Tripartite interplay: immune reconstitution dynamics in AIDS, gut microbiota, and Helicobacter pylori infection: current advances and therapeutic prospects

The gut microbiota constitutes a complex ecosystem comprising bacteria, archaea, eukaryotes, viruses, and parasites, with bacteria being the predominant members [14]. Beyond their role in synthesizing essential nutrients, the gut microbiota plays a vital role in preventing pathogen invasion and regulating immune system function [15]. Among its key metabolic products are short-chain fatty acids (SCFAs), with butyric acid (BA) being particularly significant. BA serves as the primary energy source for colonic epithelial cells, promotes the proliferation of regulatory T cells (Tregs), and enhances mucin production, thus exerting notable anti-inflammatory effects [16].

Research has demonstrated that the gut microbiota and its metabolites significantly influence intestinal immunity through several mechanisms [17, 18], including promoting the development and function of the intestinal mucosal immune system; enhancing the integrity of the intestinal mucosal barrier, thereby reducing pathogen translocation; and activating lamina propria lymphocytes (LPLs), which modulate both local and systemic immune responses.

Moreover, commensal bacteria support mucosal barrier integrity via metabolic by-products such as SCFAs. For instance, butyrate produced by Faecalibacterium prausnitzii upregulates tight junction proteins (e.g., occludin and zonula occludens-1) in intestinal epithelial cells (IECs), thereby reducing gut permeability [19]. Similarly, Akkermansia muciniphila metabolizes intestinal mucus to maintain mucosal barrier thickness [8]. Specific bacterial taxa such as Bacteroides and Firmicutes, along with their metabolites, including propionic acid and acetic acid, play a critical role in regulating the balance between Th17 cells and Tregs [20]. In addition, gut microbiota-derived metabolites such as tryptophan derivatives influence immune cell differentiation and function through the activation of the aryl hydrocarbon receptor (AhR) pathway [21]. The intricate interplay between gut microbiota and the host immune system has been implicated in the pathogenesis of several diseases, including inflammatory bowel disease and metabolic syndrome [22], highlighting promising therapeutic targets for the management of these conditions.

The intestinal mucosa serves as the body’s first line of defense against pathogenic microorganisms and toxins. This barrier function is primarily maintained by the mechanical barrier formed by IECs and the chemical barrier provided by the mucus layer [17]. Chronic bacterial colonization and proliferation can compromise the integrity of IEC tight junctions, leading to increased intestinal permeability, bacterial translocation, and the subsequent release of inflammatory mediators, which may further exacerbate immune dysregulation [23].

Most probiotics enhance intestinal barrier function by reducing permeability and promoting the expression of tight junction proteins. For example, Zhao et al. [24] reported that a combination of Bifidobacterium, Lactobacillus acidophilus, Enterococcus, and Bacillus cereus improved necrotizing enterocolitis by increasing the expression of occludin and claudin-1, thereby reducing intestinal permeability. Additionally, Bifidobacterium has been shown to significantly lower intestinal mucosal permeability in a mouse model of colitis induced by sodium dextran sulfate [25].

SCFAs, important metabolic byproducts of gut microbiota, play a critical role in mediating anti-inflammatory responses and promoting barrier repair. SCFA concentrations are positively correlated with the anti-inflammatory cytokine interleukin-10 (IL-10) and negatively correlated with pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta, and interferon-gamma [26]. SCFAs help enhance intestinal barrier integrity by modulating IEC tight junctions and influencing mucus layer viscosity [27]. Specifically, SCFAs have been shown to increase transepithelial electrical resistance, upregulate claudin-1 expression, and regulate the localization of the tight junction protein zonula occludens-1, thereby mitigating lipopolysaccharide-induced barrier dysfunction [19].

Intestinal LPLs, including T cells, B cells, dendritic cells (DCs), and innate lymphoid cells—are key components of intestinal mucosal immunity. The functions of these lymphocytes are tightly regulated by the gut microbiota and its metabolic byproducts, particularly SCFAs.

