Page 243 - Haematologica Vol. 107 - September 2022

LETTER TO THE EDITOR
ial genera across the CLL and healthy cohorts. When we visualized the relationships between the 23 most strongly proportional taxa, three clusters were formed (Online Sup- plementary Figure S2A). Abundance/depletion of the pro- portional bacterial taxa across all samples revealed clear discrimination between CLL patients and healthy controls (Online Supplementary Figure S2B; Online Supplementary Table S1). An overlap of the two analytical methodologies indicated lack of bacteria mainly from Lachnospiraceae and Ruminococcaceae families among the CLL samples. In particular, lower abundances of Anaerostipes, Bifido- bacterium, Blautia, Coprococcus, Dorea, Eubacterium, Ruminococcus, and Streptococcus were observed in CLL samples when compared to controls. The two approaches also indicated higher abundances of Bacteroides and Parabacteroides in CLL compared to controls.
While canonical metrics have revealed statistically signifi- cant differences between CLL and healthy cohorts, we note that controls are also significantly different from one another across several metrics. Thus, we set out to answer whether there exists a healthy-diseased axis such that healthy patients from both control cohorts co-vary and are distinct from CLL patients. In order to do this we characterized the structure of covariance in each cohort by their centroids in PCA-space (Figure 3A). We assessed the similarity between cohorts by calculating the angles between their centroids within this reduced multidimen- sional space (interpretation of angles in Figure 3C). On average, CLL gut profiles were inversely proportional, i.e., dissimilar, to C1 & C2 cohorts (∠CLL,C1 =140.1±38.5°, purple; ∠CLL,C2 =168.9±11°, green; Figure 3B). We also ob- served an acute relationship, i.e., similarity, between healthy cohorts (∠C1,C2 =51±43.9°). These results highlight the presence of a strong inverse axis between diseased and healthy states that is defined by the angles between centroids of the CLL and the two control groups.
The lower fecal diversity observed in the CLL cohort is in line with previous findings of reduced bacterial diversity in other inflammatory conditions including IBD, type 1 and 2 diabetes, and obesity,10,11 as well as hematologic malig- nancies.6,12 We suggest that the decreased diversity/in- crease in Bacteroidetes and Proteobacteria observed in the CLL cohort could imply a general loss of bacteria, but may also indicate a loss of complexity for the remaining microbiome.
Most of the bacterial genera in the microbial signature de- pleted in patients with CLL belonged to Lachnospiraceae and Ruminococcaceae family. Members of the Lachnospi- raceae and Ruminococcaceae families are among the main producers of short chain fatty acids, which are known to modulate the surrounding microbial environment and to directly interact with the host immune system.13 Interest- ingly, Blautia (Lachnospiraceae family) and Ruminococcus (Ruminococcaceae family) were also identified with higher
abundance among controls than among patients with CLL. High abundance of intestinal Blautia has been as- sociated with improved survival upon graft-versus-host disease,14 and is together with Ruminococcus often under- represented in feces samples from patients with color- ectal cancer.15
In conclusion, despite low sample size, the CLL micro- biome demonstrated lower microbiome diversity and lower enrichment of short chain fatty acid-producing bac- terial taxa when compared to healthy controls. We hypo- thesize that the overabundance of bacteria from the Bacteroidetes phylum together with depletion of Lachnos- piraceae and Ruminococcaceae family bacteria might play a role in – or is observed due to – immune dysfunction among CLL patients. This microbiome signature is war- ranting validation and refinement in larger CLL cohorts in- cluding patients needing treatment, patients assigned to watch and wait, patients with other hematological malig- nancies, as well as other healthy cohorts. This as a focus of ours in a follow-up study will hopefully lay foundation for defining microbiome characteristics of hematological malignancies and microbiome signatures discriminating subgroups of patients with CLL.
Authors
Tereza Faitová,1 Rebecka Svanberg,1 Caspar da Cunha-Bang,1 Emma E. Ilett,2 Mette Jørgensen,2 Marc Noguera-Julian,3,4 Roger Paredes,3,5 Cameron R. MacPherson2 and Carsten U. Niemann1,6
1Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 2PERSIMUNE Center of Excellence, Rigshospitalet, Copenhagen, Denmark; 3Institut de Recerca de la Sida-IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain; 4University of Vic-Central University of Catalonia, Barcelona, Spain; 5Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain and 6Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
Correspondence:
C. U. NIEMANN - carsten.utoft.niemann@regionh.dk
https://doi.org/10.3324/haematol.2021.280455
Received: December 1, 2021. Accepted: May 5, 2022. Prepublished: May 12, 2022.
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
CUN received research funding and/or consultancy fees from
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