Researchers Link HIV Therapy Duration to Gut Microbiome Patterns

Researchers analyzing gut microbiome profiles from 94 men with HIV in the Czech Republic reveal that antiretroviral therapy duration shapes bacterial co-occurrence patterns. Meanwhile, independent experimental models demonstrate that specific intestinal microbes, such as Prevotella species, alter ecosystem function to decrease short-chain fatty acids and IL-18, exacerbating mucosal inflammation.

Microbial Diversity and Antiretroviral Therapy in HIV Cohorts

Despite effective viral suppression achieved through modern antiretroviral therapy, HIV persists as a chronic condition with lasting systemic consequences, including significant shifts in gut microbial ecology. Researchers analyzed fecal bacterial and fungal profiles from 94 men with HIV, marking the largest cohort of its kind studied in the Czech Republic to determine how antiretroviral therapy regimen, treatment duration, and blood parameters shape gut microbiome diversity and composition.

Taxonomic analysis of the bacteriome revealed dominance by the phyla Bacillota and Bacteroidota. Within those broad groups, Prevotella emerged as the most abundant bacterial genus, while investigators also detected several genera commonly associated with short-chain fatty acid (SCFA) production, including Faecalibacterium. By contrast, the fungal mycobiome exhibited marked inter-individual variability, with Saccharomyces identified as the dominant genus.

Network Connectivity and Microbial Associations

Ecological network analysis uncovered descriptive differences in microbial interactions between ART-duration groups, with a more interconnected network observed in participants with shorter ART duration. In addition, bacterial alpha diversity differed significantly according to ART duration. Overall, findings suggest that differences associated with ART duration may be more apparent in microbial co-occurrence patterns than in overall taxonomic community composition.

Specific bacterial taxa also correlated with clinical parameters. Several Prevotella-related taxa and members of the Lachnospiraceae family were associated with viral load. Additionally, triglyceride levels correlated with taxa including Alloprevotella and Prevotella 9.

Mechanisms of Prevotella and Mucosal Inflammation

While human cohort studies map correlations between microbial abundance and clinical parameters, experimental models investigate diverse microbial signatures within the intestinal microbiota to determine whether candidate microbes actively modulate host phenotypes or passively expand within the altered microbial ecosystem. Research demonstrates that colonization of mice with a member of the genus Prevotella (Prevotella intestinalis), which has been previously associated to colitis in mice, exacerbates intestinal inflammation. This analysis revealed that Prevotella intestinalis alters composition and function of the ecosystem resulting in a reduction of short-chain fatty acids, specifically acetate, and consequently a decrease in intestinal IL-18 levels during steady state.

The functional deficit links directly to host responses. Supplementation of IL-18 to Prevotella-colonized mice was sufficient to reduce intestinal inflammation. Hence, intestinal Prevotella colonization results in metabolic changes in the microbiota, which reduce IL-18 production and consequently exacerbate intestinal inflammation, and potential systemic autoimmunity.

Intestinal homeostasis is maintained by the dynamic interplay between the gut microbiota and the host immune system, in which multiple cell types including intestinal epithelial cells (IECs) and goblet cells, serve not only as a passive barrier but also as a source of antimicrobial substances strengthening the barrier. Microbiota-derived metabolites represent important signals that impact both the mucosal immune system and proper epithelial barrier function. Alterations in the composition and function ofymbiota have been associated with a wide range of human disease including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In IBD, it has been specifically hypothesized that immune-mediated pathologies arise from dysregulated immune responses towards the intestinal microbiota, but different other non-exclusive concepts about how the microbiota promotes IBD and potentially other autoimmune diseases are debated. An overall loss of microbial diversity, changes in the balance between beneficial commensals and potential pathobionts as well as changes in microbial metabolites such as short-chain fatty acids (SCFAs) have been reported in diverse patient populations. Strikingly, altered SCFA production also modulates systemic immune responses linking intestinal dysbiosis and extra-intestinal immunity. Still, the exact identity of intestinal bacteria and their metabolites that trigger aberrant host responses and contribute to the development of IBD and other autoimmune diseases in humans are not exactly known, as the direct causal relationship between microbiota and complex diseases has been difficult to prove outside animal models. Several studies in humans described associations between IBD and increased abundance in Gammaproteobacteria and the presence of Enterobacteriaceae, particularly adherent-invasive E. coli (AIEC) strains. Notably, AIEC modulate colitis susceptibility in some mouse models and additional members of the Enterobacteriaceae family, i.e., Klebsiella pneumoniae and Proteus mirabilis were also identified to promote colitis in mice. Moreover, several other members of the murine microbiota were identified to directly exacerbate intestinal inflammation, including Akkermansia muciniphila as well as distinct Bacteroides and Helicobacter species. Recent studies have also started to shed light on the role of non-bacterial members of the microbiome such as protozoa and phages in the development of IBD, i.e., the increased intestinal inflammation in mice colonized with Tritrichomonas muris, and an enrichment of Caudovirales bacteriophages in IBD patients. Beyond these well-studied examples, microbiome studies have identified many microbes that were found enriched in disease-promoting communities, but with unknown roles in host-microbiota crosstalk, i.e., members of the Prevotella genus.

Contrasting Roles of Prevotella in Human Health

The role of members of the Prevotella genus within the intestinal microbiota and their effects on the host is not completely understood and somewhat conflicting interpretations have been reported. High prevalence and relative abundance of Prevotella is found in non-Westerners who consume a plant-rich diet. Moreover, it has been shown that Prevotella spp. can improve glucose metabolism stimulated by the intake of prebiotics. Together, these studies suggest that Prevotella spp. are beneficial microbes that have colonized humans for extended periods of time.

In contrast, other studies have associated Prevotella spp. with autoimmune diseases, insulin resistance and diabetes, and gut inflammation. Specifically, an overabundance of Prevotella copri was noted in new-onset rheumatoid arthritis (NORA) patients and also in patients with systemic autoimmunity associated with RA, but without clinical symptoms yet.