Interrelationship between altered metabolites and the gut microbiota in people living with HIV with different immune responses to antiretroviral therapy

Background

Antiretroviral therapy (ART) effectively reduces opportunistic infections and mortality in people living with HIV (PLWH); however, some patients exhibit poor immune recovery. This study explores the connections among immune responses, metabolites, and the gut microbiota in PLWH with differing reactions to ART.

Methods

We analyzed the gut microbiota composition, metabolites, and immune markers in 38 PLWH who showed an immunological response (IR) and 32 who did not (INR), as classified according to CD4+ T-cell levels after 24 months of ART. Additionally, in vitro assays using cell counting kit 8, flow cytometry, and quantitative real-time reverse transcription PCR were employed to assess the effects of the metabolites on cell viability, immune marker expression, and cytokine levels.

Results

Gut microbiota and metabolic profiles differed significantly between the IR and INR groups. Enterococcus was more abundant in the INR group, whereas [Ruminococcus]_gnavus_group levels were reduced. Significant metabolic pathway alterations included decreased folate biosynthesis and biotin metabolism. We observed negative associations of Parabacteroides with activation markers on CD4+ T-cells, and positive correlations with CD4/CD8 ratios. Enterococcus showed inverse relationships with these markers. Indole-3-acetyl-beta-1-D-glucoside (area under the curve value = 0.8931), had the best discriminatory ability. Further experiments showed that Indole-3-acetyl-beta-1-D-glucoside significantly decreased the proportions of CD4+CD57+, effector CD4+, CD4+PD1+, CD8+CD57+, effector CD8+, and CD8+HLA-DR+ T cells. Moreover, mRNA expression analysis showed that Indole-3-acetyl-beta-1-D-glucoside treatment led to a suppression of pro-inflammatory cytokines.

Conclusion

The multi-omics approach highlighted potential biomarkers for immune recovery in HIV, suggesting avenues for further research into treatment strategies.