Gut Microbiome Influences the Efficacy of PD-1 Antibody Immunotherapy on MSS-Type Colorectal Cancer via Metabolic Pathway

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Reviewed Marked as Reviewed by Fatima on 2022/10/6
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI Uniform resource identifier for web resources.
Authors
Xu X, Lv J, Guo F, Li J, Jia Y, Jiang D, Wang N, Zhang C, Kong L, Liu Y, Zhang Y, Lv J, Li Z
Journal
Frontiers in microbiology
Year
2020
Colorectal cancer (CRC) appears to be rather refractory to checkpoint blockers except the patient with deficient in mismatch repair (dMMR). Therefore, new advances in the treatment of most mismatch repair proficiency (pMMR) (also known as microsatellite stability, MSS) type of CRC patients are considered to be an important clinical issue associated with programmed death 1 (PD-1) inhibitors. In the present study, we evaluated the effects of gut microbiome of MSS-type CRC tumor-bearing mice treated with different antibiotics on PD-1 antibody immunotherapy response. Our results confirmed that the gut microbiome played a key role in the treatment of CT26 tumor-bearing mice with PD-1 antibody. After PD-1 antibody treatment, the injection of antibiotics counteracted the efficacy of PD-1 antibody in inhibiting tumor growth when compared with the Control group (mice were treated with sterile drinking water). Bacteroides_sp._CAG:927 and Bacteroidales_S24-7 were enriched in Control group. Bacteroides_sp._CAG:927, Prevotella_sp._CAG: 1031 and Bacteroides were enriched in Coli group [mice were treated with colistin (2 mg/ml)], Prevotella_sp._CAG:485 and Akkermansia_muciniphila were enriched in Vanc group [mice were treated with vancomycin alone (0.25 mg/ml)]. The metabolites were enriched in the glycerophospholipid metabolic pathway consistent with the metagenomic prediction pathway in Vanc group, Prevotella_sp._CAG:485 and Akkermansia may maintain the normal efficacy of PD-1 antibody by affecting the metabolism of glycerophospholipid. Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.

Experiment 1


Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Fatima

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
control
Group 1 name Corresponds to the case (exposed) group for case-control studies
Coli
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with colistin (2 mg/ml) in sterile drinking water (Coli group). Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.
Group 0 sample size Number of subjects in the control (unexposed) group
13
Group 1 sample size Number of subjects in the case (exposed) group
14

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.05
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes



Signature 1

Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1.Compositional differences in the gut microbiome are associated with responses to PD-1 antibody immunotherapy (B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: increased abundance in Coli

NCBI Links
Bacteroides
Ruminiclostridium
unclassified Erysipelotrichaceae

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1.Compositional differences in the gut microbiome are associated with responses to PD-1 antibody immunotherapy (B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: decreased abundance in Coli

NCBI Links
Desulfovibrio
Lachnospiraceae
Muribaculaceae

Revision editor(s): Mary Bearkland

Experiment 2


Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
control
Group 1 name Corresponds to the case (exposed) group for case-control studies
Vanc
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with vancomycin alone (0.25 mg/ml) in sterile drinking

water (Vanc group). Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.

Group 0 sample size Number of subjects in the control (unexposed) group
13
Group 1 sample size Number of subjects in the case (exposed) group
14

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V4-V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA



Signature 1

Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1(B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: increased abundance in Vanc

NCBI Links
Akkermansia
Escherichia/Shigella sp.
Lactobacillus
Parabacteroides
Parasutterella
Prevotellaceae
Roseburia
unclassified Enterobacteriaceae
Prevotellaceae NK3B31 groupPrevotellaceae NK3B31 group
clostridiales vadin bb60 groupclostridiales vadin bb60 group

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1(B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: decreased abundance in Vanc

NCBI Links
Desulfovibrio
Muribaculaceae
Lachnospiraceae

Revision editor(s): Mary Bearkland

Experiment 3


Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Coli
Group 1 name Corresponds to the case (exposed) group for case-control studies
Vanc
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with vancomycin alone (0.25 mg/ml) in sterile drinking

water (Vanc group). Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.

Group 0 sample size Number of subjects in the control (unexposed) group
14
Group 1 sample size Number of subjects in the case (exposed) group
14

Lab analysis

Sequencing type
16S
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA



Signature 1

Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1 (B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: increased abundance in Vanc

NCBI Links
Akkermansia
Escherichia/Shigella sp.
Lactobacillus
Parabacteroides
Parasutterella
Prevotellaceae
Roseburia
unclassified Enterobacteriaceae
clostridiales vadin bb60 groupclostridiales vadin bb60 group

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 1B

Description: Supplementary Figure 1 (B) Bar plot of compositional differences at genus level in the gut microbiome of three groups of mice by one-way ANOVA.

