Pb1915: the multi-faceted role of oral and gut microbiome in patients with chronic lymphocytic leukemia

Topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research Background: Growing evidence suggests the impact of structural changes in the intestinal microbiota on the development of hematologic malignancies, including chronic lymphocytic leukemia (CLL). Therefore, investigating the role of microbiome changes in CLL might unveil predictive signatures, which could facilitate precision-medicine approaches, thus improving treatment outcome. Aims: As dysregulation of human microbiota is involved in carcinogenesis and host response against immunotherapy, the aim of our study was to characterize the nasopharynx and stool microbiome changes in CLL patients compared to age-matched healthy donors. In addition, we investigated the microbiota composition of samples collected from CLL patients concerning the independent prognostic factors. Methods: The study included 92 newly diagnosed and untreated CLL patients and 21 healthy volunteers (HVs). The microbiota composition of 85 stool samples and 76 oral samples from these cases were determined by 16S rRNA next-generation sequencing. Results: Alpha-diversity analysis showed that oral samples from CLL patients exhibit lower richness and evenness than oral samples from HVs (Chao1 index p=0.049 and Shannon index p=0.006, respectively), especially regarding to women cohort (Chao1 index p=0.021 and Shannon index p<0.05). Furthermore, higher richness and evenness were observed in CLL patients with stage 1-2 Rai in comparison to stage 0 (Shannon index p=0.043). However, these metrics showed no significant differences in richness and evenness in fecal probes between CLL and HVs samples. At the phylum level, a significant increase in the relative abundance of Proteobacteria was observed in oral and stool samples from CLL patients compared to HVs (p=0.028 and p<0.032, respectively). Intriguingly, Proteobacteria was significantly more abundant in oral samples collected from CLL patients with stereotypical IGHV status (p=0.033), del11q (p=0.0049), and the presence of 2 or more cytogenetic aberrations (p=0.0096). The abundance of Bacteroidota was lower in both oral and fecal samples collected from CLL patients in comparison to HVs (p=0.002 and p<0.016, respectively). Moreover, the Firmicutes/Bacteroidota (F/B) ratio was found to be significantly higher in oral and fecal samples collected from CLL patients in comparison to HVs (p<0.0001 and p<0.0001, respectively). Regarding oral samples, CLL patients with higher F/B ratio (upper quartile of the log F/B ratio, values >4.612) exhibited a significantly shorter time to first treatment than subjects with lower F/B ratio (p<0.05) (Figure 1). Interestingly, a noteworthy higher F/B ratio was observed in both oral and fecal samples from CLL patients with stage Binet B compared to stage Binet A (p=0.0265 and p=0.0159, respectively). Furthermore, there was a tendency to the increased F/B ratio in oral samples from CLL patients with unmutated IGHV than CLL patients with mutated IGHV (p=0.0689). At the family level, we observed a higher abundance of short-chain fatty acids (SCFAs)-producing bacteria Ruminococcaceae and Lachnospiraceae in fecal samples collected from CLL patients in comparison to HVs (p=0.01 and p<0.009, respectively). Summary/Conclusion: The oral and gut microbiome of CLL patients show lower diversity and specific alterations in comparison to a healthy microbiome. Firmicutes/Bacteroidota (F/B) ratio might modulate survival of CLL patients.Figure 1. Time to first treatment (TTFT) curves of CLL patients with respect to the quartiles of the log Firmicutes/Bacteroidota ratio. Funding: Polish National Science Center (NCN 2018/29/B/NZ5/02706). Keywords: Chronic lymphocytic leukemia, Inflammation