HIV, opioid use, and alterations to the gut microbiome: elucidating independent and synergistic effects

Background: The microbiome is essential to immune development, defense against pathogens, and modulation of inflammation. Microbial dysbiosis has been reported in various diseases including human immunodeficiency virus (HIV) and opioid use disorder (OUD). Notably, people living with HIV (PLWH) have been reported to both have higher rates of OUD and use opioids at higher rates than the general public. Thus, studying gut microbial alterations in people living with HIV and with OUD could elucidate mechanisms pertaining to how these conditions both shape and are shaped by the microbiome. However, to date few studies have investigated how HIV and OUD in combination impact the microbiome.

Aim of review: Here, we review previous studies outlining interactions between HIV, opioid use, and microbial dysbiosis and describe attempts to treat this dysbiosis with fecal microbial transplantation, probiotics, and dietary changes.

Key scientific concepts of review: While the limited number of studies prevent overgeneralizations; accumulating data suggest that HIV and opioid use together induce distinct alterations in the gut microbiome. Among the three existing preclinical studies of HIV and opioid use, two studies reported a decrease in Lachnospiraceae and Ruminococcaceae, and one study reported a decrease in Muribaculaceae in the combined HIV and opioid group relative to HIV-alone, opioid-alone, or control groups. These bacteria are known to modulate immune function, decrease colonic inflammation, and maintain gut epithelial barrier integrity in healthy individuals. Accordingly, modulation of the gut microbiome to restore gut homeostasis may be attempted to improve both conditions. While mixed results exist regarding treating dysbiosis with microbial restoration in PLWH or in those with opioid dependency, larger well-defined studies that can improve microbial engraftment in hosts hold much promise and should still be explored.

1 Introduction

The microbiota consists of the many microorganisms, including viruses, bacteria, and fungi, that exist on and within the human body (1). Residing in the skin, lungs, oral cavity, vagina, and gastrointestinal (GI) tract, there are about 100 trillion currently known microorganisms (1). Together, these microorganisms work in a symbiotic relationship with the body and play a crucial role in overall host homeostasis, particularly through development and maintenance of immune function, and modulation of host nutrition and energy metabolism (2). Additionally, microbial metabolites such as tryptophan, polyamines, and amino acids influence human behavior and physiology (3). Gamma-aminobutyric acid (GABA), for example, is a known regulator of the central and enteric nervous systems and histamine has been associated with regulation of intestinal immune cells (4, 5). Short chain fatty acids (SCFAs) produced by GI microbiota ensure gut homeostasis through immune regulation, nutrient absorption, pH regulation, and mucus secretion (4). In addition to the GI tract, whose microorganisms and their contributions to the human microbiome are the most well-known, many other body organs and systems have now been found to harbor a distinct microbiome (6, 7).

Even among different body sites, it is known that microbial composition is dependent on age, geography, diet, use of antibiotics, drugs, and sexual behaviors (8, 9). Additionally, sampling methods and the level of bacterial classification applied also impact descriptions of microbial composition (3, 10, 11). While there is much variation in the composition of a healthy microbiome, experts agree that the key to a healthy microbiome lies in the balance of the many different species of microorganisms that exist within the body. Alterations to the gut microbiome may lead to dysbiosis, defined in this review as a significant change in gut microbiome diversity, composition, or function relative to controls. In the GI tract, most residing bacteria are anaerobes, though aerobes and facultative anaerobes are still present (3, 12). The four dominant bacterial phyla in the gut are Firmicutes, Bacteroidota, Actinobacteria, and Proteobacteria, of which Bacteroides, Clostridium, Faecalibacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium are the most common genera (12). Accordingly, microbial diversity has been used as a key indicator of health and disease.

The role of the microbiome in HIV infection, in particular, is an area of active interest. To date, approximately 38 million people are living with HIV infection worldwide (13). Though antiretroviral therapy (ART) has significantly decreased patient mortality, improving the quality of life for people living with HIV (PLWH) and decreasing HIV-associated comorbidities are areas of top concern. The role of the microbiome in driving some of these comorbidities is becoming increasingly clear. For instance, a number of studies have reported that microbial dysbiosis following HIV infection has been associated with increased inflammation, infection, and decreased gut epithelial barrier integrity (14). Additionally, opioid use, which commonly co-occurs with HIV, is also independently associated with microbial dysbiosis and worsened patient outcomes. Notably, PLWH are likely to have chronic pain and receive higher doses of opioids that put them at increased risk for opioid use disorder (OUD) (15). Of note, though opioids are the gold standard for pain management in the clinical setting, opioid use is associated with poorer outcomes in PLWH (16). Furthermore, high risk behaviors, such as recreational drug use, can put patients at additional risk for both HIV infection and OUD. For these reasons, there has been an increasing focus towards investigating the intersection of PLWH who use opioids, including exploring compositional and functional microbial alterations, with the goal of restoring microbial homeostasis through probiotic intervention, though this area has largely been unexplored. In this review, we aim to explore the intersection between HIV, OUD, and the gut microbiome to investigate how these conditions contribute to dysbiosis and end with an examination of potential therapeutic interventions.

