Phage therapy can directly target mycobacteria and eliminate them, leading to improved clinical outcomes [60]. On the other hand, the microbiome, including phages, of HIV-infected patients with Mycobacterium tuberculosis (MTB) shows unique changes that vary with tuberculosis (TB) status, HIV infection, and ART. Specifically, analysis of the microbiome of different TB sites showed reduced beta diversity in patients with bacteriologically confirmed TB compared with non-TB (nTB) controls [61–63]. Although there are some inconsistencies in the results of studies on the TB-specific gut microbiome, key changes generally involve changes in SCFAs-producing species (e.g., Lachnospiraceae, Ruminococcus, Blautia, Dorea, and Faecalibacterium), inflammation-associated species (e.g., Prevotella), and potentially beneficial genera (e.g., Bifidobacterium) [64]. This further demonstrates that TB-specific dysbiosis is associated with the metabolism of key SCFAs. HIV infection status and ART significantly affect these microbiome characteristics and are associated with treatment efficacy [65]. HIV-positive patients with MTB show enrichment of Mycobacterium/Bifidobacterium, while ART treatment reduces both genera. Lung involvement is associated with enrichment of Mycobacteria and depletion of Streptococci [62]. Phage therapy, as an adjunct to antibiotics for the treatment of resistant mycobacterial infections, can reduce antibiotic doses and improve their efficacy. Thus, phage therapy offers all these therapeutic benefits with a good safety profile and minimal toxicity [60]. Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) with a high degree of intrinsic and acquired antibiotic resistance, which severely limits treatment options and has a poor prognosis [66]. However, phage therapy cleared a persistent M. abscessus infection in a cystic fibrosis patient, allowing for a successful lung transplant [66]. Further studies have confirmed that phage therapy has a significant efficacy (> 50%) against mycobacterial infections [60]. Overall, these advances provide unprecedented treatment options for serious, previously untreatable mycobacterial infections and lay the foundation for future clinical trials.

Since CMV infection is associated with specific changes in the composition of the intestinal flora, including a decrease in the Firmicutes to Bacteroidetes abundance ratio [67], phage therapy targets specific intestinal flora and regulates the balance of the microbial community, which may improve intestinal flora disorders that lead to CMV replication, intestinal mucosal barrier damage, and elevated levels of pro-inflammatory cytokines in the colon, ultimately improving the progression of colitis. Additionally, phage therapy promotes intestinal flora symbiosis [68], increases SCFAs production, and improves the relationship between Treg/Th17 imbalance caused by CMV [69]. Phage therapy has also been reported to break the vicious cycle between CMV and intestinal flora, which may be initiated through type I interferon signaling [70, 71]. The interaction between CMV infection and lung flora has been less studied, and the application of phage therapy to understand this phenomenon deserves further study.

Invasive fungal disease (IFD) is a common opportunistic infection and a significant cause of hospitalization and mortality in HIV-infected patients [72]. Crucially, the diversity of lung microbiota composition appears to predict survival in patients with invasive pulmonary aspergillosis (IPA) [73], suggesting that the microbiome plays an important role in fungal infections. When it comes to the microbiome, the public often focuses on bacteria and viruses, but they often ignore the fact that the “fungal community” that accounts for a certain proportion may also play a key role [74]. During invasive fungal lung infections, phage therapy targets bacterial species in the lungs, improving bacterial richness and alpha diversity, as well as the ratio of Prevotella to Veillonella; this may improve the prognosis of IPA patients [73]. Furthermore, phage therapy mitigates invasive fungal colonization by targeting facilitating bacteria such as Pseudomonas aeruginosa, Burkholderia cepacia, and Haemophilus influenzae, thereby limiting their proliferation and reducing bacterial burden on the bronchial mucosa in cystic fibrosis patients [75]. Therefore, phages that target microbiota modulation have become a promising new approach for antifungal therapy [76]. Strategies such as phage therapy and probiotics may alter the composition of the intestinal microbiota by directly modulating immune cells or releasing health-promoting metabolites that affect systemic immunity [77].

Microbiome dysbiosis is mechanistically linked to cardiovascular pathogenesis, including heart failure, atherosclerosis, and hypertension, with mechanisms involving inflammation, metabolic reprogramming, and microbial-derived metabolites [78, 79]. In PLWH, phages targeting the elimination of pro-inflammatory microbiota (e.g., Fusobacterium nucleatum) can increase SCFAs production, and reduce the accumulation of atherogenic metabolites [e.g., imidazole propionate (ImP)], thereby jointly inhibiting the progression of vascular lesions [3, 79]. In addition to the targeted elimination of pro-inflammatory pathogens [80], phage therapy can also reduce LPS translocation, inhibit Toll-like receptor-mediated inflammation, reduce IL-6/IL-8/IL-17 levels [81–83], and slow the progression of carotid plaques, showing therapeutic potential.

