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

laboratory experiment

Citation

PMID PubMed identifier for scientific articles.

32425919

DOI Digital object identifier for electronic documents.

10.3389/fmicb.2020.00814

URI

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

Keywords:

MSS-type CRC, PD-1 antibody, gut microbiota, immunotherapy, metabolic pathway

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

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Fatima, Peace Sandy

Subjects

Location of subjects

China

Host species Species from which microbiome was sampled. Contact us to have more species added.

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,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,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

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).

relative abundances

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

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees

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

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Bacteroides
Ruminiclostridium
Parabacteroides
Erysipelotrichaceae

Revision editor(s): Mary Bearkland, Atrayees

Signature 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees

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	Quality Control	Links
Desulfovibrio
Lachnospiraceae
Bacteroidales
Parasutterella
Eubacteriales

Revision editor(s): Mary Bearkland, Atrayees

Experiment 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees, Victoria

Differences from previous experiment shown

Subjects

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.

Lab analysis

16S variable region One or more hypervariable region(s) of the bacterial 16S gene

V4-V4

Statistical Analysis

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Merit, Atrayees

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	Quality Control	Links
Akkermansia
Escherichia/Shigella sp.
Lactobacillus
Parabacteroides
Parasutterella
Prevotellaceae
Roseburia
unclassified Enterobacteriaceae
Lactobacillales
Eubacteriales

Revision editor(s): Mary Bearkland, Merit, Atrayees

Signature 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees

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	Quality Control	Links
Desulfovibrio
Lachnospiraceae
Bacteroidales
Erysipelotrichaceae

Revision editor(s): Mary Bearkland, Atrayees

Experiment 3

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Needs review

Curated date: 2022/09/17

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees, Victoria

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

Coli

Group 0 sample size Number of subjects in the control (unexposed) group

14

Lab analysis

Statistical Analysis

MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?

Not specified

Alpha Diversity

Richness Number of species

increased

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Merit, Atrayees

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	Quality Control	Links
Akkermansia
Escherichia/Shigella sp.
Lactobacillus
Parabacteroides
Parasutterella
Prevotellaceae
Roseburia
unclassified Enterobacteriaceae
Ruminiclostridium

Revision editor(s): Mary Bearkland, Merit, Atrayees

Signature 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees

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	Quality Control	Links
Bacteroides
Erysipelotrichaceae
Ruminiclostridium
Desulfovibrio
Bacteroidales
Lachnospiraceae

Revision editor(s): Mary Bearkland, Atrayees

Experiment 4

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Needs review

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees, Victoria

Differences from previous experiment shown

Subjects

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

16S variable region One or more hypervariable region(s) of the bacterial 16S gene

Not specified

Statistical Analysis

Statistical test

Mann-Whitney (Wilcoxon)

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

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

Revision editor(s): Mary Bearkland

Signature 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

Curated date: 2022/09/18

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Merit, Atrayees

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	Quality Control	Links
Bacteroides oleiciplenus
Bacteroides sp. CAG:530
Bacteroides sp. CAG:633
Parabacteroides goldsteinii
Phocaeicola massiliensis
Phocaeicola sartorii
uncultured bacterium
Bacteroides sp. CAG:462

Revision editor(s): Mary Bearkland, Merit, Atrayees

Experiment 5

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Needs review

Curated date: 2022/09/20

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Atrayees, Victoria

Differences from previous experiment shown

Subjects

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.

Lab analysis

Statistical Analysis

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

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	Quality Control	Links
Akkermansia muciniphila
Akkermansia muciniphila CAG:154
Bacteroides sp. 2_1_33B
Bacteroides uniformis
Parabacteroides distasonis
Xylanibacter rarus
unclassified Bacteroidales
unclassified Bacteroides
unclassified Parabacteroides

Revision editor(s): Mary Bearkland

Signature 2

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

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	Quality Control	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

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Needs review

Curated date: 2022/09/21

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Victoria

Differences from previous experiment shown

Subjects

Group 0 name Corresponds to the control (unexposed) group for case-control studies

coli

Group 0 sample size Number of subjects in the control (unexposed) group

7

Lab analysis

Statistical Analysis

Statistical test

ANOVA

Significance threshold p-value or FDR threshold used for differential abundance testing (if any)

Not specified

Signature 1

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

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	Quality Control	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

EditHistoryDelete

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Reviewed Marked as Reviewed by Atrayees on 2023-7-14

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	Quality Control	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