2 HIV and alterations to the gut microbiome

2.1 Viral alterations to the gut microbiome in PLWH

In recent years, many studies have detailed the importance of the microbiome in modulating immune function in PLWH. In general, these studies have found an increase in potentially pathogenic bacteria and a decrease in commensal bacteria, which has been associated with heightened inflammation (17–19). Proposed mechanisms of gut dysbiosis with HIV include disruption of microbial pattern recognition sensors, increased reactive oxygen and nitrogen radicals, and dysregulation of immune cells (Figure 1) (20). At the phylum level, several studies have reported a shift from Firmicutes, which has immune regulatory and probiotic effects, to Proteobacteria, which has been hypothesized to have potential pathogenic activity in humans (14, 20–22). In accordance with prior findings of increased systemic inflammation in PLWH, Vujkovic et al. found that bacterial communities that catabolize tryptophan were increased in the plasma of PLWH (20). In these studies, indoleamine 2,3-dioxygenase 1 (IDO-1) was used to assess tryptophan catabolism to downstream metabolites such as kynurenine, kyneuric acid, and anthrallic acid; this process is upregulated in conditions where the immune system is activated (23, 24). Other bacteria such as Bacteroides, which is associated with T-regulatory cell function, has consistently been found to decrease, while Prevotella, which is associated with pro-inflammatory effects, has been found to increase in both PLWH and rhesus macaques infected with simian immunodeficiency virus (SIV) (3, 25). An increase in potentially pathogenic bacteria, including Sarcina, Staphylococcus, Selenomonas, and Tetragenococcus, has also been found in fecal samples from chimpanzees with SIV (26). Additionally, some have shown that the Firmicutes/Bacteroides ratio is increased in PLWH (27, 28). Increases in this ratio have been associated with obesity, irritable bowel syndrome, and Clostridium difficile infection (29–31). However, the Firmicutes/Bacteroides ratio is also known to increase with age compared to that observed during childhood, with another decline seen in older adults compared to middle-aged adults (32). Mixed results exist regarding changes in the production of immunomodulatory SCFA produced from bacteria in the GI tract of PLWH. Some studies have found no differences in SCFA between PLWH- specifically men who have sex with men (MSM) and negative controls (33, 34). However, others have found that SCFAs are increased in PLWH, a finding largely driven by the SCFA propionate, since other SCFAs such as butyrate and acetate were decreased in this population relative to controls (28).

FIGURE 1

Figure 1 Proposed mechanisms of gut dysbiosis and microbial translocation in the GI tract with HIV (1). HIV causes dysregulation of immune cells such as dendritic cells, macrophages, and Th17 cells, which increases the growth of dysbiotic communities. Additionally, HIV causes a significant decrease in Th17 cells, a subtype of CD4+ T cells, which normally limit microbial translocation. Loss of Th17 cells leads to a decrease in tight junctions in the intestinal epithelium allowing microbes to travel freely between the lumen and systemic circulation. Loss of Th17 cells also causes an increase in Treg cells, which are associated with suppression of viral clearance and inappropriate tolerance of microbes. (2) Increased translocation of microbes into systemic circulation interferes with expression of the pattern recognition receptor (PRR) which ultimately increases gut inflammation, decreases immune response to viral infection, and increases growth of dysbiotic communities. (3) Increased gut inflammation from HIV infection leads to increased production of oxygen and nitrogen radicals. This is associated with increased growth of facultative anaerobes such as Enterobacteriaceae family.

Different subpopulations of PLWH have been found to have various alterations to their gut microbiome and biomarkers of inflammation. For instance, sexual behavior has been linked to changes in microbial composition in PLWH. It is hypothesized that the shift from Bacteroides to Prevotella in the MSM population is independent of HIV serostatus. MSM were also found to have increased alpha diversity, which contrasts with findings from other subpopulations living with HIV (35). Additionally, it has been found that levels of inflammatory markers sCD14, sCD163, interleukin 6, and lipopolysaccharide binding protein were already significantly higher in MSM living with HIV before seroconversion compared to controls (33). Interestingly, Chen et al. also found that various microbiota profiles were associated with the progression of HIV to AIDS; in particular, families Prevotella and Victivalla and species Bacteroides fragilis and Eubacterium cylindroides were significantly higher in MSM living with HIV who developed AIDS within 5 years than MSM who were AIDS-free for more than 10 years without ART (33). Also, family Victivallaceae and species Prevotella stercorea, Coprococcus eutactus, and Butyrivibrio crossotus were significantly higher and Gemmiger formicilis and Blautia obeum were significantly lower in MSM with HIV who developed AIDS within 5-10 years compared to MSM with HIV who were AIDS-free for more than 10 years without ART (33). Women living with HIV (WLHIV) did not have significantly different microbial diversity measures when compared to women not living with HIV (36). However, it was found that WLHIV had increases in Ruminococcus and Oscillospira and decreases in Bifidobacterium and Collinsella when compared to women without HIV. This was further associated with elevated glycerophospholipid levels which could contribute to inflammation and metabolic conditions in WLHIV (37). On the other hand, there was no correlation between Ruminococcus and amino acids or biogenic amines, but there was a positive correlation between Collinsella which is decreased in WLHIV, and glutamic acid (37) In regard to perinatal HIV infection, mixed results exist regarding microbial diversity. Flygel et al. reported that children living with HIV demonstrated significantly lower alpha diversity and higher beta diversity compared to children without HIV. This change was not associated with differences in CD4 counts or HIV viral load (38). On the other hand, Sessa et al. reported that the alpha diversity indices for perinatally-infected children with HIV were higher than controls (39). ART use for more than 10 years was associated with increased alpha diversity in perinatally-infected individuals living with HIV (38). Additionally, in parallel to adults living with HIV, perinatally infected children living with HIV had higher levels of Prevotella present despite ART usage (40).

