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Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection

Amanda Cabral da Silva,¹ Luke Flantzer,¹ Jaclyn Weinberg,² Shuya Kyu,¹ Lisa P. Daley-Bauer,¹ Anyce Godoy,¹ Ana Carolina Santana,¹ Aarthi Talla,³ Amber Rittgers,¹ Sarah Welbourn,¹ David E. Gordon,¹ Jeffrey A. Tomalka,¹ Vincent C. Marconi,⁴ Dean P. Jones,² and Souheil-Antoine Younes¹

Published July 21, 2026 - More info

The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these, p-cresol sulfate (PCS) emerged as a mechanistic prototype. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation, regulatory-like identity, and cellular senescence. In vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic findings with HIV-1 reservoir measurements revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. These findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate, promotes immune aging in PLWH, and may foster immunometabolic states linked to long-term HIV-1 reservoir persistence.

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