Fecal virome transplantation ameliorates Klebsiella pneumoniae infection, associated with rescued intestinal steroid hormone metabolism and pulmonary Treg expansion

Abstract The global spread of drug-resistant Klebsiella pneumoniae highlights an urgent need for antibiotic-independent therapeutics. While the "gut-lung axis" is a recognized therapeutic target, the enteric virome's metabolic crosstalk during severe pneumonia remains elusive. Using a lethal murine K. pneumoniae infection model, we demonstrate that pulmonary infection triggers systemic inflammation, intestinal barrier collapse, and deep gut dysbiosis. Integrated multi-omics reveals this infection drastically restricts gut viral diversity, depleting commensal phages—notably Sigmofec virus —alongside a catastrophic suppression of intestinal steroid hormone metabolism. Strikingly, therapeutic administration of sterile fecal virome transplantation (FVT) significantly mitigates pneumonia severity, enhances pulmonary bacterial clearance, and fully repairs the intestinal barrier. Mechanistically, FVT reverses bacterial dysbiosis, re-engrafts Sigmofec virus , and functionally rescues steroid hormone synthesis. Furthermore, this FVT-driven endocrine restoration is tightly coupled with a tissue-specific expansion of CD4 + CD25+Foxp3 + regulatory T cells (Tregs) in the infected lungs, decisively dampening localized immunopathology. Collectively, our study identifies a trans-kingdom "virome-metabolite-immune" axis disrupted by respiratory infection, establishing FVT as a highly promising, microbiome-sparing strategy for resolving severe bacterial pneumonia.