Much interest and considerable advances have been made in understanding the contribution of microbial translocation, the passage of microbes and microbial products to the systemic circulation; and the gut microbiome, the microbial communities that inhabit our intestines and their genes and metabolites, to HIV-associated comorbidities [8–11]. Interestingly, strong associations have been made between dysbiotic or altered microbiomes and a range of diseases fueled by chronic inflammation, echoing what is seen in HIV infection [12▪,13]. Indeed, the microbiome involvement in the transmission and pathogenesis of HIV infection is being acknowledged [8,14,15,16▪▪,17], although findings and interpretation of results diverge quite significantly between studies [18▪▪], in part because of cohort effects, sampling biogeography and perhaps most importantly because of the lack of adjustment for confounding factors, such as sexual practices  and diet . Several recent reviews have provided up-to-date information on gut dysbiosis reported in untreated HIV infection [18▪▪,21]. Concerning treated HIV infection, several studies seem to indicate that ART by itself does not restore the gut microbiome of HIV-infected individuals to healthy communities comparable to HIV-uninfected individuals [19,22–34]. Also, ARV drugs could promote further dysbiosis [18▪▪] and distinct ARV combinations could have dramatic effects on the gut microbiome as ARVs themselves have antimicrobial properties and conversely, specific microbes (mainly bacteria) could catabolize ARV drugs [35,36,37▪▪]. Furthermore, a nonnegligible proportion of ART-treated individuals suffer from gastrointestinal discomfort, commonly diarrhea, mostly associated with protease inhibitor-based ART regimens [38–40]. Indeed, despite vast improvements in drug tolerability and overall drug safety of contemporary drugs, different ARV combinations have different side effects and this could differentially affect how the gut microbiome responds: reduced diversity versus increased diversity, restoration versus further dysbiosis, and so on. Surprisingly, however, only a handful of articles have addressed the differential effects of ARV drugs on the gut microbiome, microbial translocation, enterocyte damage and inflammation/immune activation [29,30▪▪,31▪▪]. Improving our understanding of the impact of ART and different ARV combinations is needed to draw a complete picture as more HIV-infected individuals will have access to ART and become ART-experienced, and as more people are using ART as preexposure prophylaxis (PrEP) in the absence of HIV infection. Here we will review the current knowledge regarding the impact of ARV drugs on the gut microbiome and what is known on understanding the mechanisms that could be at the heart of ART-induced dysbiosis.
Overall, in untreated HIV infection, most studies report an enrichment in the genus Prevotella and Enterobacteriaceae, a Gram-negative family of the phylum Proteobacteria. Importantly, these bacteria are known to be involved in microbial translocation  and contributing to residual immune activation [8,41,42]. Indeed, the enrichment or depletion in some key species within the microbial communities’ structure of HIV-infected individuals is associated with markers of HIV disease progression [43▪▪]. Of particular interest, the depletion of butyrate-producing bacteria (BPB) has been associated with increased microbial translocation and immune activation [43▪▪]. We recommend several recent systemic reviews for up-to-date information on the gut microbiome alterations in untreated HIV infection as it is outside the scope of this review [8,14,17,18▪▪,21,44▪]. Studies on the short-term and long-term impact of ART on the gut microbiome have convincingly demonstrated that ART is unable to consistently restore gut health. The gut microbiome of treated HIV-infected individuals shows a shift away from viremic HIV-infected individuals, but yet display a distinct community structure from HIV-uninfected individuals [19,22–34]. Findings and interpretation of results are often conflicting and vary by type of sampling used (fecal versus swabs versus mucosal biopsies), time on ART and potential methods used to extract and sequence the microbial DNA [18▪▪,19,22,24–29,34,45]. Conflicting data are further complicated by the need to control for sexual practices , and overall power issues driven by sample size and the use of appropriate control groups. For example, most but not all authors reported a decrease in microbial diversity, which is an independent indicator of gut microbiome restoration, and has been proposed by Nowak et al. to reflect immune reconstitution. The impact of ART on the microbiome has been mostly studied in cross-sectional cohorts and have included HIV-infected individuals with many years on ART. Going forward, we need to disentangle two separate notions: ART can to some degree reverse HIV-associated gut dysbiosis as shown in most but not all studies. But the initiation of ART can also lead to a separate dysbiosis, which may be confounded by the HIV-associated gut dysbiosis and go unreported and unstudied. This could lead to differential outcomes: non-AIDS communicable disease such as cardiovascular disease, accelerated aging, cognitive defects, diabetes, elevated liver enzymes and alterations of fat deposits. Furthermore, almost all studies have exclusively focused on the bacterial component of the gut microbiome. Interestingly, it is worth mentioning that virome expansion seems to be more indicative of the immune dysfunction and could be used as a biomarker for immune reconstitution . Future work should include longitudinal cohorts of HIV-individuals before and after ART initiation.
