The Gut Microbiome: Another Piece in the Puzzle of HIV-Associated Atherosclerosis

The human gut microbiome is increasingly being recognized as a fundamental component that influences physiological processes and disease pathways. Accumulating evidence suggests that the gut microbiome may contribute to atherogenesis by modulating immunity and metabolism and serving as a source of antigens implicated in atherosclerosis development [1]. Although some studies suggest this association in people with human immunodeficiency virus (PWH), they have been limited by their cross-sectional design and small sample size [2].

In this issue of The Journal of Infectious Diseases, Masiá et al presented the first longitudinal study exploring the dynamics of gut microbiome composition and its correlation with the progression of subclinical atherosclerosis measured by carotid intima-media thickness (cIMT) in PWH [3]. This study prospectively examined the association between changes in gut microbiome composition and cIMT progression over a 96-week period in a cohort of virologically suppressed PWH on stable antiretroviral therapy. Their findings revealed distinct microbial signatures associated with the progression of subclinical atherosclerosis independent of traditional cardiovascular risk factors.

The study identified an enrichment of bacteria within the Agathobacter and Ruminococcus 2 genera correlated with cIMT progression. Conversely, Prevotella 7 was associated with nonprogression. These associations persisted after adjusting for potential confounders including age, sex, sexual behavior, body mass index, hypertension, dyslipidemia, smoking, and nadir CD4 cell count. The changes observed in the microbiome need to be confirmed in further studies.

Given the longitudinal design and focus on exploring longitudinal rather than cross-sectional relationships, the findings demand a nuanced interpretation. The significant changes observed—increases in Agathobacter and Ruminococcus 2 and decreases in Prevotella 7 in participants experiencing cIMT progression—may initially appear counterintuitive. Agathobacter, previously classified under the genus Eubacterium, is a prominent member of the Lachnospiraceae family. This family is often depleted in PWH [4] and is recognized for its commensal role, notably in its capacity to produce butyrate, a short-chain fatty acid (SCFA) essential for maintaining gut and immune health. SCFA support the integrity of the intestinal barrier and promote regulatory immune responses [5]. Previous research has linked a decrease in Lachnospiraceae to the development of metabolic syndrome and an increase in visceral fat in PWH [6]. Similarly, Ruminococcus 2, a clade within the Ruminococcaceae family is crucial for SCFA production. Thus, the observed relationship in the opposite direction was unexpected.

Conversely, participants without cIMT progression showed an enrichment of Prevotella 7, a finding that appears counterintuitive given its association with cardiovascular risks in the general population [7] and its link to heightened inflammation and immune dysfunction in PWH [8, 9]. These findings raise intriguing questions regarding the role of the microbiome in the progression of atherosclerosis. We speculate that, rather than acting as direct drivers of atherosclerosis, changes in Agathobacter, Ruminococcus 2, and Prevotella 7 in their study may represent ecological adaptations within the gut microbiome to counteract inflammation, a known contributor to atherosclerosis stemming from other factors (eg, residual immune dysfunction). In this context, the observed changes in microbiome composition over time could be interpreted as the microbiome's compensatory response to mitigate inflammation or cIMT progression rather than factors exacerbating them. Although changes observed in the microbiome could be used as biomarkers to allow additional stratifications of patients, they may not necessarily imply direct pathogenic microbial involvement. Microbial metabolomics analyses could provide additional pathogenesis insights.

Although the study by Masiá et al provides valuable insights into the gut microbiome signatures linked to atherosclerosis progression in PWH, proposing causal associations between differential taxa in observational studies remains speculative. The potential impact of unmeasured confounders, such as dietary habits and environmental factors, could also explain the divergent findings across studies. Substantial research is needed to establish causality and elucidate the mechanistic underpinnings of the observed associations. Integrative analyses incorporating multiomics data, including metabolomics and immunological profiles, together with experimental validation of the links between the microbiome and diseases established in observational studies, could provide deeper insights into the complex interplay between the gut microbiome, host immunity, and cardiovascular disease pathogenesis in PWH [10].

Nonetheless, this study represents a step forward in elucidating the role of the gut microbiome in HIV-associated cardiovascular disease. Their results support further research on how the microbiome may influence the progression of atherosclerosis in PWH and suggest the potential of targeting the microbiome therapeutically. Additionally, although current evidence suggests that specific microbiome signatures may yet not reliably predict long-term cardiovascular disease risk, this study provides support to further investigate the microbiome as a source of biomarkers for cardiovascular disease.

In conclusion, the study by Masiá and colleagues highlights the gut microbiota as a factor associated with the progression of subclinical atherosclerosis in PWH, unveiling distinct microbial signatures associated with this process. Further research is necessary to validate and expand upon these results; however, the findings support investigating the microbiome’s prognostic and therapeutic potential to reduce excess cardiovascular risk in PWH.

Notes

Financial support. This work was supported in part by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional, Acción Estratégica en Salud (grant numbers ICI20/00058, PI20/00869, and PI21/00041).

References

Author notes