2.2 ART-induced alterations to the gut microbiome in PLWH

Even though ART has been effective in decreasing the viral load, morbidity, and mortality of PLWH (41, 42), ART does not reverse HIV-related gut dysbiosis, leaving patients vulnerable to conditions such as GI and metabolic syndromes associated with gut dysbiosis (42, 43). In fact, up to nearly 75% of PLWH who are on ART experience one of the following GI symptoms with 30% experiencing three or more symptoms: nausea and/or vomiting, dyspepsia, heartburn, diarrhea, constipation, and flatulence (43, 44). Several studies have demonstrated that the gut microbiomes of PLWH using ART differ significantly from healthy controls (9, 17, 22, 45–47). However, the results of these studies are difficult to interpret as it is unclear whether the changes in the microbiome are associated with HIV infection or ART use; additionally, the confounder of sexual behavior is inconsistently accounted for. Compared to studies focused solely on PLWH using ART, studies that included PLWH not using ART found that PLWH using ART have microbiomes more similar to PLWH not using ART than to healthy controls in both the long- and short-term (42, 48). This finding could support that ART does not reverse gut dysbiosis in PLWH (42, 48). While some have reported that dysbiosis persists after ART initiation (49) others have found a decrease in dysbiosis over time (including a decrease in Prevotella abundance) (17, 50). On the other hand, those not on ART have been reported to have increased abundance of the bacteria Pseudomonas aeruginosa (21, 33), Enterobacterodales (51), and Bacteriodales (51). Others have also shown that ART causes microbiome changes independent of changes associated with HIV infection (17, 42). For instance, it has been reported that there is decrease in alpha diversity in PLWH who are on ART compared to PLWH not on ART (43); this could imply that ART may independently induce gut dysbiosis since decreased alpha diversity is associated with various diseases such as inflammatory bowel disease (52) and known side effects of ART such as diarrhea are also clinical indices of gut dysbiosis (43). However, mixed results exist regarding the association between ART and alpha diversity. In contrast to the above, McHardy et al. found that the reduction in alpha diversity in PLWH was partially reversed with ART (46). Clarifying this discrepancy could be important as alpha diversity has been shown to correlate with CD4+ T cell count; this is significant since decreases in CD4+ T cell count leave PLWH more susceptible to disease (17). Other confounders in studies addressing ART use and dysbiosis, such as the impact of direct drug metabolism by gut microbes, differences in ART regimen, duration of ART, and the success of ART in reducing the viral load, should also be considered in future studies (42).

3 Opioid use results in distinct alterations to the microbiome

3.1 Direct opioid induced alterations to the gut microbiome

Approximately 21% to 53% of PLWH are prescribed opioids and often at higher doses (15). PLWH have an increased incidence of chronic pain with up to 90% of PLWH experiencing chronic pain (53). Management of chronic pain in PLWH is difficult due to interactions with ART, increased side effect profiles, and considerations of comorbid conditions such as OUD (53). Studies have shown that there is a higher risk of OUD in PLWH, although exact estimates are unknown (15). Given that opioid use has been strongly tied to microbial dysbiosis, and microbial dysbiosis has been linked to a variety of health impairments, opioid use in PLWH poses an additional set of challenges.

