JCI insightJul 21, 2026

Gut bacteria products influence helper T-cell development and immune aging in HIV-1 infection

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 22, 2026

Abstract

A network of aromatic gut-derived bacterial metabolites is linked to alterations in CD4⁺ T-cell metabolic and functional states.

Cell-associated abundance of specific gut-derived metabolites, particularly p-cresol sulfate (PCS), is associated with changes in CD4⁺ T-cell metabolism.
Higher levels of PCS correlate with transcriptional programs indicative of impaired T-cell differentiation and cellular aging.
PCS exposure in vitro leads to cell-cycle arrest and mitochondrial dysfunction in CD4⁺ T cells.
The presence of specific immune cell states associated with gut-derived metabolites is linked to levels of intact proviral DNA in people living with HIV-1.

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, 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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Gut bacteria products influence helper T-cell development and immune aging in HIV-1 infection

Abstract

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