To date, three articles have purposefully evaluated the effects of distinct ARV combinations on the gut microbiome [29,30▪▪,31▪▪] rather than ART as a whole. The main study endpoints were to investigate the effects of distinct ART regimens on the gut (fecal) microbiome and markers of microbial translocation, inflammation/immune activation and endothelial damage with one specific question in mind: which ART combinations were best to restore the HIV-associated dysbiosis (Table 3). 16S profiles were generated and conclusions were drawn by the authors based on the analysis of a cohort of ART-treated HIV-infected individuals on different ART regimens. Interestingly, Villanueva-Millán et al.[31▪▪] showed that ART combinations tested: protease inhibitors, NNRTIs and INSTIs with NRTIs backbone, increased significantly the plasma levels of endothelial damage markers compared with HIV-uninfected controls; with protease inhibitor-based regimen showing the most endothelial damage compared with both NNRTIs and INSTIs. On the order hand, Pinto-Cardoso et al.[30▪▪] showed that ritonavir-boosted protease inhibitor-ART regimen increased endothelial damage compared with both NNRTIs and HIV-uninfected controls; whilst NNRTI-based ART damage was significantly increased compared with HIV-uninfected controls. Both authors included soluble CD14 (sCD14), a marker that is released after monocyte activation in response to lipopolysaccharide (LPS)  and has been shown to independently predict mortality in HIV infection . Villanueva-Millán et al.[31▪▪] also used the LPS-binding protein as a surrogate marker of microbial translocation but no differences were observed. Both articles concluded that protease inhibitor-based ART combinations were more detrimental because of both microbial translocation and endothelial damage, and this was associated with increased inflammation in individuals with protease inhibitor-based regimens only [31▪▪], accentuating the idea that the least favorable ART combination was protease inhibitor-based. Both articles had limitations; mainly lack of adjustment for known confounding factors (Table 3). Taken together, however, these results provide strong evidence that ARV combinations promote differential dysbiosis leading to inflammation. One possible explanation for the differential effects of ARV drugs on the gut microbiome and markers of microbial translocation, inflammation and immune activation would be the differential penetration of ARV drugs on the gastrointestinal tissue and their pharmacokinetics. Raltegravir has been shown to penetrate faster in the gastrointestinal tract (GIT) . Indeed, multiple dosing administration of Raltegravir in a cohort of 14 HIV-uninfected men penetrated rapidly into the gut-associated-lymphoid tissue (GALT; terminal ileum) and reached concentrations higher than that of blood and plasma. Furthermore, novel work by Hladik et al. demonstrated that ARV drugs may have direct effects on inducing inflammation and epithelial damage at mucosal sites. Interestingly, INSTI-based regimens have shown greater propensity to decrease inflammation compared with NNRTIs . On the other hand, bacteria that maintain epithelial health and immune homeostasis, for example, by providing short-chain fatty acids (SCFAs) such as butyrate, have been consistently found to be depleted in HIV-infected individuals on ART [30▪▪,31▪▪,43▪▪]. Butyrate is a metabolite produced in the colon by a subset of gut commensal bacteria, the BPB, through the fermentation of nondigestible carbohydrates . Butyrate is utilized by the host, and is the main energy source for the colonocytes. Of the many SCFAs, butyrate and propionate have been shown to have the most health-promoting functions [52▪]. Interestingly Dillon et al.[43▪▪] confirmed these observations and further showed that butyrate is essential for the prevention and repair of the intestinal epithelial barrier in the context of HIV infection. Collectively, these studies indicate that interventional therapies to prevent and recover disrupted homeostasis should include the repopulation of the gut with BPB.
Microbiome composition at mucosal sites where HIV is first encountered may have significant impact on early HIV infection, and therefore, disease progression. Indeed, despite very early ART treatment in HIV-infected individuals, dysbiosis still occurs and persists . Although it is accepted and well studied that bacteria can metabolize dietary products and produce key metabolites such as vitamins and SCFAs, metabolism of other compounds, such as drugs, has not overtly been studied, despite the remarkable ability for bacteria to metabolize many xenobiotic compounds . Many studies have demonstrated that several subgroups of bacteria possess enzymes, or enzyme analogs, that are known to play a role in drug pharmacokinetics and metabolism [54–60]. Metabolism and/or biodegradation, however, of drugs by bacteria and how this contributes to human health has remained understudied. Recent studies have begun to provide important information demonstrating that gut microbes can affect the efficacy of several drugs . Klatt et al.[37▪▪] recently demonstrated that the microbiota in the female reproductive tract (FRT) can directly metabolize the ARV, tenofovir, and the presence of these bacteria (Gardnerella vaginalis) was associated with decreased efficacy of topical PrEP in women [62▪]. Furthermore, they showed that classes of bacteria in the FRT that are also commonly found in the gut, such as Prevotella spp. and Escherichia coli, can metabolize tenofovir, indicating that ARVs may be impacted by gut bacteria [37▪▪]. Interestingly, oral PrEP efficacy does not seem to be affected in adherent women with vaginal dysbiosis as defined by Nugent scoring, however, this should be further investigated in larger studies [63▪▪]. This highlights the need to better understand the pharmacokinetics of oral and non-oral ARV drugs, fully characterize the microbiome (in particular, the rectal, penile and vaginal microbiome for non-oral ARV drugs) and understand how microbial communities affect the ARV drug metabolism either locally (genital microbiome) or systemically (gut microbiome). This is of a particular interest for microbicide-based HIV prevention strategies [64,65]. For the moment, however, these important questions remain unanswered, and studies examining the role of microbiome on ARV drug metabolism in HIV-infected individuals or in the context of PrEP are warranted.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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This review discusses the current strategies to reduce residual immune activation, from timing of ART initiation and ART intensification to reducing microbial translocation. This research area is of great importance as residual immune activation remains linked to non-AIDS comorbidities associated with aging and more and more HIV-infected individuals are starting ART early and living longer.
