage biology. In 2025, researchers from the Bhatt and Gavin Sherlock groups reported isolation of prototypical crAssphage, a highly abundant human gut bacteriophage that had remained difficult to cultivate despite its prevalence in metagenomic datasets. The isolated phage showed an unusual dual lifestyle associated with its bacterial host, providing a tractable system for studying one of the dominant viral components of the intestinal microbiome.
These different research directions are linked by the same experimental principle: mobile genetic elements are active drivers of microbial phenotype and evolution.
In E. faecium, insertion sequences can alter bacterial gene regulation during adaptation to the hospital and host environment. In the gut microbiome, phages can reshape bacterial populations and move DNA between microbial genomes. In genome engineering, recombinases evolved by mobile genetic elements can be repurposed to insert therapeutic DNA into mammalian cells.
The medically relevant outputs are therefore different. Microbiome sequencing may help identify reservoirs of bloodstream infection. Transposable-element analysis may reveal mechanisms underlying hospital adaptation. Phage-derived and other microbial recombinases may provide tools for precise, large-payload genome integration.
The connection is molecular rather than rhetorical: all three depend on understanding how DNA moves, integrates and changes function inside genomes.
Sources :
Stanford Medicine — Ami Bhatt on the Microbiome, Superbugs, and Cancer Therapy, The Future of Medicine, 7 September 2026.
Grieshop MP et al. Transposable elements are driving rapid adaptation of Enterococcus faecium. Nature 653, 1139–1147 (2026). DOI: 10.1038/s41586-026-10373-2.
Durrant MG et al. Systematic discovery of recombinases for efficient integration of large DNA sequences into the human genome. Nature Biotechnology 41, 488–499 (2023). DOI: 10.1038/s41587-022-01494-w.
Stanford SPARK — Stylus Medicine emerges from stealth to develop in vivo genetic medicines, 3 June 2025.
Stanford Medicine — The Microbiome’s Most Abundant Resident: Team of Stanford Researchers Isolates crAssphage for the First Time, 14 August 2025.
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