While limited data exist regarding microbiome changes in humans with OUD due to confounding variables like polydrug use among people with OUD (54–56), two studies found increased species diversity in those using opioids (57). Specifically, Xu et al. (57) found an abundance of Thauera, Paracoccus, and Prevotella in fecal samples from humans with substance use disorder (SUD) compared to healthy controls. In humans, opioid use has been shown to increase microbial diversity partially attributed to opioid-induced increased GI transit time. This GI stasis could allow for more microbial growth in the colon (58). Additionally, Barengolts et al. showed an increase in Bifidobacteria in opioid users compared to non-users (59). Microbial dysbiosis following opioid use has also been associated with alterations in cellular and metabolic pathways in humans. Species involved with translation, DNA replication and repair, and cell growth and death were found to be increased in those with SUD (57). The clinical implications of these findings are unclear, but have shown that dysbiosis is associated with the cardiovascular and digestive systems, which are common comorbidities of OUD (57). Lastly, several studies have shown increased intestinal barrier permeability with opioid use. opioid antagonists have been demonstrated to promote mucosal healing in people with Crohn’s disease (60), bacterial translocation (61), and increased risk of infection related to the GI system (62, 63).

In general, preclinical models of opioid use have cited an increase in potentially pathogenic microbiome species (64, 65); in particular, an increase in gram-positive bacteria, including Enterococcaceae, Staphylococcaceae, Bacillaceae, Streptococcaceae, and Erysipelotrichaceae, all belonging to the phylum Firmicutes, has been reported (56, 65). Mice with chronic opioid exposure also were found to have a decreased abundance of the beneficial bacterial order Bacteriodales, Clostridiales, and Lactobacillales (66). From these studies, some have proposed that gut dysbiosis in those with OUD is driven by slowed GI motility via μ-opioid receptors, modulation of IL-17 by gram-positive organisms, and/or altered phenotypes of facultative anaerobes using evidence from both human and mice studies (Figure 2) (56, 63, 67). Conflicting results regarding the impact of opioids on species diversity has been reported in animal studies. For instance, two studies found increases in diversity and community richness (65, 68), and one study found a decrease in species diversity (69). Additionally, increases in bacterial taxa involved with amino acid metabolism have been reported during opioid administration, extinction, and reinstatement (68). These taxonomical changes were associated with alterations in protein synthesis, gene transcription, cell signaling, and synaptic plasticity (68). Additionally, decreases in bacteria and bacterial products involved in the bile acid transformation pathway, such as Bacteroidetes and Bilophila, have been reported with opioid use (65, 68–70). Specifically, significant changes in bile acid and the morphine-3-glucuronide/morphine biotransformation pathways in the gut were found in a morphine-murine model (69). Changes in species associated with bile acid metabolism have also been reported in humans using opioids (70). Importantly, bile acid metabolism is associated with the metabolism, elimination, and enterohepatic recirculation of opioids which contributes to the bioavailability of morphine and its effectiveness as an analgesic (69). Thus, a decrease in species associated with bile acid metabolism could be connected to opioid tolerance over time and contribute to opioid misuse and OUD (69). Gicquelais et al. also found a decreased abundance of Roseburia which is a SCFA producer (70). This reduction in SCFAs could be due to decreases in butyrate-producing bacteria (BPB) (71). SCFAs act on various free fatty acid receptors to regulate the production of eicosanoids, chemokines, and cytokines involved in inflammatory responses (72). Collectively, these studies show profound changes to the gut microbiome and metabolome with opioid use.

FIGURE 2

Figure 2 Proposed mechanisms of gut dysbiosis and microbial translocation with opioid use (1) Opioid use is associated with decreased gastrointestinal motility via direct action on μ-opioid receptors. This can lead to small bowel overgrowth, gut dysbiosis, and microbial translocation. (2) Some opioids (e.g., morphine) have been shown to directly alter the phenotype of gram-negative organisms such as Pseudomonas aeruginosa which causes decreased mucus secretion in the gut, altering microbial homeostasis. (3) Opioids can also worsen sepsis via modulation of IL-17 by gram-positive organisms. (4) Opioids also cause a decrease in Th1 and an increase in Th2 cells which lead to decreased antibody production and MHC-II expression; this increases the risk of infection and decreases pathogen elimination. (5) Lastly, opioids modulate myosin light chain kinase in a toll-like receptor dependent manner which causes loss of bacterial tight junctions and impaired gut barrier function. This increases microbial translocation and impairs β-glucuronidase-mediated hydrolysis, which can in turn impair morphine metabolism and elimination. Notably, alterations in opioid metabolism can decrease the effectiveness of morphine as an analgesic agent and increase morphine tolerance.

3.2 Effect of medication assisted treatments for OUD on microbial dysbiosis

Great strides have been made in the treatment of OUD and it is generally agreed upon that MAT leads to positive outcomes for patients (73). However, research on the effect of MAT on the gut microbiome is limited due to the novelty of OUD research and the difficulty of studying those with OUD. Currently, only two studies to date detail interactions between medication assisted treatments (MATs) such as methadone and buprenorphine and the gut microbiome.

