Latent tuberculosis infection (LTBI) is an important modifier of gut microbiome composition and immune-metabolic interactions in people living with HIV, producing a distinct microbial and immune-metabolic profile that persists even after antiretroviral therapy.
Key Findings
Results
HIV+LTBI+ individuals exhibited alpha diversity comparable to HIV-negative groups despite the dysbiotic background of HIV infection.
Alpha diversity in HIV+LTBI+ individuals was comparable to both HIV-LTBI- and HIV-LTBI+ groups.
This contrasted with HIV+LTBI- individuals, who showed expected HIV-associated gut dysbiosis.
The study used a cross-sectional design with five categorized groups: HIV-LTBI-, HIV-LTBI+, HIV+LTBI-, HIV+LTBI+, and HIV+TB+.
All participants were ART-naive at baseline.
Results
HIV+LTBI+ individuals formed a distinct microbial community characterized by a lower Firmicutes/Bacteroidota ratio compared to HIV+LTBI- individuals.
The Firmicutes/Bacteroidota ratio was reduced in HIV+LTBI+ compared to HIV+LTBI- individuals.
This community was also characterized by depletion of butyrate-producing Firmicutes.
Despite depletion of butyrate-producing taxa, fecal propionate concentrations were maintained in HIV+LTBI+ individuals.
The distinct microbial community was identified using amplicon sequence variants (ASVs) in an integrated cross-sectional and exploratory longitudinal analysis.
Results
LTBI in PLHIV was associated with enrichment of specific microbial taxa including Megasphaera, Prevotella, Bifidobacterium, and Streptococcus.
These taxa were enriched in HIV+LTBI+ individuals compared to HIV+LTBI- individuals.
Enrichment of these ASVs was identified as part of the distinct microbial community profile associated with LTBI against the background of HIV infection.
The study used ASV-level resolution for microbial community characterization.
Predicted functional analysis revealed reduction in aromatic amino acid metabolic pathways in the HIV+LTBI+ group.
Functional predictions were derived from microbiome composition data as part of the integrated analysis.
This functional alteration was identified as a distinguishing feature of the LTBI-associated microbiome profile within HIV-positive individuals.
Results
The gut microbial co-occurrence network in HIV+LTBI+ individuals was densely connected with greater vulnerability to hub-node loss.
Co-occurrence network analysis revealed a denser network structure in HIV+LTBI+ compared to other groups.
Greater vulnerability to hub-node loss suggests the network is more fragile to targeted disruption despite its density.
This network topology was identified as a distinguishing feature of the LTBI-associated microbiome in PLHIV.
Results
Staged correlation analyses revealed progressive remodeling of host-microbiome associations across HIV and TB disease states.
Prevotella ASVs were associated with PD-1+CD8+ T cells and plasma IP-10 across disease states.
In HIV+TB+ individuals, increased calprotectin and sCD14 were observed together with reduced associations among butyrate-associated taxa.
These associations indicated progressive immune-metabolic remodeling from HIV-negative through HIV+LTBI- to HIV+LTBI+ and HIV+TB+ states.
IP-10 (interferon gamma-induced protein 10) and markers of gut permeability (sCD14, calprotectin) were included in the immune-metabolic analyses.
Results
ART did not restore a microbiome resembling that of HIV-negative individuals in exploratory longitudinal analyses.
Following ART initiation, microbiome composition remained closer to the baseline HIV+LTBI+ profile rather than shifting toward HIV-negative profiles.
This finding was based on exploratory longitudinal analyses in ART-naive individuals followed after treatment initiation.
The persistence of the LTBI-associated microbiome profile under ART suggests LTBI exerts an independent and durable effect on gut microbiome composition.
Results
Microbiome divergence and short-chain fatty acid (SCFA) profiles were associated with the CD4/CD8 ratio rather than CD4 count alone during ART.
The CD4/CD8 ratio, rather than absolute CD4 count, was associated with microbiome divergence and SCFA profiles in longitudinal analyses.
This was observed in exploratory longitudinal analyses following ART initiation.
SCFAs assessed included propionate and butyrate-related measures.
The finding suggests the CD4/CD8 ratio may be a more informative immunological marker for tracking microbiome-immune interactions in PLHIV than CD4 count alone.
Background
The annual risk of tuberculosis reactivation in PLHIV with LTBI is increased 3%–16% compared to HIV-negative individuals.
This elevated reactivation risk is cited as the clinical rationale for characterizing LTBI-associated microbiome changes in PLHIV.
Despite this elevated risk, microbiome alterations associated with LTBI in PLHIV were described as 'poorly characterized' prior to this study.
The study included an HIV+TB+ group to provide a disease continuum from latent to active tuberculosis.
What This Means
This research suggests that latent tuberculosis infection (LTBI) — a dormant form of TB with no active symptoms — leaves a distinct fingerprint on the gut microbiome of people living with HIV (PLHIV), even before TB becomes active. Using stool samples and blood markers from HIV-negative individuals, HIV-positive individuals without LTBI, HIV-positive individuals with LTBI, and HIV-positive individuals with active TB (all before starting HIV treatment), the researchers found that PLHIV who also had LTBI had a surprisingly diverse gut microbiome — more similar to HIV-negative people than to HIV-positive people without LTBI. However, this apparent diversity came with its own distinct pattern: fewer bacteria that produce butyrate (a gut-protective molecule), enrichment of specific bacterial groups like Prevotella and Bifidobacterium, and a more fragile bacterial network that could collapse if key bacterial 'hubs' were disrupted.
The study also found that specific immune markers — including a marker of T cell exhaustion (PD-1+CD8+ T cells) and an inflammation signal (IP-10) — were linked to particular bacteria in ways that changed progressively from HIV infection through latent TB to active TB. In people with active TB, there were additional signs of gut barrier damage. When some participants were followed after starting HIV treatment (antiretroviral therapy, ART), their gut microbiomes did not return to a healthy, HIV-negative pattern; instead, they stayed closer to the LTBI-associated profile. Interestingly, the ratio of CD4 to CD8 immune cells was a better predictor of microbiome health during treatment than the commonly used CD4 cell count alone.
This research matters because it suggests that LTBI is not truly 'silent' — it actively reshapes the gut environment and immune interactions in PLHIV in ways that could influence the risk of TB reactivation and response to HIV treatment. These findings could inform future studies exploring whether changes in the gut microbiome can serve as early warning signs of TB progression or as targets for interventions to reduce TB risk in PLHIV.
Devadiga P, Batgire J, Karandikar K, Bhowmick S, Birje S, Kerkar S, et al.. (2026). Latent tuberculosis infection shapes gut microbiome and immune-metabolic interactions in people living with HIV.. Gut microbes. https://doi.org/10.1080/19490976.2026.2721739