SHORT-CHAIN FATTY ACID-PRODUCING GUT MICROBIOTA: DYNAMICS AND IMPACT ON INTESTINAL PERMEABILITY AND CLINICAL OUTCOMES DURING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Short-chain fatty acids (SCFA)-producing bacteria may modulate intestinal permeability and impact clinical outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Throughout the allo-HSCT process, international studies consistently demonstrate profound depletion of SCFA-producing microbiota. This depletion serves as an important prognostic factor and has been associated with decreased overall survival and higher Graft-versus-Host disease (GvHD) incidence and severity. Nevertheless, the dynamics of SCFA-producing microorganisms and their clinical impact in Brazilian patients remain poorly characterized. This study aimed to evaluate the dynamics of three SCFA-producing bacteria and determine their impact on intestinal permeability and clinical outcomes in Brazilian allo-HSCT patients. This multicenter, prospective study, approved by the Research Ethics Committee, included patients > 12 years old undergoing allo-HSCT with fecal and blood specimens collected at baseline and D+30. Fecal DNA was extracted, and 16S sequencing was performed by using the Illumina platform. Intestinal permeability was evaluated using zonulin levels measured by ELISA. The relative abundance of three SCFA-producing bacterial genera (Roseburia, Faecalibacterium, and Blautia) was determined. Patients were stratified based on changes (∆) in zonulin levels and bacterial genera relative abundance (D+30 – baseline). Cox regression analysis was used to evaluate associations between ∆ relative abundance and mortality, cumulative incidence of GvHD and severe GvHD. Correlations between ∆zonulin and ∆relative abundance were analyzed using Spearman's rank correlation. Stool samples were obtained from 25 patients at both time points (baseline and D+30), with concurrent blood samples available in 20 cases (80%). Over time, there was an overall decrease in the relative abundance of all three bacterial genera: Roseburia (0.85 ± 1.44 vs . 0.18 ± 0.35), Blautia (0.38 ± 0.39 vs . 0.22 ± 0.38) and Faecalibacterium (2.00 ± 2.64 vs . 1.14 ± 3.16). Similarly, there was a decrease in zonulin levels during allo-HSCT (51.98 ± 21.64 vs . 50.75 ± 22.85). ∆Blautia, ∆Faecalibacterium, and ∆Roseburia were not significantly associated with mortality (p = 0.2, p = 0.062, p = 0.5), GvHD (p = 0.8, p = 0.3, p > 0.9), or severe GvHD (p = 0.5, p = 0.4, p = 0.6), respectively. ∆zonulin correlated weakly with ∆Blautia (r = -0.19), ∆Faecalibacterium (r = 0.12), and ∆Roseburia (r = -0.29). Despite profound depletion of Blautia, Roseburia, and Faecalibacterium over the first 30 days of the allo-HSCT, none of these SCFA-producing genera showed significant associations with clinical outcomes. Additionally, zonulin levels remained relatively stable over time and correlated weakly with ∆ bacterial changes. Although these findings suggest that other SCFA-producing bacterial genera may be more important in modulating intestinal permeability and outcomes in Brazilian patients, future, larger, multicenter studies are needed to validate these findings. FAPESP 2023/08142-0; 2022/12989-6