Taxa from four bacterial phyla – Proteobacteria, Fusobacteria, Bacteroidetes, and Firmicutes – have been reported in multiple studies to differ between HIV-infected and HIV-uninfected individuals. Proteobacteria were more abundant in HIV-infected individuals in 10 of the 16 published studies whereas others reported no change [17,18▪▪,19,20▪,21▪▪,22▪,23▪▪,24▪,27▪,30▪▪,32▪▪,33▪]. The phylum Proteobacteria includes numerous pathogens, such as Shigella, Salmonella, and Helicobacter. Many specific Proteobacteria genera have been shown to be enriched in HIV-infected individuals and are capable of potentially pathogenic activities in this context : Pseudomonas [21▪▪,95] is an opportunistic pathogen that is capable of impairing host mucus production [97,98]; Desulfovirbrio  can produce hydrogen sulfide compounds and inflame the host epithelium ; Acinetobacter [23▪▪] can produce LPS  and in vitro is able to induce IL-8 production and neutrophil recruitment that could lead to inflammatory tissue damage [101,102]; and Campylobacter [20▪] produces multiple toxins  that can induce mucosal inflammation . The Proteobacterial family Enterobacteriaceae is associated with inflammation [105,106] and was enriched in HIV-infected individuals in seven of the 16 studies surveyed [20▪,21▪▪,24▪,29▪▪,31▪▪,32▪▪,33▪] (most frequently driven by its constituent genus Escherichia, which is capable of pathogenic bile acid transformations and degradation of host mucus [98,107]). The phylum Fusobacteria, which is of particular interest because of its previous associations with intestinal inflammation and colorectal cancer [108–110], was enriched (most frequently driven by its constituent genus Fusobacterium) in HIV-infected individuals in four of the 16 previously published studies [19,20▪,22▪,32▪▪].
Taxa in the phylum Bacteroidetes, including the families Prevotellaceae, Porphyromonadaceae, Bacteroidaceae, and Rikenellaceae, exhibited a more heterogeneous pattern of changes in HIV-infected individuals. The family Prevotellaceae (most frequently driven by its constituent genus Prevotella) was enriched in HIV-infected individuals in seven of 16 studies [17,18▪▪,20▪,23▪▪,26▪,27▪,28▪▪,33▪] and depleted in one study [31▪▪]. Taxa within the family Prevotellaceae have been associated with inflammation (particularly in the context of autoinflammatory disease [111,112]) and activation of gut dendritic cells [28▪▪], but a greater abundance of Prevotellaceae is also characteristic of the baseline enteric microbial community of healthy individuals in developing world countries such as Burkina Faso, Venezuela, Malawi, or Papua New Guinea [17,113–117]. Taxa from the family Porphyromonadaceae (most frequently driven by the genera Barnesiella or Odoribacter) were generally depleted in HIV-infected individuals, exhibiting a decrease in nine of 16 studies [17,18▪▪,20▪,21▪▪,22▪,23▪▪,30▪▪–32▪▪,33▪] and an increase in two studies [19,24▪]. Independent of HIV, Porphyromonadaceae exhibit a diverse and complex array of functions, with both positive [110,118,119] and negative  associations with colorectal cancer, and negative associations with C. difficile [120–122], Salmonella , vancomycin-resistant Enterococcus , and Citrobacter rodentium [125,126] infection that imply a putative protective role. The family Bacteroidaceae (mostly driven by the abundance of the genus Bacteroides) is overall depleted in HIV infection, showing a reduced HIV-associated abundance in 10 of 16 studies [17,18▪▪,21▪▪,23▪▪,26▪,28▪▪–31▪▪,33▪]. This family is generally considered to play an anti-inflammatory role [127–131], with the species Bacteroides fragilis promoting regulatory T-cell differentiation and IL-10 production via secreted bacterial products [127–129]. The family Rikenellaceae (mostly driven by the abundance of the genus Alistipes) is also depleted in HIV infection, with decreased abundance in seven studies [17,18▪▪,19,20▪,21▪▪,23▪▪,24▪,28▪▪] and this bile-tolerant family  displays protective properties against C. difficile infection  and a negative association with obesity  as well as positive associations with both type 1  and type 2  diabetes mellitus.