First, Gicquelais et al. (70) studied gut microbiota characteristics related to the use of opioid agonists and antagonists among people receiving outpatient addiction treatment. In their studies, they reported a decrease in microbial species diversity in patients who used opioid agonists (without antagonists), a decreased abundance of Bacteroidetes enterotypes, and decreased Roseburia and Bilophila, which are butyrate and bile acid-related species, respectively. However, there were no differences in the gut microbiome in those using opioid agonist-antagonist combinations (e.g., buprenorphine-naloxone), antagonists alone (e.g., naltrexone, or those using neither opioid agonists nor antagonists. This study had several limitations including a smaller sample size and lack of healthy controls. Additionally, as nearly all measures were self-reported, this study was subject to selection bias. Still, this was the first study to describe enterotypes among humans with OUDs and allows for comparisons to other disorders to identify common mechanisms underlying dysbiosis.

Next, Cruz-Lebron et al. also studied the impact of methadone maintenance treatment on the gut microbiome, metabolome, and intestinal barrier integrity. This group found that methadone-treated individuals had decreased fecal bacterial diversity as measured by beta diversity as well as decreased evenness and richness (74). Additionally, it was found that bacteria involved with the production of SCFAs, mucus degradation, and maintenance of intestinal barrier integrity were decreased in those who used methadone, which could leave those individuals at risk for conditions associated with decreased intestinal barrier integrity (75).

Ultimately, the limited number of studies do not permit generalizations on the effect of MAT on microbial dysbiosis, and further work should be done to investigate the impact of MAT on the microbiome. However, the currently available data suggests that MAT also induce alterations to the gut microbiome; whether these alterations are less severe than those imposed by other opioid agonists themselves still needs to be explored in larger well-designed studies using appropriate control groups.

4 HIV, opioids, and alterations to the gut microbiome

Understanding how HIV and opioid use, in combination, impact the microbiome is of growing importance, with the opioid epidemic leaving no populations untouched and opioids still widely used in clinical settings for pain management (76). In addition, those living with both HIV and OUD are more likely to receive suboptimal HIV testing and delayed entry into HIV care and treatment, and less likely to be adherent to ART treatment (16). Of note, opioids and MAT can also interact with and reduce the efficacy of ART (16). Thus, detailing interactions between HIV and opioid use is paramount to improving patient care and coordinating disease management.

Many studies have separately examined differences in microbial composition in animal and human models of HIV and opioid use and have concluded that both of these conditions significantly impact the microbiome. However, with accumulating evidence of the interaction of opioids and HIV infection, it is logical to assess the compounding effect they may enact together on the gut ecosystem. Of the few studies that exist, there is strong evidence that HIV in conjunction with opioid use can cause microbial dysbiosis that is distinct from the dysbiosis seen in HIV/SIV infection or those with opioid use alone (77–79). Additionally, this dysbiosis, like that seen with HIV infection or opioid use alone, is associated with inflammation (77–79). To date, only three preclinical studies have described microbial changes with HIV and opioid use; one study assessed dysbiosis in humanized mice injected with HIV and then administered morphine, and two studies assessed dysbiosis in rhesus macaques treated with morphine followed by SIV infection (Table 1) (77–79).

TABLE 1

Table 1 Summary of preclinical studies detailing HIV and opioid-induced microbial alterations.

Meng et al. reported gut microbial dysbiosis in a mouse model of HIV infection subsequently administered morphine (79). It was found that the alpha diversity in mice treated with HIV and morphine (HIV/morphine) was significantly lower than in placebo mice treated with morphine or HIV alone. This could indicate an additive effect of HIV and morphine on microbiome dysbiosis. In the HIV/morphine group, there was a greater abundance of Firmicutes and Proteobacteria and a lower abundance of Bacteroides, Actinobacteria, and Tenericutes. Interestingly, a depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae was found in the same group (79). These bacteria are commonly associated with SCFA production in the gut, which is essential in modulating inflammation via histone deacetylase inhibition (80). In fact, SCFAs, like butyrate, are the preferred energy substrates for colonocytes, and decreased butyrate production is associated with inflammatory conditions like Crohn’s disease and ulcerative colitis (81, 82). Additionally, butyrate is responsible for upregulating the tight junction protein Claudin-1, which promotes intestinal epithelial barrier integrity (83). This study also found that HIV/morphine mice had significant epithelial intestinal damage. Additionally, Staphylococcus was found to be increased in mice with HIV infection, and Enterococcus was found to be increased in HIV/morphine mice. These are common pathogens associated with bacteremia in PLWH (84) and in those using opioids (85). Lactobacillus, a common microbe of the intestine that is anti-apoptotic and anti-inflammatory, was also found to be depleted (86). How these findings translate to humans remains to be elucidated.