DCs, as essential antigen-presenting cells, play a pivotal role in orchestrating immune responses. Commensal bacteria help educate gut-associated lymphoid tissue (GALT) by promoting the differentiation of regulatory T cells (Tregs). For instance, Lactobacillus plantarum OLL2712 stimulates DCs to secrete IL-10, thereby inducing Treg polarization and fostering immune tolerance [28]. In response to intestinal pathogen invasion, type II conventional DCs (cDC-II) contribute to reducing colonic pathogen infiltration and promote mucosal healing by upregulating ferritin expression [29]. In individuals with HIV, microbial dysbiosis impairs Treg differentiation, leading to an imbalance in the Th17/Treg ratio and resulting in chronic inflammation [30].

CD4⁺ T cells are central to the adaptive immune response, particularly within the intestinal lamina propria and mesenteric lymph nodes. Lyu et al. [31] demonstrated that lactic acid produced by symbiotic intestinal bacteria enhances CD4⁺ T cell proliferation. Similarly, Lactobacillus rhamnosus has been shown to promote the differentiation of CD4⁺ T cells [31]. Furthermore, SCFAs inhibit CD4⁺ T cell activation and proliferation while promoting their differentiation into Th1 and Th17 subtypes, ultimately reducing the production of pro-inflammatory cytokines [32].

HIV infection significantly alters the composition and abundance of the gut microbiota, a phenomenon first identified by Gori et al. In healthy individuals, gut microbiota rich in Bifidobacterium support carbohydrate digestion and help inhibit pathogenic microorganisms [25]. However, in individuals with HIV/AIDS, studies have reported a marked reduction in Bacteroidetes and an increase in Proteobacteria, contributing to mucosal barrier damage and microbial translocation [30, 33].

Fecal analyses have shown significantly elevated levels of Pseudomonas aeruginosa and Candida albicans in HIV-infected individuals, alongside a notable decrease in Bifidobacterium [34]. Alterations in bacterial phyla include reduced Bacteroidetes and increased Firmicutes, a shift associated with elevated intestinal pH levels that may create a more favorable environment for viral replication [33]. At the genus level, the gut microbiota of HIV-infected individuals is primarily composed of Bacteroides, Prevotella, Fusobacterium, Helicobacter, and Escherichia coli-Shigella [35]. Research has shown that individuals with HIV/AIDS exhibit significantly reduced microbial diversity compared to healthy controls [35]. There is an increased abundance of Gram-negative bacteria, including Bacillus and Monascus species, while the abundance of Clostridium is notably diminished [30]. These microbial alterations are positively correlated with elevated levels of pro-inflammatory cytokines and negatively correlated with anti-inflammatory cytokines, underscoring the role of gut dysbiosis in chronic HIV-related inflammation [30]. Overall, HIV infection is associated with an increased relative abundance of Gram-negative bacteria and a decreased abundance of Gram-positive bacteria, with a particularly marked reduction in immunomodulatory microbial populations [36].

Alterations in gut microbial diversity not only influence the progression of HIV/AIDS but are also closely linked to immune status [37]. Studies have demonstrated that individuals with HIV/AIDS exhibit significantly reduced gut microbiota diversity compared to healthy controls, and these changes are associated with immune function and clinical indicators.

The association between gut microbial diversity and immune status has been extensively investigated. Alpha (α)-diversity, a key measure of microbial diversity, is significantly reduced in HIV-infected individuals, regardless of whether they have initiated ART. This reduction is positively correlated with CD4⁺ T cell counts and negatively correlated with markers of microbial translocation and monocyte activation [30]. Additionally, immune reconstitution following ART is associated with the partial restoration of microbial diversity; as CD4⁺ T cell levels recover, corresponding improvements in gut microbiota diversity have been observed [30]. Notably, the decline in α-diversity is more pronounced in individuals with lower CD4⁺ T cell counts, highlighting a strong relationship between microbial diversity and immune competence [38]. Gender and sexual behavior have also been identified as factors influencing gut microbiota diversity in HIV-infected populations. Among women and heterosexual men, HIV infection is associated with a marked decrease in α-diversity. However, this pattern is not consistently observed among men who have sex with men, suggesting that sexual behavior may modulate the impact of HIV on gut microbial composition [39].

