Alterations in the Oral Microbiome in HIV Infection: Causes, Effects, and Potential Interventions
Human immunodeficiency virus (HIV) infection is characterized by a severe deficiency of the host immune system, primarily due to the massive depletion of CD4+ T lymphocytes. This depletion leads to an imbalance between the human microbiome and immune responses. While much attention has been given to the gut microbiota in HIV infection, the oral microbiome has been relatively understudied. However, emerging evidence indicates that the oral microbiome undergoes significant dysbiosis in people living with HIV (PLWH). This dysbiosis is likely driven by immunodeficiency in the oral cavity, which includes changes in secretory components such as reduced levels of enzymes and proteins in saliva, as well as altered cellular components involved in innate and adaptive immune responses. These disruptions in oral immunity contribute to an imbalance between the oral microbiome and local immune responses, potentially leading to the development of HIV-related diseases and HIV-associated non-acquired immunodeficiency syndrome (AIDS) comorbidities. Although antiretroviral therapy (ART) has significantly reduced the occurrence of opportunistic oral infections in PLWH, dysbiosis of the oral microbiome persists. Furthermore, ongoing studies are exploring the potential of probiotics to regulate oral microbiota dysbiosis in HIV-infected individuals. However, the effects of ART and probiotics on the oral microbiome in HIV-infected individuals remain unclear. This article reviews the composition of the oral microbiome in healthy and HIV-infected individuals, the potential effects of oral microbiome dysbiosis on HIV-associated oral diseases, and the influence of ART and probiotics on the oral microbiome in HIV infection. A deeper understanding of the composition and function of the oral microbiome is critical for developing effective preventive and therapeutic strategies for HIV infection.
Introduction
HIV infection leads to a severe deficiency of the host immune system, primarily through the depletion of CD4+ T cells. According to the World Health Organization, approximately 38 million people were living with HIV worldwide at the end of 2019, with around 67% receiving ART. Despite the effectiveness of ART, several oral diseases, such as oropharyngeal candidiasis (OPC) and periodontitis, are frequently reported in all stages of HIV infection. Additionally, as the life expectancy of PLWH increases, the risk of HIV-associated non-AIDS comorbidities, including cardiovascular disease, neurocognitive disorders, cancer, and liver and kidney disease, is increasingly reported. Older HIV-infected individuals who have received ART may also present with a higher incidence of age-related oral diseases.
Recent studies have shown that the composition of the gut microbiome in PLWH differs from that of HIV-uninfected individuals, with an increase in the abundance of Prevotella and a decrease in the abundance of Bacteroides. These alterations in the gut microbiome may promote HIV-associated inflammation and immune activation. Similarly, the oral microbiome diversity may also play a critical role in systemic inflammation in HIV-infected individuals. Studies have found that CD4+ T lymphocytes in gut-associated lymphoid tissue are greatly reduced in the early stages of HIV infection, resulting in the loss of T helper (Th) 17 cell subsets. These interleukin-17- and interleukin-22-producing cells are essential for maintaining intestinal epithelial integrity and gastrointestinal barrier function. The loss of Th17 cells may contribute to microbial translocation from the gut mucosa into the systemic circulation, promoting inflammation and immune activation in HIV-infected adults. Th17 cells are also essential for controlling fungal colonization in the oral mucosa, and the structure and network of the oral mucosal immune system are similar to those of the gastrointestinal mucosal immune system. This accumulating evidence suggests that the oral microbiota, like the gut microbiota, might induce systemic diseases through systemic translocation in HIV infection. Additionally, oral species, including opportunistic pathogens, might diffuse from the oral cavity to the gut, directly causing inflammation in the gut. Therefore, understanding the effects of the oral microbiome on HIV is critical.
The Human Oral Microbiome
The oral microbiome is an important part of the human microbiome and includes various microbes, such as bacteria, fungi, viruses, mycoplasma, and protozoa. Bacteria are the predominant group, with approximately 700 bacterial species identified. The oral microbiome plays a critical role in human metabolism, physiology, and immunity, including inhibiting pathogenic microorganism colonization, maintaining the acid-base balance, regulating local oral immunity, and participating in salivary nitrate metabolism.