In accordance with Meng et al., Johnson et al. reported that rhesus macaques that were first administered morphine, injected with SIV, and then given ART (SIV/ART/morphine) to suppress viral load had decreased alpha diversity in fecal samples collected. Notably, there was decreased Firmicutes, in particular Ruminococcacea (77). It was hypothesized that the Ruminococcacea depletion was the result of morphine treatment, since there was a trend toward decreased BPB in the SIV/ART/morphine group compared to SIV/ART alone. Interestingly, the authors found that the decreased BPB was likely not due to the Ruminococcacea since there was no correlation between Ruminococcacea and BPB. However, there was a positive correlation between Lachnospiraceae and BPB which could indicate that, of the SCFA-associated bacteria found to be decreased in the SIV/ART/morphine macaque, Lachnospiraceae could be important in SCFA production. Johnson et al. also found that SIV/ART/morphine primates had increased Bacteroidetes such as Prevotellaceae; this contrasts with Meng et al. who reported decreased Bacteroidetes. Still, increases in Prevotella are often associated with increased risk of other inflammatory conditions such as rheumatoid arthritis and colitis due to changes in mucosal immune responses (87, 88). While this study did not assess temporal changes in the gut microbiome, future studies would benefit from this evaluation.

In contrast to the above studies, rhesus macaques that were first administered morphine and then injected with SIV did not have significantly different alpha diversity in the microbiome during early SIV infection when compared to the placebo group, the SIV group, or the morphine group (78). Additionally, there was no significant difference in microbial composition in the group with SIV infection alone. The group with morphine administration had increased Methanobacteriaceae of the domain Archaea and decreased Streptococcaceae and Ruminococcaceae family microbes. A similar finding was seen in SIV/morphine primates, which could indicate that morphine primarily contributes to dysbiosis in early infection. In accordance with both Meng et al. and Johnson et al., Sindberg et al. also found a decrease in Ruminococcaceae. These differences in microbial composition in the morphine group and the SIV/morphine group were associated with altered metabolites such as bile acids, sphingolipids, and serotonin. Bile acid metabolism and dysregulation of this pathway associated with microbiome dysbiosis is also seen in many studies assessing dysbiosis in opioid use alone, which could indicate the important role of opioid metabolism in dysbiosis during early HIV infection (65, 68–70). Bile acids play a role in bacterial translocation, which is associated with HIV replication and might occur earlier in PLWH who also use opioids (69). Thus, the bile acid metabolism pathway could serve as a potential target for decreasing HIV replication.

Together these studies suggest that HIV and opioid use together can create a state of microbial dysbiosis that is distinct from dysbiosis caused by either state alone (Figure 3). It is imperative to highlight that there are no human studies in this field precluding generalizations to humans. Nonetheless, animal models are known to recapitulate human conditions. For example, humanized mouse models of HIV model HIV-1 infection of human cells in vivo. Similarly, research in SIV infection in macaques has evolved to developing SIV/HIV hybrid viruses to further resemble of the viruses to one another, which is currently the most widely accepted model of HIV (89). Likewise, SUD animal models have shown great validity due to similarities between neurochemical and neuroanatomical substrates involved in drug-intake behavior (90). Specifically, mice models have been shown to be translationally relevant and useful for studying opioid use disorder. Slivicki et al. showed that mice voluntarily self-administer oxycodone; some mice even demonstrated drug taking that is resistant to aversive consequences (91), similar to OUD. While animal models have helped elucidate mechanisms, more studies that are focused on human subjects are needed.

FIGURE 3

Figure 3 Microbiome and metabolite changes in clinical and preclinical studies of HIV and opioid use. The left represents microbiome and metabolite changes in PLWH and animal models of HIV/SIV. The right represents microbiome and metabolite changes in those with OUD and animal models of opioid use/OUD. The middle represents the overlapping microbiome detailed in existing animal models of both HIV/SIV and opioid use. The text in green represents information from studies done in humans. The red text represents information from studies done in animal models of HIV/SIV and opioid use. The text in purple represents information from both studies done in humans and animals.

5 Treatment of dysbiosis in PLWH with OUD

Alterations to the microbiome observed in those with HIV, OUD, or both could implicate significantly adverse downstream effects. While there are no papers to date about treating dysbiosis in PLWH with co-occurring OUD, there have been studies that have investigated microbial restoration in people with either HIV or OUD. Specifically, therapies such as prebiotic supplementation and fecal microbiota transplantation (FMT) have been attempted and investigated (Figure 4).

FIGURE 4

Figure 4 Summary of clinical and preclinical studies detailing the impact of probiotics with HIV or opioid use. (Left panel) Lactobacillus supplementation has been shown to have a positive impact on the microbiomes of both clinical and preclinical models of HIV or opioid use. In PLWH, Lactobacillus supplementation has been shown to increase CD56+ cells, T-lymphocytes, and IL-23 and to decrease levels of TGFβ, IL-10, IL-12 and IL-1β. This is thought to lower systemic immune activation and to increase CD4+ counts in PLWH. Lactobacillus supplementation also decreases cystatin C (image from https://www.sinobiological.com/resource/cystatin-c/proteins) which in turn, decreases cardiovascular risk and inflammation in PLWH. Lactobacillus supplementation in conjunction with Bifidobacteria supplementation also has been shown to attenuate analgesic tolerance in morphine-treated mice. (Middle panel) Additionally, in preclinical models of chronic opioid use, an n-3 omega-3 polyunsaturated fatty acids (n-3 PUFA) enriched diet increased species richness, phylogenetic diversity, and evenness, as well as decreased oxycodone-seeking behaviors. (Right panel) Lastly, a unique oligosaccharide mixture supplementation including short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS), and pectin hydrolysate derived acidic-oligosaccharides (pAOS) in PLWH has been shown to decrease pathogenic bacteria, sCD14, and CD4+ T-cell activation in PLWH, as well as to improve NK cell activity.

