Gut Microbiota, Plasma Metabolomic Profiles, and Carotid Artery Atherosclerosis in HIV Infection

Abstract

Background: Alterations in gut microbiota and blood metabolomic profiles have been implicated in HIV infection and cardiovascular disease. However, it remains unclear whether alterations in gut microbiota may contribute to disrupted host blood metabolomic profiles in relation to atherosclerosis, especially in the context of HIV infection. Methods: We analyzed cross-sectional associations between gut microbiota features and carotid artery plaque in 361 women with or at high risk of HIV (67% HIV+), and further integrated plaque-associated microbial features with plasma lipidomic/metabolomic profiles. Furthermore, in 737 women and men, we examined prospective associations of baseline gut bacteria-associated lipidomic and metabolomic profiles with incident carotid artery plaque over 7-year follow-up. Results: We found 2 potentially pathogenic bacteria, Fusobacterium and Proteus , were associated with carotid artery plaque; while the beneficial butyrate producer Odoribacter was inversely associated with plaque. Fusobacterium and Proteus were associated with multiple lipids/metabolites which were clustered into 8 modules in network. A module comprised of 9 lysophosphatidylcholines and lysophosphatidylethanolamines and a module comprised of 9 diglycerides were associated with increased risk of carotid artery plaque (risk ratio [95% CI], 1.34 [1.09–1.64] and 1.24 [1.02–1.51] per SD increment, respectively). Functional analyses identified bacterial enzymes in lipid metabolism associated with these plasma lipids. In particular, phospholipase A1 and A2 are the key enzymes in the reactions producing lysophosphatidylcholines and lysophosphatidylethanolamines. Conclusions: Among individuals with or at high risk of HIV infection, we identified altered gut microbiota and related functional capacities in the lipid metabolism associated with disrupted plasma lipidomic profiles and carotid artery atherosclerosis.

Metabolomic Profiling of Cardiac Fibrosis and Steatosis in Women With or at Risk for HIV

“…Fasting plasma stored at 280°C since collection (2017-2019) was sent to the Broad Institute (Cambridge, MA) for performance of untargeted metabolomics by tandem liquid chromatography/mass spectrometry. 21 Two separate methods were performed to measure lipid and polar metabolites in each sample, as previously described. 27 Raw data from Orbitrap mass spectrometers were processed using Progenesis QI software (NonLinear Dynamics, Durham, NC) for feature alignment, untargeted signal detection, and signal integration.…”

Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection

“…Semi-annual visits consisted of structured questionnaire interviews, physical examinations, and specimen collection. In 2015, a multiomics study was initiated among WIHS participants aged ≥ 35 years at three sites (Bronx, Brooklyn, and Chicago) to evaluate the etiology and progression of carotid artery atherosclerosis (15). Among them, 361 provided fecal samples for microbiome profiling and received assessments of carotid artery plaque, and 251 had plasma tryptophan metabolites measured.…”

“…High-resolution B-mode carotid artery ultrasound following a standardized protocol was used to image 8 locations in the right carotid artery: the near and far walls of the common carotid artery, carotid bifurcation, and internal and external carotid arteries (15,16). Focal plaque measures were obtained at a centralized reading center (University of Southern California).…”

“…Fecal samples were collected using a home-based self-collection kit during WIHS corevisit as described previously (15,17). 16S ribosomal RNA (rRNA, V4 region) sequencing was performed on DNA extracted from fecal samples to profile the gut microbiome.…”

“…After quality control, average coverage was approximately 35000 reads per sample. Details on the 16S rRNA sequencing method used in this study have been published (15,17). In addition, shotgun metagenomic sequencing based on a novel shallow-coverage method using the Illumina NovaSeq platform was performed in the same fecal samples among 141 women who had tryptophan metabolites data.…”