The Human Oral Microbiome Database contains records for a total of 775 microbial species, of which approximately 57% have been cultivated and named, 13% can be cultivated but not named, and 30% are uncultivated. The human oral bacterial microbiome primarily consists of six phyla: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Spirochaetes, and Fusobacteria. The most abundant genus in the oral cavity is Streptococcus, followed by Haemophilus, Neisseria, Prevotella, Veillonella, and Rothia. In addition to bacterial communities, different fungi are also widely colonized in the human oral cavity. In elderly and immunocompromised individuals, oral commensal fungi can serve as opportunistic pathogens. The oral mycobiome comprises 74 culturable and 11 nonculturable fungal genera, with Candida being the most common genus, followed by Cladosporium, Aureobasidium, Saccharomycetales, Aspergillus, Fusarium, and Cryptococcus.
The Alterations in the Oral Microbiome in HIV Infection
The homeostasis of oral microbiota can be affected by multiple factors, including diet, smoking, and drugs. Changes in secretory components in saliva, innate and adaptive immune responses, and the physiological structure and function of the oral mucosa can also cause dysbiosis of the oral microbiome. Several studies have demonstrated significant differences in the oral microbiome between PLWH and HIV-uninfected healthy controls. However, the potential mechanisms of oral microbiota changes in HIV infection remain unclear.
Alterations in salivary composition and function in HIV infection might play a key role in the dysbiosis of the oral microbiome. Saliva contains various secretory components essential for maintaining oral homeostasis, including immunoglobulin A (IgA), lysozyme, and host defense peptides such as antimicrobial peptides, defensins, and histones. These components play an important role in microbial control and oral mucosal immunity. A recent study indicated that the composition and function of saliva change in HIV infection, with decreased salivary IgA, defensins, and cytokines impairing local immunity. This impairment might convert commensal microorganisms to pathogenic ones, leading to dysbiosis of oral microbiota and increasing the risk of opportunistic infections. HIV-infected individuals, regardless of whether they are receiving ART, have a higher frequency and load of opportunistic microorganisms than HIV-uninfected controls. The diversity and bacterial load in salivary samples from HIV-infected individuals are significantly higher than those in HIV-uninfected samples. Additionally, a negative correlation between oral lesions and CD4+ T-cell counts has been reported, suggesting that disrupted oral mucosal immunity in HIV infection might destroy the colonization of commensal bacteria in the oral cavity, leading to increased oral microbial diversity and an increased risk of HIV-associated oral diseases. However, some studies have shown that the oral bacterial diversity in PLWH is significantly decreased compared to that in HIV-uninfected individuals, possibly due to the increased proportion of opportunistic pathogens caused by immunodeficiency in HIV infection.
In addition to secretory components, cellular innate immune components in the oral cavity, such as macrophages, natural killer cells, polymorphonuclear leukocytes, and dendritic cells, also protect the oral mucosa from pathogenic microorganisms. These innate immune cells recognize pathogens through pattern recognition receptors (PRRs), which include Toll-like receptors, C-type lectin receptors, retinoic acid-inducible gene-like receptors, and nucleotide-binding oligomerization domain-like receptors. The binding of PRRs to pathogen-associated molecular patterns induces the production of cytokines, chemokines, and vasoactive molecules, regulating the innate immune response to infection and promoting adaptive immune responses. However, innate immune responses in the oral cavity are impaired in HIV infection, leading to dysbiosis of the oral microbiome and increased opportunistic infections.
Adaptive immune responses are also defective in HIV infection, promoting oral microbiota dysbiosis. Th17 cells are essential for controlling fungal infections and inflammation of the oral mucosa, while Th1 cells mediate early gingival inflammatory lesions in response to bacterial plaques by producing cytokines such as interferon-gamma (IFN-γ). Th2 immune responses are closely related to the progression of periodontal diseases. Despite these findings, the results of different studies on oral microbiome composition in HIV infection are not consistent. Some studies have shown increased abundance of Streptococcus and decreased abundance of Neisseria in HIV-infected individuals, while others have found no significant differences in the oral microbiome between HIV-treated patients and healthy controls. Alterations in the oral fungal community composition in PLWH have also been noted, with increased Candida colonization being a common finding.
