Gut Microbiome Changes Associated With HIV Infection and Sexual Orientation

Abstract

Background: Many studies have explored changes in the gut microbiome associated with HIV infection, but the consistent pattern of changes has not been clarified. Men who have sex with men (MSM) are very likely to be an independent influencing factor of the gut microbiome, but relevant research is still lacking. Methods: We conducted a meta-analysis by screening 12 published studies of 16S rRNA gene amplicon sequencing of gut microbiomes related to HIV/AIDS (six of these studies contain data that is relevant and available to MSM) from NCBI and EBI databases. The analysis of gut microbiomes related to HIV infection status and MSM status included 1,288 samples (HIV-positive (HIV+) individuals, n = 744; HIV-negative (HIV-) individuals, n = 544) and 632 samples (MSM, n = 328; non-MSM, n = 304), respectively. The alpha diversity indexes, beta diversity indexes, differentially enriched genera, differentially enriched species, and differentially enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways related to gut microbiomes were calculated. Finally, the overall trend of the above indicators was evaluated. Results: Our results indicate that HIV+ status is associated with decreased alpha diversity of the gut microbiome. MSM status is an important factor that affects the study of HIV-related gut microbiomes; that is, MSM are associated with alpha diversity changes in the gut microbiome regardless of HIV infection, and the changes in the gut microbiome composition of MSM are more significant than those of HIV+ individuals. A consistent change in Bacteroides caccae, Bacteroides ovatus, Bacteroides uniformis, and Prevotella stercorea was found in HIV+ individuals and MSM. The differential expression of the gut microbiome may be accompanied by changes in functional pathways of carbohydrate metabolism, amino acid metabolism, and lipid Metabolism. Conclusions: This study shows that the changes in the gut microbiome are related to HIV and MSM status. Importantly, MSM status may have a far greater impact on the gut microbiome than HIV status.

Keywords: 16S rRNA gene amplicon sequencing; AIDS; HIV; gut microbiome; sexual orientation.

Figure 1

The technical route of the study.

Figure 2

Forest plots comparing HIV+ to HIV– individuals. The fixed effects models (FEMs) with a 95% CI above or below zero were considered statistically significant. The heterogeneity analysis included estimates of Chi² and I². Before controlling for other confounding factors, the alpha diversity of the HIV+ individuals was significantly lower than that of the HIV– individuals (a, Simpson index). When restricting the analysis to women (b, Observed index), non-MSM individuals (c, Simpson index), individuals with CD4⁺T cell count of <500 (d, Shannon index), and non-ART individuals (e, Shannon index), HIV+ status was associated with a significant decrease in alpha diversity.

Figure 3

Boxplots showing the alpha diversity in terms of the Simpson index by study and HIV status (red, HIV– individuals; blue, HIV+ individuals). Most studies showed decreased alpha diversity in HIV+ individuals compared to HIV– individuals.

Figure 4

Forest plots comparing MSM to non-MSM (NonMSM) individuals. Before controlling for other confounding factors, the alpha diversity of the MSM was significantly lower than that of the non-MSM individuals (a, Simpson index). When restricting the analysis to HIV+ (b, Fisher index), age ≥45 years (e, Fisher index), BMI = 24–27.9 (f, Fisher index) individuals, MSM status was associated with an increase in alpha diversity. When restricting the analysis to HIV– individuals (c, Invsimpson index) and age <45 years (d, Invsimpson index), MSM status was associated with a significant decrease in alpha diversity.

Figure 5

Boxplots showing the alpha diversity in terms of the Simpson index by study and MSM status (red, MSM; blue, non-MSM). All studies showed decreased alpha diversity in MSM compared to non-MSM.

Figure 6

The PCoA ordination plots by study and HIV status. PCoA ordination plots of Bray–Curtis showing that the microbiomes in the datasets by Lozupone et al. (2013) (R² = 0.154, FDR p < 0.001), Dubourg et al. (2016) (R² = 0.080, FDR p < 0.001), and Armstrong et al. (2018) (R² = 0.059, FDR p < 0.001) showed better cluster according HIV status.

Figure 7

The PCoA ordination plots by study and MSM status. PCoA ordination plots of Bray–Curtis of Noguera-Julian et al. (2016) (R² = 0.122, FDR p < 0.001), Vesterbacka et al. (2017) (R² = 0.081, FDR p < 0.001), Armstrong et al. (2018) (R² = 0.090, FDR p < 0.001), and Li et al. (2019) (R² = 0.115, FDR p < 0.001) showed better cluster according to MSM status.

Figure 8

Differential genus (A) and species (B) map related to HIV status. From left to right, the first column represents the differential genus or species, and the third column represents the studies. The third column represents the research corresponding to the differential genus or species. The second column shows the differential enrichment of genus or species in HIV+ and HIV– individuals. Red indicates that the genus or species were significantly enriched in HIV+ individuals. Blue indicates that the genus or species were significantly enriched in HIV– individuals.

Figure 9

Differential genus (A) and species (B) map related to MSM status. From left to right, the first column represents the differential genus or species, and the third column represents the studies. The third column represents the research corresponding to the differential genus or species. The second column shows the differential enrichment of genus or species in MSM and non-MSM. Red indicates that the genus or species were significantly enriched in MSM. Blue indicates that the genus or species were significantly enriched in non-MSM.

Figure 10

Differential KEGG functional pathways map related to HIV status. From left to right, the first column represents the KEGG I functional pathways, and the second and fourth columns represent the KEGG II and KEGG III functional pathways, respectively, under KEGG I. The third column shows the differential enrichment of the KEGG III functional pathways in HIV+ and HIV– individuals. Red indicates that the functional pathways were significantly enriched in HIV+ individuals in at least three studies. Blue indicates that the functional pathways were significantly enriched in HIV– individuals in at least three studies. Yellow indicates that the abundances of the functional pathways were significantly different in at least three studies, but the direction of changes related to HIV status was inconsistent.

Figure 11

Differential KEGG functional pathways map related to MSM status. From left to right, the first column represents the KEGG I functional pathways, and the second and fourth columns represent the KEGG II and KEGG III functional pathways, respectively, under KEGG I. The third column shows the differential enrichment of the KEGG III functional pathways in MSM and non-MSM individuals. Red indicates that the functional pathways were significantly enriched in MSM in at least three studies. Blue indicates that the functional pathways were significantly enriched in non-MSM in at least three studies.