Microbiome dysbiosis underlies the development of metabolic diseases in PLWH [84]. HIV disrupts SCFAs-mediated glucose regulation through mucosal damage, translocation of microbiota in mucosa, chronic inflammation, and tryptophan catabolism via the kynurenine pathway [85, 86], and phage-specific targeting can mitigate the risk of T2D. In addition, ART improves survival, but it leads to insulin resistance, dyslipidemia, and fat redistribution. These are precursors to metabolic syndrome, T2D, and cardiovascular disease [87]. Emerging evidence supports phage-mediated precise elimination of Prevotella to restore butyrate synthesis and improve insulin sensitivity [88], thereby modulating homeostasis model assessment of insulin resistance (HOMA-IR) and adiponectin in PLWH and improving diabetes outcomes [89]. Therefore, phage therapy strategies targeting the microbiome are an important component of long-term HIV management [88].

Obesity is a significant comorbidity in PLWH, and rapid weight gain is associated with a higher risk of diabetes and metabolic sequelae compared with the general population [90]. Due to obesity- and HIV-induced dysbiosis, gut microbiota-derived SCFAs and BAs—key regulators of inflammation and metabolism, are reduced [91, 92]. Targeted phage therapy for dysbiosis could mitigate the direct effects of HIV proteins and ART on adipocyte biology, genetic susceptibility, microbial translocation, adaptive immune dysregulation, tissue inflammation, and accelerated fibrosis [93]. In PLWH, enrichment of Ruminococcus and Streptococcus, taxa linked to MASLD, compromises intestinal tight junctions, facilitating translocation of bacteria and LPS to the liver, where LPS-driven activation of hepatic stellate cells worsens steatosis and may promote fibrosis [94, 95]. Phage-mediated reduction of Gram-negative bacterial load may ultimately improve liver enzyme profiles and reduce lipid deposition [94, 95]. Given the current lack of effective obesity interventions for PLWH, phage-targeted bacterial regulation of the microbiota has become a key therapeutic strategy in the metabolic diseases [90] and is expected to open up new therapeutic avenues for obesity management in this population.

Neurocognitive function declines more rapidly in PLWH, frequently leading to HIV-associated neurocognitive disorder. For example, the severity of distal neuropathic pain (DNP) in this population is associated with reduced intestinal α-diversity and increased abundance of Blautia/Clostridium [96]. HIV-induced gut microbiota dysbiosis results in significantly lower levels of circulating butyrate and valerate than in HIV-seronegative people, disrupts the mucosal endothelial barrier, and leads to persistent microbial translocation and systemic inflammation [97, 98]. Therefore, phages target specific microbiota, affect key SCFA metabolites, repair intestinal epithelial integrity, and regulate immune levels [99], ultimately changing this pro-inflammatory environment and disrupting gut-brain axis signal transduction, which may mediate the pathogenesis of HIV-associated neurocognitive disorder. In addition, phages mediate intestinal microbiota balance, which has a parallel mechanism with mood regulation [100]. Notably, alterations in the gut microbiota of individuals with HIV, including a decline in Bacteroides and a rise in aerotolerant bacteria, have been associated with adverse emotional outcomes [101]. Conversely, in HIV-HCV co-infected individuals, depression is linked to elevated Bacteroides abundance and disrupted BA metabolism [102]. Although phage regulation of neuroactive microbial pathways and serotonin metabolism represents a promising therapeutic approach, its mechanistic evidence is still preliminary and warrants further study.

Kidney disease, including HIV-associated nephropathy (HIVAN), is a serious complication of HIV infection, and gut dysbiosis is associated with this pathogenesis. ART can alleviate direct renal damage caused by HIV to varying degrees, but HIV-affected or ART-induced gut dysbiosis persists for a long time and may accelerate renal failure through inflammatory cascades and the production of uremic toxins [103]. The microbiota of patients with chronic kidney disease (CKD) shows a significant expansion of uremic toxin precursor-producing bacteria [104]. Phages intervene in the regulation of microbial flora and metabolites, reduce chronic inflammation and repair mucosal barriers, avoid microbial translocation (such as Enterobacteriaceae) [105], and affect Kupffer cells through portal circulation, reduce systemic inflammation and glomerular damage, and reduce renal fibrosis formation [95].

