Intestinal Blautia regulates gastrointestinal toxicity in ...
Transcript of Intestinal Blautia regulates gastrointestinal toxicity in ...
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
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Toxic patients Non-toxic patients
Non-Toxic-60
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(% re
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5-FU based chemotherapy disrupts microbial diversity and composition
Figure 2: Significantly
affected bacterial species in toxic and
non-toxic individuals.
T0 T5-5
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5
10
15
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ativ
e A
bund
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Faecalibacterium prausnitzii
T0 T5-20
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e A
bund
ance
E coli
T0 T5-5
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5
10
15
20
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ativ
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bund
ance
Intestinibacter bartlettii
T0 T5-20
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20
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60
80Streptococcus thermophilus
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bund
ance
T0 T5
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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
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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
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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