Effects of the Oral Microbiome on HIV-Associated Oral Diseases
The oral microbiome plays an important role in host health and disease. Dysbiosis of the oral microbiome has been found in various oral diseases, such as dental caries, periodontal diseases, oral mucosal diseases, and oral cancer. Additionally, dysbiosis of oral microbiota has been observed in systemic diseases, including inflammatory bowel disease, liver cirrhosis, pancreatic cancer, Alzheimer’s disease, diabetes, rheumatoid arthritis, cardiovascular diseases, adverse pregnancy outcomes, and polycystic ovary syndrome. The oral cavity is one of the most common sites for opportunistic infections in PLWH, with several oral diseases frequently occurring, including periodontal diseases, OPC, oral warts, oral hairy leukoplakia, and Kaposi sarcoma (KS), even in those receiving ART. OPC, caused by various Candida species, remains the most common oral manifestation in HIV infection. The incidence of OPC is influenced by immune status, bacteriome-mycobiome interaction, antifungal therapy, and ART. Low CD4+ T-cell levels in HIV-infected individuals might persistently alter oral microbiota, increasing the prevalence of dental caries and periodontal diseases. Distinct oral microbiota might affect the development of oral diseases in PLWH, with different microbial compositions observed in HIV-infected individuals with oral KS compared to those without.
Effects of Potential Interventions on the Oral Microbiome
Although ART can inhibit HIV replication, increase CD4+ T lymphocytes, and reduce the occurrence of oral lesions, it cannot completely restore the oral microbiome of PLWH to normal. Studies have shown that the oral microbiome compositions in HIV-infected individuals with ART become more similar to those in HIV-uninfected controls, but differences remain. Specific ART regimens are associated with alterations in both gut and oral bacterial diversity. Some studies have shown increased abundance of Fusobacterium, Campylobacter, Prevotella, Capnocytophaga, Selenomonas, Actinomyces, Granulicatella, and Atopobium in HIV-infected individuals after receiving ART, while Aggregatibacter is significantly decreased. PLWH with persistently low CD4+ T-cell counts have significantly increased bacterial richness and Shannon diversity, indicating that shifts in oral microbiota may play an important role in the recovery of CD4+ T-cell counts. Long-term ART has more suppressive effects on the composition and diversity of microbiota in the gut than in the oral cavity. Although ART can reduce the risk of OPC in HIV-infected individuals, it does not decrease the colonization of Candida in the oral cavity. ART may play a key role in maintaining homeostasis between host immunity and the oral microbiome, but further studies are necessary to understand the potential mechanisms of ART on oral microbiome colonization.
In addition to ART, probiotics have been explored as a new therapeutic approach to improve the quality of life in PLWH. Probiotics regulate the immune system and control pathogen colonization, preventing and treating various disorders, including acute gastroenteritis, inflammatory bowel diseases, Clostridium difficile-associated diarrhea, allergies, neonatal sepsis, and respiratory tract infections. Probiotics have also been used to prevent oral diseases such as dental caries, gingivitis, and periodontitis. Studies have shown that probiotics can reduce the filamentation of Candida albicans and decrease the development of candidiasis in immunosuppressed mice. Prebiotics have also been studied for their role in promoting oral health by stimulating beneficial bacteria. A study on the impact of prebiotic intervention on the saliva microbiome of PLWH showed decreased diversity and richness of the saliva microbiome after prebiotic intervention, with increased Actinobacteria Rothia mucilaginosa and decreased potential pathogens such as Corynebacterium, Fusobacterium, and Prevotella melaninogenica in viremic ART-untreated individuals. These studies suggest that probiotics and prebiotics may be beneficial in regulating oral microbiota dysbiosis in HIV infection and preventing HIV-related oral diseases. However, further clinical studies are needed to determine the efficacy and safety of probiotics in different clinical conditions.
Conclusion
Increasing evidence suggests a significant link between oral microbiome changes and HIV infection. This article summarizes recent findings on alterations in oral microbiota in HIV infection, the potential roles of these shifts in HIV-associated oral diseases, and the effects of ART and probiotics on oral microbiota in HIV-infected individuals. The oral microbiome plays an essential role in the pathogenesis of HIV disease, and a better understanding of its composition and function is critical for improving the oral health of HIV-infected patients. Further investigations are needed to evaluate the impact of potential interventions on the oral microbiome in HIV infection, which will be foundational for developing novel approaches for the prevention and therapy of HIV/AIDS-associated diseases.
doi.org/10.1097/CM9.0000000000001825
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