Post on 10-Dec-2021
Intestinal Blautia regulates gastrointestinal toxicity in cancer patients receiving standard dose chemotherapy
Wardill HR, Bowen JM, Secombe KR, Tissing WJE, Harmsen HJM, Stringer AM, Al-DasooqiN, Mayo B and Gibson RJ.
Dr Hannah Wardill, PhDNHMRC CJ Martin Biomedical Research FellowThe University of Adelaide (Australia) University Medical Centre Groningen (Netherlands)
@hannahrwardill@ToxicitiesGroup
The microbiome: a new risk prediction tool?• Microbiome is unique and individualized
• Microbiome is uniquely position to modulate cancer treatment efficacy and toxicity due to influence on:
• Drug metabolism • Mucosal immunology / barrier integrity / inflammation • Tolerance / immunogenic cell death
The microbiome: a new risk prediction tool?• Microbiome is unique and individualized
• Microbiome is uniquely position to modulate cancer treatment efficacy and toxicity due to influence on:
• Drug metabolism • Mucosal immunology / barrier integrity / inflammation • Tolerance / immunogenic cell death
• Unlike human genome, the microbiome is highly plastic enabling risk modification and fine tuning of treatment outcomes
Retrospective cohort investigation • Archival fecal samples from N=12 patients undergoing standard dose 5-FU
based chemotherapy for CRC and breast cancer
Retrospective cohort investigation • Archival fecal samples from N=12 patients undergoing standard dose 5-FU
based chemotherapy for CRC and breast cancer
• Patients donated N=2 stool samples samples:
• 1 X before chemotherapy cycle • 1 X day 5 (peak diarrhea)
Retrospective cohort investigation • Archival fecal samples from N=12 patients undergoing standard dose 5-FU
based chemotherapy for CRC and breast cancer
• Patients donated N=2 stool samples samples:
• 1 X before chemotherapy cycle • 1 X day 5 (peak diarrhea)
• Toxicity was assessed using NCI CTCAE v5.0; • Toxic = G3+ diarrhea• Non-toxic = G0/G1 diarrhea
5-FU based chemotherapy disrupts microbial diversity and composition
Figure 1: Species diversity (Shannon’s index) pre- and post-chemotherapy in toxic and non-toxic patients.
T0 T50
1
2
3
4
Sha
nnon
's d
iver
sity
inde
x
Toxic patients Non-toxic patients
Non-Toxic-60
-40
-20
0
20
Cha
nge
in S
peci
es D
ives
ity
(% re
lativ
e to
bas
elin
e)
5-FU based chemotherapy disrupts microbial diversity and composition
Figure 2: Significantly
affected bacterial species in toxic and
non-toxic individuals.
T0 T5-5
0
5
10
15
Rel
ativ
e A
bund
ance
Faecalibacterium prausnitzii
T0 T5-20
5
10
15
20
Rel
ativ
e A
bund
ance
E coli
T0 T5-5
0
5
10
15
20
Rel
ativ
e A
bund
ance
Intestinibacter bartlettii
T0 T5-20
0
20
40
60
80Streptococcus thermophilus
Rel
ativ
e A
bund
ance
T0 T5
0
5
10
Rel
ativ
e A
bund
ance
Ruminococcus bromii
Toxic and non-toxic patients have distinct microbial signatures before chemotherapy
-1.0 -0.5 0.5 1.0
-0.8
-0.6
-0.4
-0.2
0.2
0.4
0.6
0.8
PC2
P
C3
Non-toxic Toxic
16%
11%
Figure 3: Principle component analysis of pre-treatment microbiome composition
Toxic and non-toxic patients have distinct microbial signatures before chemotherapy
TOXIC NON-TOXIC
Figure 4: Microbial composition (genera level) in toxic and non-toxic individuals
Toxic and non-toxic patients have distinct microbial signatures before chemotherapy
TOXIC NON-TOXIC
before chemotherapy
Figure 4: Microbial composition (genera level) in toxic and non-toxic individuals
Figure 5: Relative abundance of Blautia in toxic and non-
toxic individual.
Blautia correlates with toxicity outcome
• Microbial composition aligning with PC considered protective
• Correlated species with PC2 -1.0 -0.5 0.5 1.0
-0.8
-0.6
-0.4
-0.2
0.2
0.4
0.6
0.8
PC2
P
C3
Non-toxic Toxic
16%
11%
Blautia correlates with toxicity outcome
! Microbial composition aligning with PC considered protective
! Correlated species with PC2 -1.0 -0.5 0.5 1.0
-0.8
-0.6
-0.4
-0.2
0.2
0.4
0.6
0.8
PC2
P
C3
Non-toxic Toxic
16%
11%
Collinsellaaerofaciens
Streptococ. Thermophil.
Blautia lutiRuminococcus
lactaris
Correlation coefficient
-0.839*** -0.593** 0.744** 0.616**
Blautia luti in vitro activity• Isolated blautia luti from fresh human faeces (healthy individual)
• Cultured anaerobically in YCFAG, isolated supernatant via centrifugation
• Investigated impact of blautia luti supernatant (B-SPN) on:
• Colonic epithelial proliferation (xCELLigence system)
• Epithelial barrier function (trans-epithelial electrical resistance)
Conclusions• 5-FU based chemotherapy causes microbial dysbiosis reflected by a decrease in
species diversity, a loss of butyrate-producing commensals and an increase in opportunistic pathogens
• Pre-treatment microbial composition critical in determining outcomes
• Blautia genera associated with favourable toxicity outcomes
• Restoration of blautia genera may be important in protecting against gastrointestinal toxicity, via:
• Promotion of epithelial restitution• Restoration of the intestinal barrier • Stimulation of commensal expansion
Acknowledgments Wim Tissing, Hermie Harmsen and Ana Rita da Silva Ferreira: University Medical Centre Groningen (Netherlands)
Kate Secombe, Joanne Bowen, Rachel Gibson, Ysabella Van Sebille, Bronwen Mayo, Noor Al-Dasooqi, Dorothy Keefe and Imogen Ball:The University of Adelaide and University of South Australia (Australia)
FUNDING National Health and Medical Research CommitteeThe University of AdelaideThe Royal Adelaide Hospital
@hannahrwardill@ToxicitiesGroup