{
  "abstract": "Anaerobe-depleting antibiotic exposure is associated with inferior progression-free survival after CD19 CAR T-cell therapy in large B-cell lymphoma, yet the cellular mechanisms linking gut dysbiosis to the CAR T-cell product and whether this imprint is reversible have remained undefined. In two independent CAR-T candidate cohorts, low stool valerate at the time of CAR-T eligibility identified a multi-metabolite-deficient dysbiotic gut microbiome state marked by depletion of fiber-fermenting commensals and loss of carbohydrate-fermentation, SCFA-biosynthesis, and amino-acid metabolism pathways. Reanalysis of single-cell RNA sequencing from 42 lymphoma patients stratified by piperacillin-tazobactam/imipenem/meropenem (PIM) exposure revealed that PIM-exposed CAR T-cell products were CD4-skewed, with significantly elevated AP-1/immediate-early gene (IEG) and cellular activation signatures that together predicted inferior progression-free survival. Ex vivo conditioning of CAR T-cells with valerate produced a chromatin and transcription factor program distinct from butyrate or propionate, characterized by KLF/SP/EGR family engagement, KLF4 promoter opening, and broad induction of AP-1/IEG and MHC class II transcripts, whereas butyrate drove broader chromatin remodeling with TBX21/EOMES/NF-{kappa}B gains and KLF2 promoter closure, and propionate induced an NFY-centered program with preferential commitment to low-mitochondrial-content states. Untargeted metabolomics confirmed valerate uptake and mitochondrial {beta}-oxidation in CAR T-cells, while dietary sodium valerate supplementation in meropenem-treated mice bearing A20 lymphoma significantly reduced tumor burden and extended survival compared with CAR T-cells alone. These findings identify stool valerate as a bedside-deployable biomarker of dysbiosis-imprinted CAR T-cell dysfunction and support ex vivo or dietary valerate supplementation as a clinically tractable strategy to improve CAR-T anti-tumor function in patients with disrupted gut microbiomes.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Stem Cell Transplantation and Cellular"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 28,
  "authors": [
    {
      "name": "L. Rehman"
    },
    {
      "name": "W. Song"
    },
    {
      "name": "A. Rehman"
    },
    {
      "name": "K. Singh"
    },
    {
      "name": "S. G. Rawat"
    },
    {
      "name": "F. Darbaniyan"
    },
    {
      "name": "C. C. Le"
    },
    {
      "name": "F. M. Aletti"
    },
    {
      "name": "J. Weng"
    },
    {
      "name": "J. Liu"
    },
    {
      "name": "X. Cheng"
    },
    {
      "name": "Y. Tang"
    },
    {
      "name": "S. Patchva"
    },
    {
      "name": "M. D. Richard"
    },
    {
      "name": "F. Chu"
    },
    {
      "name": "J. Cao"
    },
    {
      "name": "C. R. Flowers"
    },
    {
      "name": "E. J. Shpall"
    },
    {
      "name": "M. R. Tanner"
    },
    {
      "name": "J. Fahrmann"
    },
    {
      "name": "E. Elinav"
    },
    {
      "name": "C. K. Stein-Thoeringer"
    },
    {
      "name": "M. D. Jain"
    },
    {
      "name": "R. R. Jenq"
    },
    {
      "name": "A. Jain"
    },
    {
      "name": "S. S. Neelapu"
    },
    {
      "name": "Y. Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Y. Saini"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ex7h5jjdkezgq.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.01.748711",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748711v1.full",
  "id": "ex7h5jjdkezgq",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748711v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|CAR-T cell therapy research"
    ]
  ],
  "openalex": "W7207731285",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748711v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/ex7h5jjdkezgq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:52Z",
      "native_id": "10.64898/2026.09.01.748711",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.01.748711v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Microbial valerate is associated with CAR T dysbiosis and its supplementation enhances CAR T function in B-cell lymphoma",
  "title_text": "Microbial valerate is associated with CAR T dysbiosis and its supplementation enhances CAR T function in B-cell lymphoma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:52Z",
  "url": "https://research.draconitic.com/paper/ex7h5jjdkezgq",
  "venue": "bioRxiv",
  "versions": []
}