Given these associations, gut microbiota remodeling has been proposed as a potential therapeutic strategy to support immune restoration in patients with HIV/AIDS.

The primary function of the intestinal immune system is to provide both innate and adaptive immune protection to the intestinal mucosa [40]. HIV infection severely compromises the integrity of this system, thereby accelerating disease progression. During the early stages of HIV infection, there is a substantial depletion of CD4⁺ T cells, particularly Th17 cells, in the gastrointestinal tract. This loss leads to significant damage to the intestinal mucosa and increased intestinal permeability [41‐43]. As a result, microbial translocation occurs, allowing pathogens and their metabolites to cross the compromised mucosal barrier and enter systemic circulation, thereby triggering widespread immune activation. Chronic immune activation and persistent inflammation further exacerbate immune dysfunction. Continuous HIV replication not only depletes CD4⁺ T cells but also accelerates the turnover of T and B lymphocytes, leading to excessive production of pro-inflammatory cytokines [44]. Concurrently, gut microbiota dysbiosis and the translocation of bacterial metabolites into the bloodstream contribute to sustained immune activation and systemic inflammation [45, 46]. DCs play a central role in regulating intestinal immunity. Dillon et al. [47] demonstrated that DC activation in HIV/AIDS patients is essential for maintaining intestinal homeostasis but also contributes to immune activation. Thus, the depletion of immune cells caused by HIV, along with DC activation and other immune disturbances, collectively leads to intestinal immune damage and aggravates the progression of AIDS [48].

Although ART effectively suppresses viral replication, certain patients do not attain optimal immune reconstitution. Research has identified an imbalance in gut microbiota as a potential contributing factor to this phenomenon [49]. The mechanism of gut microbiota disorder involves several aspects. First, the gut microbiota may activate the immune system over an extended period, leading to chronic inflammation and metabolic disorder by forming virus shelters, resisting ART, and promoting damage to the intestinal mucosal barrier and other mechanisms [37, 50]. Additionally, inflammatory factors such as TNF-α and IL-6 are elevated in the blood of HIV-infected patients, mediating systemic inflammatory responses and negatively impacting immune reconstitution [51].

Impaired immune reconstitution is characterized by a decrease in both the quantity and functionality of T lymphocytes, an imbalance in the Th17/Treg ratio, and elevated levels of pro-inflammatory cytokines [11]. Patients with insufficient immune recovery are at increased risk of gut microbiota dysbiosis and abnormal immune activation [11]. The effect of blood microflora is also significant. Patients with poor immune reconstitution exhibit higher concentrations of abnormal inflammation-related proteins in their peripheral blood compared to those with better immune recovery. These proteins are negatively correlated with CD4⁺ T cell counts and positively correlated with blood microbiota and HIV viral load. This suggests that blood microorganisms may influence disease progression by eliciting inflammatory responses [52].

The relationship between gut microbiota and immune reconstitution has been extensively studied, particularly about specific microbial populations. Notably, butyrate-producing bacteria have been identified as key modulators of immune activation and CD4⁺ T cell recovery, with emerging evidence suggesting a potential adverse effect on immune restoration in patients with HIV/AIDS [53]. Although ART partially mitigates intestinal mucosal damage and reduces microbial translocation into the bloodstream, it does not fully restore the composition of gut microbiota or completely eliminate microbial translocation. This persistent gut dysbiosis may play a significant role in the inadequate immune reconstitution observed in certain patients [54].

