Short-chain fatty acids play a key role in antibody response to SARS-CoV-2 infection in people living with HIV.

High SARS-CoV-2-specific antibody levels can protect against SARS-CoV-2 reinfection. The gut microbiome can affect a host's immune response. However, its role in the antibody response to SARS-CoV-2 in people living with HIV (PLWH) remains poorly understood. Here, we categorised PLWH and healthy individuals into high- and low-antibody-response groups. Shotgun metagenomic sequencing and targeted metabolomic assays were used to investigate the differences in the gut microbiome and metabolic functions between the high- and low-antibody-response groups. PLWH demonstrated a higher abundance of short-chain fatty acid (SCFA)-producing species, accompanied by high serum levels of several SCFAs, in the high-antibody-response group than in the low-antibody-response group. In contrast, healthy individuals demonstrated higher enrichment of pilus-bearing bacterial species, with flagella-expressing genes, in the high-antibody-response group than in the low-antibody-response group. Therefore, gut-microbiota-derived SCFAs play a key role in antibody responses in PLWH but not in healthy individuals. Our results afford a novel understanding of how the gut microbiome and its metabolites are associated with host immunity. Moreover, they may facilitate the exploration of modalities to prevent SARS-CoV-2 reinfection through various gut-microbiota-targeted interventions tailored to different populations.