Abundance in Group 1: decreased abundance in Vanc

NCBI Links
Bacteroides
Erysipelotrichaceae
Ruminiclostridium

Revision editor(s): Mary Bearkland

Experiment 4


Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
control
Group 1 name Corresponds to the case (exposed) group for case-control studies
Coli
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with colistin (2 mg/ml) in sterile drinking water (Coli group). Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
7

Lab analysis

Sequencing type
WMS
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA



Signature 1

Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Control vs. Coli

Abundance in Group 1: increased abundance in Coli

NCBI Links
Bacteroidaceae bacterium
Bacteroides ovatus
Bacteroides xylanisolvens
Parabacteroides sp.
unclassified Bacteroidales
uncultured prokaryote

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Control vs. Coli

Abundance in Group 1: decreased abundance in Coli

NCBI Links
Phocaeicola massiliensis
Parabacteroides goldsteinii
uncultured bacterium BAC10G6
Phocaeicola sartorii
Bacteroides sp. CAG:633
Bacteroides sp. CAG:530
uncultured bacterium
Bacteroides oleiciplenus
Bacteroides sp. CAG:461Bacteroides sp. CAG:461

Revision editor(s): Mary Bearkland

Experiment 5


Needs review

Curated date: 2022/09/20

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
control
Group 1 name Corresponds to the case (exposed) group for case-control studies
Vanc
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with vancomycin alone (0.25 mg/ml) in sterile drinking water (Vanc group) Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
7

Lab analysis

Sequencing type
WMS
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA



Signature 1

Needs review

Curated date: 2022/09/20

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Control vs. Coli groups of mice before PD-1 antibody treatment by one-way ANOVA.

Abundance in Group 1: increased abundance in Vanc

NCBI Links
Akkermansia muciniphila
Akkermansia muciniphila CAG:154
Bacteroides sp. 2_1_33B
Bacteroides uniformis
Parabacteroides distasonis
Prevotella rara
unclassified Bacteroidales
unclassified Bacteroides
unclassified Parabacteroides

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/21

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Control vs. Vanc group of mice before PD-1 antibody treatment by one-way ANOVA.

Abundance in Group 1: decreased abundance in Vanc

NCBI Links
Bacteroides sp. CAG:927
Firmicutes bacterium ASF500
Lachnospiraceae bacterium A4
Phocaeicola massiliensis
Prevotella sp. CAG:1031
Prevotella sp. CAG:873

Revision editor(s): Mary Bearkland

Experiment 6


Needs review

Curated date: 2022/09/21

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Subjects

Location of subjects
China
Host species Species from which microbiome was sampled (if applicable)
Mus musculus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
antimicrobial agent antibiotic,antibiotics,Antibiotika,Antibiotikum,antibiotique,antimicrobial,antimicrobial agents,microbicide,microbicides,antimicrobial agent
Group 0 name Corresponds to the control (unexposed) group for case-control studies
coli
Group 1 name Corresponds to the case (exposed) group for case-control studies
Vanc
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Group 1 mice were treated with vancomycin alone (0.25 mg/ml) in sterile drinking water (Vanc group) Mice (in all groups) were then subcutaneously injected into the right axillary with 0.25 live CT26 tumor cells.
Group 0 sample size Number of subjects in the control (unexposed) group
7
Group 1 sample size Number of subjects in the case (exposed) group
7

Lab analysis

Sequencing type
WMS
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Statistical test
ANOVA



Signature 1

Needs review

Curated date: 2022/09/21

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Vanc vs.Coli groups of mice before PD-1 antibody treatment by one-way ANOVA.

Abundance in Group 1: increased abundance in Vanc

NCBI Links
Prevotella sp. CAG:485
Parabacteroides distasonis
Akkermansia muciniphila
unclassified Bacteroidales
Bacteroides uniformis
unclassified Parabacteroides
Akkermansia muciniphila CAG:154
Parasutterella excrementihominis

Revision editor(s): Mary Bearkland

Signature 2

Needs review

Curated date: 2022/09/21

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland

Source: supp fig 2

Description: Bar plot of compositional differences at species level in the Vanc vs.Coli groups of mice before PD-1 antibody treatment by one-way ANOVA.

Abundance in Group 1: decreased abundance in Vanc

NCBI Links
Bacteroides sp. CAG:927
Prevotella sp. CAG:1031
Prevotella sp. CAG:873
Prevotella sp. CAG:279
Phocaeicola vulgatus
Lachnospiraceae bacterium A4
Firmicutes bacterium ASF500

Revision editor(s): Mary Bearkland