5.1 Treatment of dysbiosis in PLWH

Prebiotic, probiotic, and symbiotic supplementation has had some success in modulating gut dysbiosis in PLWH. Interestingly, enriching the microbiome with Lactobacillus has been shown to be associated with higher CD4 counts and lower immune activation in peripheral blood of PLWH (47, 92). Specifically, Lactobacillus supplementation has been linked to increased T-lymphocytes, CD56+ cells, and serum IL-23 in peripheral blood of PLWH (93). Supplementation has also been associated with decreased mRNA levels of TGFβ, IL-10, IL-12 and IL-1β (93). This study also found a decrease in cystatin C, which is associated with lower inflammation and cardiovascular risk (93). These studies are in line with the finding that ART-treated individuals who fail to have an immune response (defined by a CD4 count < 200) have lower levels of anti-inflammatory microbes such as Lactobacilli and increased inflammatory markers such as IL-6 sCD14, and LPS (94–96). While ART did not improve gut microbiome dysbiosis, probiotic supplementation was shown to significantly decrease markers of inflammation and of microbial translocation (97). However, conflicting studies exist regarding probiotics in PLWH who are not on ART. Gori et al. found that probiotic supplementation in combination with a unique oligosaccharide mixture including short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS), and pectin hydrolysate derived acidic-oligosaccharides (pAOS) significantly decreased pathogenic bacteria, sCD14, and CD4+ T-cell activation (CD25) and improved NK cell activity in this population (98). However, limited or no success with probiotic supplementation has also been evenly reported. For instance, Kim et al. found no significant differences in immune activation markers of 40 PLWH not on ART after probiotic supplementation with a commercially available supplement that included 900 bacterial colony forming units (99).

Fecal microbiota transplantation (FMT) to treat gut dysbiosis in PLWH has also had mixed results. To date, only three studies have investigated the use of FMT to treat dysbiosis in PLWH (100–103). Vujkovic-Cvijin et al. selected control donors for FMT who had a low abundance of Proteobacteria and a high abundance of Bacteroides in their fecal sample. It was found that PLWH had a microbiome composition that resembled their donors at two and four weeks; however, this shift was lost by week eight. At that point, the microbiome of PLWH was more like their microbiome before FMT. Additionally, no changes in HIV-associated inflammation markers such as plasma levels of immune activation markers including IL-6 or sCD14 were found over time (101). Of note, this study had a small sample size with only six participants and two controls. Similarly, Serrano-Villar et al. selected donors for FMT who had a low abundance of Prevotella and a high abundance of Bacteroides (102). The donors were also all on effective ART therapy. It was found that there was a significant decrease in intestinal damage assessed by lipopolysaccharide-binding protein and intestinal fatty acid binding protein at week four in PLWH who received FMT. However, similar to Vujkovic-Cvijin et al.’s study, there were no changes in inflammatory markers or disease progression markers associated with HIV such as CD4+ T-cells, CD8+ T-cells, CD4/CD8 ratio, sCD14, IP-10, sCD163, sTNFR-II, D-Dimer, and lipoteichoic acid (102).

Finally, Hensley-McBain et al. studied FMT in non-humans with SIV infection. Stool samples from SIV-negative animals were transplanted into SIV-positive animals. It was found that the animals who received antibiotics before transplantation had decreased CD4+ T-cells, increased Th17 and Th22, and increased engraftment and uptake of FMT. There was also an incremental increase in alpha diversity that was seen until week 6. However, after this time point, this increase diminished and diversity returned to baseline levels (103). While FMT interventions in PLWH has been limited in its success, there has been more success with FMT use in PLWH who have Clostridiales difficile infection (104). Additionally, some studies suggest that the use of antibiotics could improve the uptake of FMT (103, 105, 106). However, much more work is needed in this area, with specific attention paid to maintaining successful engraftment for long-term improvements in PLWH.