H. pylori is a Gram-negative, microaerophilic bacterium that persistently colonizes the human gastric mucosa. Globally, the infection rate of H. pylori exceeds 50%, with a prevalence of approximately 30% in developed countries and up to 80% in developing regions [55]. Co-infection with HIV and H. pylori presents a significant global health concern, although its prevalence varies considerably across geographic regions. Studies report that the prevalence of H. pylori in individuals with HIV/AIDS ranges from 10 to 76% [56]. Notably, several investigations have found that H. pylori infection rates are significantly lower among HIV/AIDS patients compared to healthy controls [57, 58]. Moreover, there is evidence suggesting a negative correlation between H. pylori prevalence and the degree of immunosuppression in HIV/AIDS patients, implying that progressive immunodeficiency may impair the bacterium’s ability to colonize the gastric mucosa [57, 58]. H. pylori may influence HIV pathogenesis through direct or indirect mechanisms; however, the precise pathways remain inadequately understood.

The interplay between H. pylori infection and the host immune system is intricate and multifaceted; however, the specific impacts on immune reconstitution remain inadequately elucidated. H. pylori exhibits similarities to HIV concerning both epidemiology and pathophysiology. H. pylori predominantly colonize the gastric mucosa; however, in instances of gastric metaplasia within the duodenal mucosa, they may also establish colonization in the duodenum, subsequently eliciting both local and systemic immune responses. This process involves various immune cell types, including CD4⁺ T cells, DCs, regulatory T cells (Tregs), and Th17 cells, all of which are also implicated in the pathogenesis of AIDS [13]. H. pylori infection has been demonstrated to enhance both local and systemic immune activation in patients with HIV/AIDS [59]. Specifically, H. pylori stimulates mononuclear macrophages, increases the expression of the chemokine receptor CCR5 on T cells, induces a Th1 immune response, and downregulates the function of CD8⁺ T cells [60, 61].

The relationship between H. pylori infection and the progression of AIDS has been the subject of various studies. These investigations indicate that H. pylori infection is correlated with a decrease in immune activation markers among HIV/AIDS patients receiving ART. Given that immune activation is a significant factor in the progression of AIDS, it has been hypothesized that H. pylori infection may affect the progression of the disease or the susceptibility to HIV [62].

In recent years, there has been a growing interest in the relationship between H. pylori infection and gastrointestinal microbiota. H. pylori alters the composition of gut microbiota by modifying the gastrointestinal microenvironment, which includes changes in pH levels, cytokine production, antimicrobial peptide activity, and immune responses. This disruption undermines the biological barrier, increases intestinal permeability, facilitates bacterial translocation, and contributes to the progression of various diseases [63, 64]. H. pylori infection disrupts gut microbiota via three key mechanisms.

In a 2021 study, Wu Xue et al. [70] demonstrated that treatment with Shenling Guben Immune Granules, which contain Ganoderma lucidum, Panax quinquefolius, Polygonum cuspidatum, and other components, significantly increased CD4⁺ T cell counts in HIV/AIDS patients with poor immune reconstitution after 24 weeks, while also promoting the proliferation of beneficial gut bacteria. Similarly, a 2023 study by Liu Yanan et al. [71] found that treatment with Yiaikang Capsules, composed of Panax ginseng, Astragalus membranaceus, fried Atractylodes macrocephala, Poria cocos, Angelica sinensis, Ligusticum chuanxiong, and other herbs, significantly improved CD4⁺ T cell counts, increased the abundance of beneficial gut bacteria, and reduced harmful bacterial populations. These findings suggest that modulating gut microbiota composition and function can effectively support immune reconstitution.

Prebiotics promote the growth of beneficial bacteria such as Bifidobacterium and Lactobacillus, which inhibit pathogenic microorganisms. Through fermentation, prebiotics produce SCFAs like butyrate, acetate, and propionate, which strengthen the intestinal barrier and reduce inflammation. Clinical studies have shown that prebiotic supplementation can improve gut microbiota balance, decrease intestinal permeability, and lower inflammatory markers in individuals with HIV [72]. Moreover, prebiotic use has been linked to increased CD4⁺ T cell counts and enhanced immune recovery [47]. However, the effectiveness of prebiotics varies depending on the initial gut microbiota composition, leading to significant individual differences in response [73].

