Latent tuberculosis infection shapes gut microbiome and immune-metabolic interactions in people living with HIV

Abstract

The silent presence of latent tuberculosis infection (LTBI) in people living with HIV (PLHIV) increases the annual risk of tuberculosis (TB) reactivation by 3%–16%. Although gut dysbiosis is well documented in HIV, microbiome alterations associated with LTBI in PLHIV remain poorly characterized. Using integrated cross-sectional and exploratory longitudinal analyses, we investigated the gut microbiome composition, predicted function, and immune-metabolic interactions in ART-naive individuals categorized as HIV−LTBI−, HIV−LTBI+, HIV+LTBI−, HIV+LTBI+, and HIV+TB+. Against the dysbiotic background associated with HIV, LTBI was associated with a distinct gut microbial and immune–metabolic profile. Compared with HIV+LTBI−, HIV+LTBI+ individuals exhibited alpha diversity comparable to the HIV-negative groups while forming a distinct microbial community, characterized by a lower Firmicutes/Bacteroidota ratio, depletion of butyrate-producing Firmicutes, enrichment of ASVs assigned to Megasphaera, Prevotella, Bifidobacterium, and Streptococcus, reduced predicted aromatic amino acid metabolic pathways, maintained fecal propionate concentrations, and a densely connected co-occurrence network with greater vulnerability to hub-node loss. Staged correlation analyses revealed progressive remodeling of host‒microbiome associations across HIV and TB disease states, including associations between Prevotella ASVs, PD-1+CD8+ T cells, plasma IP-10, and, in HIV+TB+, increased calprotectin and sCD14 together with reduced associations among butyrate-associated taxa. In exploratory longitudinal analyses, ART did not restore a microbiome resembling that of HIV-negative individuals; instead, the microbiome composition remained closer to the baseline HIV+LTBI+ profile, while microbiome divergence and SCFA profiles were associated with the CD4/CD8 ratio rather than CD4 count alone. These findings identify LTBI as an important modifier of the gut microbiome composition and immune-metabolic interactions in PLHIV and provide a framework for future studies investigating microbiome changes associated with progression to active TB.