In addition to renal pathology, HIV also induces skin flora imbalance (such as a decrease in skin bacilli) and barrier dysfunction, and there is a bidirectional relationship between the two [106]. Local phage therapy may restore ecological balance and improve diseases such as atopic dermatitis [106]. Microbiome composition also affects vaccine response. The enrichment of Bifidobacterium/Faecalibacterium in PLWH is associated with higher titers of coronavirus disease 2019 (COVID-19) vaccine-induced IgGs [107], suggesting that application of phages to control microbial species can optimize vaccine immunogenicity. The elevated risk of HIV-associated cancers—including Kaposi sarcoma, lymphoma, and anal cancer—is further promoted by gut dysbiosis. This occurs through several oncogenic pathways: chronic inflammation, local and systemic immunosuppression, direct DNA damage, and the production of pro-tumorigenic microbial metabolites [108]. Notably, anal precancerous lesions in HIV-infected individuals are associated with enrichment of Prevotella [109]. Thus, local phage therapy could be a strategy to target carcinogenic microbiota. Elucidating the tripartite interactions between HIV, the microbiota, and extraintestinal pathologies remains critical for developing targeted interventions to restore microbiota balance and improve clinical outcomes.

The application of phage therapy to modulate the HIV-associated microbiome is fraught with complexity, primarily due to the intricate triad of microbiome-immune-viral pathogenesis interactions. A major obstacle is the considerable inter-individual variation in microbial composition, influenced by genetics, lifestyle, and environment, which confounds the establishment of universal definitions for “health” and “dysbiosis”. This variability, compounded by significant heterogeneity in clinical study designs, challenges the reproducibility and broader applicability of research outcomes [110]. This can be addressed by establishing cross-scale phage therapy research platforms that perform dynamic predictive modeling through multi-omics data fusion (metagenomics/metabolomics/immunoassays). Poorly defined interactions between HIV, sexual behavior, dietary habits, and microbial ecology further obscure causal relationships, which can be mitigated by machine learning-driven barrier integrity assessment (via SCFA ratios such as propionate/butyrate) and CD4⁺ T cell-stratified precision pharmacokinetics (for sustained-release formulations with counts < 200/μL) to enhance mechanistic elucidation. Mechanistically, the host-phage-microbiome [111] is perturbed by HIV-mediated alterations in quorum sensing [112] and antiretroviral drugs (ARVs), which result in a unique and complex microenvironment. For this unique and complex microenvironment, synergistic combination strategies can be adopted to improve efficacy. Critical knowledge gaps persist due to technical limitations in analyzing high-dimensional omics data, particularly in proteomics and metabolomics. These gaps may be addressed through staged ecological reprogramming—a sequential process involving pathogen-specific phage deployment, probiotic or FMT-mediated introduction of beneficial colonies, and the use of engineered phages to promote a stable microbial ecosystem.

These complexities introduce research uncertainties into the design of phage therapy in the context of HIV. First, the broad spectrum of infecting pathogens (ranging from ESKAPE pathogens to rare fungi like Talaromyces marneffei) can be targeted precisely using the staged ecological reprogramming strategy. Secondly, ART (e.g., the rilpivirine/dolutegravir regimen) exerts varying effects on the host microbiome, and personalized treatment hinders the study of regular patterns—this can be addressed by real-time monitoring methods to spatially track phage localization and bacterial clearance dynamics. In addition, bacterial-phage competition increases the evolutionary escape rate of bacteria in immunosuppressed hosts by 2-3-fold, elevating drug resistance risk, which can be prevented through resistance gene monitoring.

Despite clear therapeutic potential, phage delivery confronts multiple translational challenges, including formulation and storage instability, scalable GMP compliant production and purification, limited mucosal penetration and rapid host immune neutralization, emergent bacterial resistance and risk of endotoxin mediated inflammation or horizontal gene transfer, unclear pharmacokinetics and dosing regimens, and unresolved regulatory and clinical evidence requirements that must be addressed to enable safe and effective clinical deployment. A central challenge in therapeutic phage delivery is their unique pharmacokinetic-pharmacodynamic (PK/PD) behavior, stemming from the capacity of phages to replicate at the infection site. This results in nonlinear and context-dependent kinetic profiles that integrate pathogen load, mucosal colonization time, and spatial structure into treatment exposure [113, 114]. Clinical translation is constrained by phage immunogenicity that provokes neutralizing antibodies and cellular responses, by rapid bacterial evolution of phage resistance, and by the practical barriers to producing scalable, individualized phage cocktails. Addressing these challenges necessitates a dual strategy: first, the multidisciplinary quantification of critical phage metrics (e.g., mucosal residence time, in situ replication, clearance) to build predictive PK/PD models; and second, the development of pragmatic delivery solutions, including immune-evasive encapsulation, phage cocktails, integrated diagnostic libraries, and harmonized production standards. Thus, reconciling the complexity of HIV-related diseases with therapeutic goals demands multidimensional innovation to transform phage therapy into viable clinical translation.