Probiotics may significantly contribute to immune reconstitution in patients with AIDS through several mechanisms: modulating gut microbiota composition and restoring microbial balance; enhancing intestinal barrier function to reduce bacterial translocation and systemic inflammation; and promoting a balanced Th1/Th2 response to strengthen immune defense. Clinical studies have shown that supplementation with probiotic strains such as Lactobacillus and Bifidobacterium is linked to decreased inflammatory markers, including IL-6 and TNF-α, in individuals with HIV [74]. Furthermore, some research reports increases in CD4⁺ T cell counts and overall immune improvements following probiotic use [75]. However, probiotic effects are strain-specific, and further research is needed to determine their long-term safety and efficacy.

Fecal microbiota transplantation (FMT) directly restores gut microbiota diversity and functionality. By modulating microbial metabolites, including SCFAs, and influencing immune responses, FMT strengthens intestinal barrier integrity and systemic immunity. Preliminary studies suggest that FMT can significantly correct gut microbiota imbalances and reduce inflammation in individuals with HIV [76]. Additionally, FMT has been shown to lower inflammatory protein levels in HIV-infected patients [77]. Malik et al. [78] reported that FMT effectively restored gut microbiota composition in patients with Clostridium difficile infections, thereby decreasing the risk of gastrointestinal complications in those undergoing ART. However, challenges such as donor screening and procedural standardization remain major obstacles to widespread clinical use.

Antibiotic therapy targeting H. pylori may restore gut microbiota balance by eliminating the pathogen and reducing inflammation. One study demonstrated that H. pylori eradication decreased plasma LPS levels and improved CD4⁺ T cell recovery in HIV/AIDS patients, without compromising viral suppression [59, 69]. However, broad-spectrum antibiotics can transiently disrupt the gut microbiota, highlighting the need to combine treatment with probiotics to mitigate dysbiosis [74]. These findings suggest that concurrent H. pylori eradication during ART may enhance immune restoration in HIV-infected individuals.

Gut microbiota plays a critical role in the pathogenesis and progression of AIDS. Although ART effectively suppresses viral replication, persistent issues such as gut microbiota dysbiosis, chronic inflammation, and immune system dysregulation contribute to incomplete immune reconstitution (INR) in some patients. INR remains a significant challenge in contemporary AIDS management. Modulating the gut microbiota offers a promising therapeutic avenue to enhance immune recovery and establish a more scientifically grounded framework for comprehensive AIDS care.

Despite advances in AIDS treatment, research on gut microbiota regulation is still limited, and the efficacy and mechanisms of such interventions require further elucidation. It is anticipated that gut microbiota modulation will become a major breakthrough in immune reconstitution research for AIDS. Future research directions should prioritize several key areas to enhance the effectiveness of ART and improve immune reconstitution outcomes. First, the development of novel microbiota modulators, including engineered bacteria and metabolite analogs, offers the potential for precise regulation of gut microbiota, thereby enhancing ART efficacy. Second, multi-omics integration approaches, encompassing comprehensive analyses of the gut microbiota, metabolome, and immune system, are essential for uncovering the molecular mechanisms that underlie the synergistic effects of microbiota modulation and ART. Such insights will provide a theoretical foundation for the implementation of personalized treatment strategies. Third, robust clinical validation is necessary, particularly through large-scale, multi-center randomized controlled trials, to evaluate the safety and long-term efficacy of interventions such as prebiotics, probiotics, and FMT. Finally, there is a need to explore combination therapies that integrate gut microbiota modulation with immunotherapy, anti-inflammatory treatments, and other complementary approaches. These strategies aim to more effectively restore immune function and improve the overall quality of life for patients living with HIV/AIDS. In summary, gut microbiota regulation holds great potential for addressing immune reconstitution disorders in AIDS. Continued research advancements are expected to drive the development of comprehensive therapeutic strategies and improve clinical outcomes for patients living with AIDS.