5.2 Treatment of dysbiosis with OUD or models of opioid-dependency

With regards to OUD-associated dysbiosis, prebiotics and dietary supplementation seem to be promising treatments. Zhang et al. found that prebiotics enriched with Bifidobacteria and Lactobacillaeae attenuated analgesic tolerance in morphine-treated mice (94). Increasing certain metabolites has also proved to be an important modulator of the gut microbiome. In one study, an omega-3 polyunsaturated fatty acids (n-3 PUFA) enriched diet was found to reduce oxycodone-seeking behaviors in a mouse model of chronic opioid administration (107). Specifically, Hakimian et al. found that n-3 PUFA supplementation increased species richness, phylogenetic diversity, and evenness (107) N-3 PUFA is found in fish and plants and has been shown to have anti-inflammatory and anti-anxiolytic properties (108, 109), which is relevant as anxiety is often a co-morbid condition in those with SUD (110). Modulation of the microbiome using antibiotics has also been shown to improve dysbiosis in rodent models of opioid abuse. Lee et al. found that intermittent morphine treatment in mice was associated with microglial activation, hyperalgesia, and impaired reward response. When antibiotics (ABX) were used to deplete gut microbiota, reduced opioid analgesic potency was observed. Colonization of these ABX-treated mice with a control microbiota resulted in restoration of microglial activation (54). Kang et al. further found that ABX could actually prevent chronic morphine-induced increases in gut permeability, colonic mucosal destruction, colonic IL-1β expression, and the development of antinociceptive tolerance to chronic morphine (66). Collectively, these studies show the profound role of the gut microbiota in modulating analgesic potency, drug tolerance/reward, gut barrier integrity, and immune activation. However, widespread use of antibiotics to modulate gut-microbiota-mediated effects is noted to be impractical in the clinical setting, with microbial resistance becoming a growing public health concern.

Lastly, few studies have investigated FMT in the treatment of OUD-associated dysbiosis. In a preclinical study, Thomaz et al. examined how FMT influences opioid withdrawal, using number of jumps as a somatic sign of withdrawal in mice, and evaluated whether FMT from morphine-treated or saline donors could lessen withdrawal symptoms (111). Their results demonstrated that morphine-dependent mice which received FMT from morphine-treated donors exhibited fewer naloxone-precipitated jumps than those which had saline-treated donors (111). Additionally, broad-spectrum ABX reduced somatic signs of withdrawal in mice, whereas probiotics and a gut permeability inhibitor called ML-7 did not cause a significant change in physical withdrawal symptoms (111). These promising results show that therapeutic manipulations of the gut microbiome may reduce opioid-associated comorbidities.

6 Conclusion

In this review, we have described how HIV and OUD can impact the gut microbiome and how alterations to the gut microbiome can influence HIV disease progression. Investigating how HIV in conjunction with OUD impacts the gut microbiome is greatly warranted because of the high co-occurrence of HIV and OUD, growing rates of chronic pain in PLWH, and increased rates of prescription opioid use in PLWH. However, few studies exist regarding this topic. All three studies that exist report various microbial changes in animal models of HIV that were administered opioids. These bacteria are involved with modulating immune function, decreasing colonic inflammation, and maintaining gut epithelial barrier integrity in healthy individuals.

It is imperative to acknowledge the various limitations of this review. While the effect of either HIV or opioid use alone on the microbiome has been studied extensively, very few articles have looked at their combined effect. Additionally, the few that have done so have been carried out in animal models alone. Evaluation of microbiome compositional and functional shifts in PLWH with OUD are necessary. Secondly, there is great inconsistency in the way microbial changes are described in literature, making comparisons of existing studies difficult. Additionally, while animal studies can carefully control for confounding variables, including polysubstance use that typically occurs with PLWH with OUD, differences in species used amongst animal studies further complicate gut microbiome comparisons and limit generalizations to humans.

Still, our review is the first to look at the interaction of HIV and opioids and serves to elucidate a knowledge gap for future human studies. A review of existing studies has shown that changes in the gut microbiome from HIV in conjunction with opioid use are distinct from changes observed in HIV or opioid use independently. These changes are also associated with increased inflammation and decreased gut epithelial barrier integrity. While mixed results exist regarding treating dysbiosis with microbial restoration in PLWH or in those with OUD, larger well-defined studies that can extend microbial engraftment or delivery of metabolites hold much promise and should still be explored. Future studies should further investigate how manipulating the microbiome can impact key characteristics of HIV and OUD which have not been previously explored, such as CD4 counts, viral load, opioid seeking behavior, and neuroinflammation, for example. Additionally, investigations into how ART and MAT impact the microbiome, cellular processes and metabolism are warranted.

Author contributions

SS: Conceptualization, Methodology, Creating figures, Writing-original draft, Writing-review & editing. YA: Conceptualization, Methodology, Writing-review & editing. DG: Writing-review & editing, Assisting with figures. RKD: Writing-review & editing, Visualization. SR: Writing-review & editing, Supervision, Project administration, Funding acquisition. All authors contributed to the article and approved the submitted version.

Funding

National Institutes of Health, Grant/Award Numbers: F31DA053795, R01 DA050542, R01 DA047089, R01 DA043252 and R01 DA044582.

Acknowledgments

We would like to thank Dr. Valerie Gramling, Senior Lecturer in Writing Studies at the University of Miami, for her assistance with editing and organizing this manuscript. Figures created with BioRender.com.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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