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Excellent overview of the interplay between the host and the commensal microbiota, focusing on the effect of the microbiome on the innate and adaptive immune system and how this latter can drive inflammation.
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This systematic review discusses the main conclusions and future directions in the field of HIV and microbiome from the first HIV microbiome workshop, which took place in 2015 at the National Institute of Health. It was the first time, officially that scientists from different countries and disciplines gathered purposefully to discuss microbiome research in HIV infection. After the success of this first workshop, organizers announced follow-up 2-day yearly meetings.
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This systemic review gives an excellent overview of the current knowledge in the field of HIV and microbiome.
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30▪▪. Pinto-Cardoso S, Lozupone C, Briceño O, et al. Fecal bacterial communities in treated HIV infected individuals on two antiretroviral regimens. Sci Rep 2017; 7:43741.
One of two recent articles presenting data on the differential effects of two first line ARV combinations on fecal microbiome, microbial translocation, gut epithelial and immune activation. The study shows that ART-experienced HIV-infected individuals lack specific bacteria, important for the return of gut homeostasis. The study also highlights that protease inhibitor-based regimen has more microbial translocation and gut endothelial damage as compared with NNRTI-based regimen.
31▪▪. Villanueva-Millán MJ, Pérez-Matute P, Recio-Fernández E, et al. Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients. J Int AIDS Soc 2017; 20:1–13.
This article is among one of the first to evaluate the differential effects of antiretroviral drugs and ARV combinations on the fecal microbiome of ART-experienced HIV-infected individuals and includes patients on INSTIs; showing that HIV-infected individuals on integrase inhibitors fully restore their gut microbiome richness (to level comparable with HIV-uninfected). It is also one of the first HIV-associated gut microbiome study to compare individuals with or without co-infections (HCV and HBV).
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37▪▪. Klatt NR, Cheu R, Birse K, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science 2017; 356:938–945.
First article to put forward evidence that microbial communities in the reproductive tract of women can affect ARV drug metabolism by directly degrading the ARV drug (1% tenofovir, locally administered) before it can be metabolized by target cells. This was linked to reduced efficacy of the tenofovir microbicide gel in the CAPRISA 004 study in women with non-Lactobacillus spp. vaginal microbiomes. This article is extremely relevant to all microbicide-related HIV-prevention strategies.
38. Logan C, Beadsworth MB, Beeching NJ. HIV and diarrhoea: what is new? Curr Opin Infect Dis 2016; 29:486–494.
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40. Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and management in the era of combination antiretroviral therapy. Infect Dis Ther 2014; 3:103–122.
41. Klase Z, Ortiz A, Deleage C, et al. Dysbiotic bacteria translocate in progressive SIV infection. Mucosal Immunol 2015; 8:1009–1020.
42. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 2014; 7:983–994.
43▪▪. Dillon SM, Kibbie J, Lee EJ, et al. Low abundance of colonic butyrate-producing bacteria
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This article demonstrates that the absence of butyrate-producing bacteria (in specific Roseburia intestinalis) is highly detrimental for gut homeostasis in ART-naïve HIV-infected individuals; higher immune activation, more gut endothelial damage and overall enteric growth is observed in the absence of these BPB and has been linked to the absence of the main produced metabolite, butyrate.
44▪. Williams B, Landay A, Presti RM. Microbiome alterations in HIV infection a review. Cell Microbiol 2016; 18:645–651.
Excellent systemic review on the microbiome alterations associated with HIV infection discussing important aspects of this research field: methodology, results from primate studies, HIV pathogenesis (gut microbiome) and transmission (genital microbiome).
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52▪. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol 2017; 19:29–41.
This review gives an excellent overview of the bacteria and metabolic pathways contributing to butyrate and propionate formation.
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62▪. Velloza J, Heffron R. The vaginal microbiome and its potential to impact efficacy of HIV preexposure prophylaxis for women. Curr HIV/AIDS Rep 2017; 14:153–160.
Excellent review discussing oral and non-oral PrEP efficacy in women in the context of the vaginal microbiomes, drug formulation and drug delivery mechanisms.
63▪▪. Heffron R, McClelland RS, Balkus JE, et al. Efficacy of oral preexposure prophylaxis (PrEP) for HIV among women with abnormal vaginal microbiota: a posthoc analysis of the randomised, placebo-controlled Partners PrEP Study. Lancet HIV 2017; 4:e449–e456.
First study to demonstrate that oral PrEP is as efficacious in women with or without bacterial vaginosis; providing strong evidence that HIV prevention is achievable among women regardless of their vaginal microbiomes, with high adherence using orally administered PrEP.
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