Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection

Abstract

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.

Host genetic associations with the gut microbiota in HIV-1-infected subjects: a pilot exploratory study

“…Using a DNA-microarray-based genotyping strategy, we performed a pilot exploratory study to investigate whether the host genomic background could influence the gut microbiome composition in HIV-1-infected subjects 23,24 . Following a GWAS-like analysis approach 31,33 , we found no statisticallysignificant associations between the covered host genetic background and Bacteroides vs.…”

“…We analyzed the exomes of 147 subjects from the MetaHIV cohort 23,24 using the Illumina Infinium CoreExome microarray, which covers 547,644 putative functional exonic variants ( Table 1). Our study included 30 (20%) females and 117 (80%) males, most of them Caucasian (79.6%).…”

“…Our study included 30 (20%) females and 117 (80%) males, most of them Caucasian (79.6%). The gut microbiota of these participants had been characterized using 16S rRNA gene amplicon sequencing 23 and whole metagenome shotgun sequencing 24 in previously published studies. Using 16S rRNA, 61 individuals from our cohort (41.5%) were classified as Bacteroides-rich, whereas 86 subjects (58.5%) were categorized as Prevotella-rich .…”

“…We assessed the interaction between QC-filtered genetic variants and three different gut microbial traits: gut enterotype (Bacteroides vs. Prevotella), methanogenic archaea (presence vs. absence) and gut microbial gene richness (as a continuous variable). Two independent logistic models were performed to test the association of genetic variants with the gut enterotype 23 and the presence of methanogenic archaea 24 . A linear regression model was used for microbial gene richness.…”

“…European subjects with different HIV-1 phenotypes (MetaHIV cohort) 23,24 , we previously showed that men who have sex with men (MSM) were enriched in Prevotella and, after controlling for HIV-1 risk group, there was no consistent microbial dysbiosis pattern discernible by 16S rRNA sequencing 25 . Using shotgun metagenomics analyses in the same cohort, we identified a strong, dose-dependent relationship between gut microbial richness and nadir CD4+ T-cell counts 24 , which is the major surrogate marker of excess mortality, systemic inflammation and clinical complications in chronically HIV-1-infected subjects 26,27 . In our study, changes in microbial richness reflected multidimensional modifications in microbial species composition and functions, including increases in reactive oxygen and nitrogen-resistant species (ROS/RNS) like the Gram-negative generalists Bacteroides and Proteobacteria, and decreases in ROS/RNS-sensitive Gram-positive syntrophic microbes, including hydrogen-consuming methanogenic archaea.…”