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

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.