Similar to the phylum Bacteroidetes, bacterial families within the phylum Firmicutes were in general reduced in abundance in HIV-infected individuals, though this pattern did not hold true for every family within this phylum. The phylum overall behaved in this manner, with decreased abundance in five of 16 studies [19,20▪,22▪,23▪▪,27▪] and increased abundance in two studies [30▪▪,33▪]. The Firmicutes phylum is quite diverse, but broadly can be characterized as associated with developed world individuals  as well as obesity and increased energy harvest from diet [137,138]. Within the Firmicutes, the class Clostridia, which was overall depleted in HIV infection with decreased abundance in eight of 16 studies [19,20▪,21▪▪,22▪,23▪▪,30▪▪,32▪▪,33▪], is characterized by taxa that often function in anti-inflammatory roles by producing butyrate and other short-chain fatty acids (SCFA) [107,139] and shifting T-cell differentiation toward regulatory T cells [140–143]. Within the class Clostridia, the family Lachnospiraceae, which was decreased in abundance in HIV-infected individuals in six of 16 studies [19,20▪,21▪▪,23▪▪,25▪,30▪▪], includes members that are commonly found to be uniquely effective metabolizers of complex polysaccharides [144,145] and characterized by the production of SCFA such as butyrate  and acetate  that are thought to be anti-inflammatory. Also within the class Clostridia, the family Peptostreptococcaceae varied in its HIV-associated shifts, with two of 16 studies [20▪,32▪▪] showing a relative decrease in abundance in HIV-infected individuals and one study  showing a relative increase. Peptostreptococcaceae have been found to function in mostly a proinflammatory role, with positive associations with C. difficile infection [121,148], viral diarrhea , intestinal inflammation , and the mucosal  and fecal  communities of individuals with colorectal cancer. In contrast to the family Peptostreptococcaceae, the Clostridia family Ruminococcaceae was in general decreased in HIV infection, with 10 of 16 studies [19,20▪,21▪▪,22▪,23▪▪,26▪,28▪▪–30▪▪,32▪▪] reporting decreased abundance in HIV-infected individuals and only one study [17,18▪▪] reporting increased abundance. Ruminococcaceae have been associated with both protective and disruptive roles within the gut microbial community, such as the production of anti-inflammatory SCFA  or the degradation of host mucus and potential proinflammatory role in IBD , and functional effects within this family have been found to be highly species dependent [132,154–156]. The bacterial family Erysipelotrichaceae, which is contained within the separate class Erysipelotrichia, was on the whole found to be increased in association with HIV infection with a greater abundance demonstrated in six of 16 studies [17,18▪▪,20▪,21▪▪,24▪,26▪,33▪] and decreased abundance in only one study [31▪▪]. Erysipelotrichaceae are described as adhesive and potentially pathogenic , and have been found to be positively associated with obesity [158,159] and luminal microbial communities in colorectal cancer [151,160]. Interestingly, this family is also found to be enriched in the enteric communities of the Hadza hunter-gatherers of Tanzania .
Some of the variation in the findings among these studies may be attributed to the differences in body site sampled and sampling methodology. The predominant collection method was stool sampling [17,18▪▪,20▪,23▪▪,24▪–26▪,28▪▪–32▪▪,33▪,161▪–164▪] which is most representative of the luminal microbial community, though anal swabs and washings [19,22▪,165] or mucosal biopsies [20▪,21▪▪,23▪▪,27▪,28▪▪] were also used. Independent of HIV, mucosal and luminal microbial communities have been shown to differ to varying degrees [166–171], though in some contexts, the mucosal and luminal communities correlate strongly and are representative of one another . With regard to functional differences, facultative anaerobes have been found to be more abundant in mucosal-associated environments, whereas obligate anaerobes are more prevalent in the gut lumen . Studies of the HIV-associated microbiota that used both mucosal and luminal-targeted sampling techniques [20▪,23▪▪,28▪▪] found a variety of differences between these techniques. In the most concordant finding, the two sampling sites produced similar conclusions, with most taxa showing the same patterns of HIV-associated enrichment or depletion at both sampling sites (Fig. 1 and Table S1, http://links.lww.com/COID/A16) [20▪]. However, the HIV-associated reduction in diversity was more pronounced in mucosa than stool samples. Other studies found greater variation in the HIV-associated differences by body site. For instance, Dillon et al. [28▪▪] detected an HIV-associated increase in abundance of Prevotellaceae at both sampling sites, but only observed HIV-associated decreases in taxa in the phyla Bacteroidetes and Firmicutes and increases in Proteobacteria in the mucosal samples. The study with the greatest discordance between mucosal and luminal findings observed many more HIV-associated differences in mucosal-associated communities than luminal communities [23▪▪]. In addition, mucosal community composition changes were more closely associated with mucosal cellular immune activation. Mucosal findings may be more sensitive or representative of the causative community, as these microorganisms are in the closest contact with epithelial cells and immune cells. These advantages, however, must be weighed against the relative difficulty of obtaining mucosal samples.
The heterogeneity of the conclusions drawn to date within this field may be in part because of the variation in study populations and methods employed (Fig. 2 and Table S1, http://links.lww.com/COID/A16). Greater coordination of methodologies would allow more robust analysis of multiple studies and potentially reconcile conflicting conclusions. There is also a need to more finely examine the taxa differentially abundant in HIV infection, as meaningful functional variation can often occur at the species or strain level rather than the family or genera level [196–198]. 16S rRNA gene sequencing cannot provide this taxonomic resolution, creating a role for techniques such as shotgun metagenomic sequencing, which could detect strain or gene content variation. In light of the current findings of HIV-associated Prevotellaceae enrichment and the great abundance of this taxa in developing world populations that constitute the majority of HIV-infected individuals, there is a dire need for further examination of HIV-associated gut microbial differences in developing world populations. It is possible that therapeutic strategies that consider Prevotellaceae enrichment a pathogenic state would be ill suited for HIV-infected individuals in the developing world. In addition, microbiota-targeted probiotic interventions have produced mixed results, with some therapeutics reducing inflammatory markers and others lacking efficacy [162▪,199–208]. Further understanding of the enteric microbial changes associated with HIV infection, especially among developing world populations that bear the greatest burden of HIV infection, is therefore necessary to design therapeutic strategies that could alleviate the sequelae of systemic inflammation and NCD in chronic HIV infection.
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