Signature changes in gut microbiome are associated with increased susceptibility to HIV-1 infection in MSM

Abstract

Background: Men who have sex with men (MSM) have been disproportionately affected by HIV-1 since the beginning of the AIDS pandemic, particularly in the USA and Europe. Compared to men who have sex with women (MSW), MSM have a distinct fecal microbiome regardless of HIV-1 infection. However, it is unclear whether the MSM-associated gut microbiome affects the susceptibility and progression of HIV-1 infection. We studied fecal microbiome profiles, short-chain fatty acids, and blood plasma inflammatory cytokines of 109 HIV-1 seroconverters (SC) from the early, 1984-1985 phase of the HIV-1 pandemic in the Multicenter AIDS Cohort Study (MACS) before and after HIV-1 infection compared to 156 HIV-1-negative MACS MSM (negative controls [NC]).

Results: We found that family Succinivibrionaceae, S24-7, Mogibacteriaceae, Coriobacteriaceae, and Erysipelotrichaceae were significantly higher (p<0.05), whereas Odoribacteraceae, Verucomicrobiaceae, Bacteroidaceae, Barnesiellaceae, and Rikenellaceae were significantly lower (p<0.05), in SC before HIV-1 infection compared to NC. At the species level, Prevotella stercorea, Eubacterium biforme, and Collinsella aerofaciens were significantly higher (p<0.05), and Eubacterium dolichum, Desulfovibrio D168, Alistipes onderdonkii, Ruminococcus torques, Bacteroides fragilis, Bacteroides caccae, Alistipes putredinis, Akkermansia muciniphila, Bacteroides uniformis, and Bacteroides ovatus were significantly lower (p<0.05) in SC before HIV-1 infection compared to NC. After HIV-1 infection, family Prevotellaceae and Victivallaceae and species Bacteroides fragilis and Eubacterium cylindroides were significantly higher (p<0.05) in SC who developed AIDS within 5 years compared to the SC who were AIDS free for more than 10 years without antiretroviral therapy (ART). In addition, family Victivallaceae and species Prevotella stercorea, Coprococcus eutactus, and Butyrivibrio crossotus were significantly higher (p<0.05) and Gemmiger formicilis and Blautia obeum were significantly lower (p<0.05) after HIV-1 infection in SC who developed AIDS within 5-10 years compared to the SC who were AIDS-free for more than 10 years without ART. Furthermore, plasma inflammatory cytokine levels of sCD14, sCD163, interleukin 6, and lipopolysaccharide binding protein were significantly higher in SC with p<0.05 before HIV-1 infection compared to NC.

Conclusions: Our results suggest that pathogenic changes in the gut microbiome were present in MSM several months prior to infection with HIV-1 in the early phase of the AIDS pandemic in the USA. This was associated with increased inflammatory biomarkers in the blood and risk for development of AIDS. Video abstract.

Keywords: AIDS; Fecal microbiome; HIV seroconversion; Inflammation; MSM (men who have sex with men).

Fig. 1

The profiles of CD4⁺ T cell counts (A), CD8⁺ T cell counts (B), and CD4⁺/CD8⁺ T cell ratio (C) of SC and NC at visit 1 and visit 2, and HIV loads of SC (D) at visit 2. NC visit 1: N=156, visit 2: N=77; SC visit 1: N=87, visit 2: N=57

Fig. 2

Fecal microbiome alpha diversity at the family level of SC and NC. A Alpha diversity of SC and NC at visit 1. B Alpha diversity of SC and NC at visit 2. C Loss of alpha diversity (Shannon diversity index) of SC and NC at visit 2 compared to alpha diversity at visit 1. Observed: observed species; Shannon: Shannon diversity index

Fig. 3

PCoA plot of the fecal microbiome beta diversity (Bray-Curtis dissimilarity) at the family level. Ellipses stand for 68% of data coverage. Lines are connected between samples and the corresponding group spatial median. P-values from both PERMANOVA (p1) and PERMDISP (p2) tests are given in the plot. A Beta diversity of visit 1 and visit 2 of NC; B Beta diversity of visit 1 and visit 2 of SC; C Beta diversity of SC and NC at visit 1; D Beta diversity of SC and NC at visit 2

Fig. 4

Waterfall plot of log fold change (natural log) of absolute abundances for differentially abundant families. A SC vs. NC at visit 1; B SC vs. NC at visit 2; C visit 2 vs. visit 1 among SC; D time to develop AIDS < 5 years/5–10 years vs. > 10 years among SCs at visit 1; E time to develop AIDS < 5 years/5–10 years vs. > 10 years among SCs at visit 2. Data are represented by log fold change (shown as a column) ±SE (shown as error bars) derived from the ANCOM-BC model. All effect sizes with p < 0.05 are indicated as follows: *significant at 5% level of significance, **significant at 1% level of significance, and ***significant at 0.1% level of significance. Taxa in blue were also significant after multiple testing correction was applied at FDR < 0.05. Exact p-values can be found in Supplementary Table 1

Fig. 5

Waterfall plot of log fold change (natural log) of absolute abundances for differentially abundant species. A SC vs. NC at visit 1, B SC vs. NC at visit 2, C visit 2 vs. visit 1 among SC, D time to develop AIDS < 5 years/5–10 years vs. > 10 years among SCs at visit 1, and E time to develop AIDS < 5 years/5–10 years vs. > 10 years among SCs at visit 2. Data are represented by log fold change (shown as a column) ±SE (shown as error bars) derived from the ANCOM-BC model. All effect sizes with p < 0.05 are indicated as follows: *significant at 5% level of significance, **significant at 1% level of significance, and ***significant at 0.1% level of significance. Taxa in blue were also significant after multiple testing correction was as applied at FDR < 0.05. Exact p-values can be found in Supplementary Table 3

Fig. 6

Correlation of fecal SCFA levels and log₂ ratio of the peripheral blood CD4⁺/CD8⁺ at visit 1 (A) or visit 2 (B) of SC. SC visit 1: N=87, visit 2: N=57

Fig. 7

A Relative abundances of peripheral blood inflammatory cytokines at visit 1 between NC (N=156) and SC (N=87). B Relative abundances of peripheral blood inflammatory cytokines between visit 1 (N=87) and visit 2 (N=57) of SC. The measurement for each cytokine is IL-6 (pg/ml), sCD163 (ng/ml), IP-10 (pg/ml), CRP (ng/ml), LBP (ng/ml), and sCD14 (ng/ml). For visualization purposes, scatter points with values belonging to the first/last 10 percentile were not shown

Fig. 8

Correlation of peripheral blood inflammatory cytokines and log₂ ratio of CD4⁺/CD8⁺ at visit 1 (A) and visit 2 (B) of SC

Fig. 9

Correlation analysis of peripheral blood inflammatory cytokines and log₁₀ HIV loads at visit 2 of SC