The goal of highly active antiretroviral therapy (HAART) is immune reconstitution following successful viral suppression in HIV-infected patients [2]. Despite with complete viral suppression, the CD4 + T cell is not reversed completely and microbial translocation continues after peripheral CD4 + T cell restoration [19–22]. The gut microbiota has been reported had critical impact on human biology and pathophysiology. The gut microbiota as a key factor for immune homeostasis is accepted widely now [22]. Compositional and functional changes of the gut microbiota have pointed a novel link between the gut bacterial community and immunity in treated HIV-infected individuals [7, 23]. However, the way the microbiome contributes to immune activation in HIV positive individuals is poorly understood. We supposed that gut microbiome may play an important role in different immune response to long-term ART in HIV + individuals. So in this study, we investigated the fecal microbiome and immune activation in HIV + individuals with different immune response to long-term ART in China.
The microbiome dysbiosis in HIV-infected individuals has been described in several studies [7], however, there is only few study included a handful of IR and INR patients and without considering the immune response to HAART [24]. The current study, which included the so far higher number of IR and INR patients, expand the previous observations and investigate the relationship between gut microbiota and immune activation. It found that ecological indices of microbiota (including community diversity, richness and observed species numbers) were significantly lower in IR and INR group when compared to health control. Additionally, PCoA analysis showed remarkable differentiation of bacterial communities between IR, INR and health control. These suggested that the diversity and composition of gut microbiota could not be recovered completely as normal gut environment in HIV-infected individuals although with immunological response after long-term effective ART.
Furthermore, we found that IR and INR group had a unique bacterial signature at phylum level. Proteobacteria, Fusobacteria, and Saccharibacteria were more abundant, whereas Bacteroidetes, Actinobacteria and Lentisphaerae were depleted in IR and INR group. At the genus level, the predominant genera Fusobacterium, Ruminococcus_gnavus and Megamonas were more abundant, whereas Faecalibacterium, Alistipes, Bifidobacterium, Eubacterium rectale, and Roseburia were depleted in IR and INR group than health control. Taxa from bacterial phyla Proteobacteria, Fusobacteria and Bacteroidetes have been reported different between HIV positive and negative individuals in studies. Our result is consistent with most of published studies which reported Proteobacteria were more abundant in HIV-infected individuals although others reported no change [10, 11, 25–30]. The phylum Fusobacteria (most driven by its constituent genus Fusobacterium) which was reported associated with intestinal inflammation [31, 32] and enriched in HIV-infected individuals in some studies [26, 30, 33, 34]. Here, we found Fusobacterium enriched in IR and INR group. Furthermore, inflammation markers and translocation biomarkers (LPS) were positively correlated with Fusobacterium, while nadir and current CD4 + T-cell counts were negatively correlated to Fusobacterium in this study.
The phylum Bacteroidetes which include the families Bacteroidaceae, Prevotellaceae, Porphyromonadaceae, and Rikenellaceae, exhibited a more heterogeneous pattern of changes in HIV-infected individuals [10, 11, 22, 25–30, 33–37]. The family Bacteroidaceae (mostly driven by the abundance of the genus Bacteroides) is generally considered to play an anti-inflammatory role [38–41], were depleted in IR and INR group. The bile-tolerant family Rikenellaceae (mostly driven by the abundance of the genus Alistipes) which is protective properties against C. difficile infection [41, 42], were overall depleted in IR and INR group. Actinobacteria which was reported similar in the proximal gut of HIV-infected patients and negative controls [29], were depleted in IR and INR group in this study. The Alistipes was negatively correlated to CD8 + CD57 + T-cell and positively correlated to nadir CD4 + T-cell counts. Notably, the commonly used probiotics Bifidobacterium which belong to the phylum of Actinobacteria were depleted in IR and INR group than health control [43].
Although the abundance of phylum Firmicutes is similar in the three groups, the genus such as Faecalibacterium and Ruminococcaceae were depleted in IR and INR group than health control. Ruminococcaceae have been associated with both protective and disruptive roles within the gut microbial community, such as the production of anti-inflammatory SCFA[44] or the degradation of host mucus and potential proinflammatory role in IBD[45]. In this study, the Faecalibacterium and Ruminococcaceae UCG-002, which belong to the family of Ruminococcaceae were depleted in IR and INR group than health control, Interestingly, Ruminococcaceae were positively correlated to the current and nadir CD4 + T-cell counts while negatively correlated to CD8 + CD57 + T-cell. In additionally, inflammation markers and LPS were positively correlated to the abundance of genus Ruminococcus. The Faecalibacterium has been reported as anti-inflammatory commensal genus [26, 46]. In this study, the genus Faecalibacterium was positively correlated to CD4/CD8 ratio, while negatively correlated with inflammation markers and LPS. The family Enterobacteriaceae is associated with inflammation[47], Escherichia-Shigella which belonged to Enterobacteriaceae were negatively correlated to CD4/CD8 ratio, but positively correlated to CD8 + CD57 + T-cell which is hallmark of immunosenescence in HIV infection[48, 49]. Furthermore, Escherichia-Shigella was more abundant in IR group than INR group in this study. These suggested that Fusobacterium, Alistipes, Ruminococcaceae, Faecalibacterium and Escherichia-Shigella maybe the major genus contributed to different immune response in immunodiscordant and immunoconcordant patients on long-term suppressive ART.
Altogether, these results highlight that immune activation in HIV-infected patients is associated with the observed gut microbiota dysbiosis. Based upon these findings, we speculate that the gut microbiota may be one of the factors contributing to different immune response to HAART. We acknowledge that the extensive dietary data and living conditions of these subjects which are not controlled may lead to biases in our analysis. On the other hand, while correlation analysis is useful to have clues of biological links to the impact of dysbiosis in immune response in these patients, a direct manipulation of microbiome is needed to validate their cellular and biochemical action in vitro or in vivo. And the exact mechanisms how HIV infection induced dysbiosis in the gut need to be studied in future study.