Abstract
Background
Despite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation, increasing morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplant (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo.
Methods
This double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo over eight weeks on systemic inflammation in 29 PWH on stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected. Proteomic changes in 344 inflammatory proteins in plasma were quantified using the Proximity Extension Assay, with samples collected at baseline and weeks 1, 8, and 24. Concurrently, we characterized shifts in gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with the microbiome composition and functionality over time using linear mixed models.
Results
FMT significantly reduced plasma levels of 45 inflammatory proteins, including established mortality predictors like IL-6 and TNF. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including proteins like CCL20 and CD22. We identified changes in FT3LG, IL17A, IL6, IL10RB, and others, which correlated with multiple bacterial species. We found specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae, and the Clostridium genus, along with their associated genes and functions, to be significantly correlated with changes in inflammatory markers.
Conclusions
Targeted modulation of the gut microbiome through FMT effectively modulated systemic inflammation in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions.