bioRxiv : the preprint server for biologyFeb 6, 2026

Gut Microbiome Chemicals Influence Helper T Cell Development and Immune Aging in Long-Term HIV-1 Infection

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Cell-associated gut-derived bacterial metabolites were linked to senescence-like CD4+ T-cell states in chronic HIV-1 infection.

Evidence

This ex vivo and in vitro immunometabolic study profiled paired plasma and CD4+ T cells from people living with HIV-1, then tested p-cresol sulfate exposure with flow cytometry, single-cell RNA sequencing, transcriptomics, proteomics, and intact proviral DNA measurements.

Caveat

The in vivo reservoir link is associative, and p-cresol sulfate is a mechanistic prototype rather than proof that all gut-derived metabolites drive HIV-1 reservoir persistence.

Simplified

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 metabolites, p-cresol sulfate (PCS) emerged as a mechanistic prototype investigated in depth. 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 capacity, regulatory-like identity, and cellular senescence. Consistently, 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 features with measurements of HIV-1 reservoir size in PLWH revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. Together, these findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate and promotes immune aging-associated states in PLWH. Our data suggest that cell-associated GDBMs may foster immunometabolic CD4⁺ T-cell states previously linked to long-term HIV-1 reservoir persistence in vivo.