Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients

Study information

Reviewed Marked as Reviewed by Peace Sandy on 2024-1-18

study design

prospective cohort

Citation

PMID PubMed identifier for scientific articles.

28923537

DOI Digital object identifier for electronic documents.

10.1016/j.neo.2017.08.004

URI

https://pubmed.ncbi.nlm.nih.gov/28923537/

Authors

Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, Koh AY

Journal

Neoplasia (New York, N.Y.)

Year

2017

This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT-particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.

Experiment 1

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-18

Curated date: 2022/08/30

Curator: Sharmilac

Revision editor(s): Sharmilac, Fatima, Peace Sandy

Subjects

Location of subjects: United States of America

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

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: Response to immunochemotherapy Response to immunochemotherapy,response to immunochemotherapy

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Non responders (Progressive disease)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Responders

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Twenty-four patients showed RECIST response (19, 49%) or stable (5, 13%) disease to ICT, what we classify as responders in this study

Group 0 sample size Number of subjects in the control (unexposed) group: 16

Group 1 sample size Number of subjects in the case (exposed) group: 23

Lab analysis

Sequencing type: WMS

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: Not specified

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: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

Signature 1

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-18

Curated date: 2022/08/30

Curator: Sharmilac

Revision editor(s): Sharmilac, Aiyshaaaa

Source: Figure 2, text

Description: MSS identifies specific bacterial species that are enriched in the gut microbiomes of melanoma patients who are responding to ICT therapy. Relative abundance of gut bacterial taxa as determined by MetaPhlAn analysis of MSS data generated from fecal specimens collected from melanoma patients prior to receiving ipilimumab/nivolumab, pembrolizumab, ipilimumab alone, or nivolumab alone.Differential taxonomic abundance was analyzed by linear discriminate analysis coupled with effect size measurements (LEfSe) projected as a histogram (A, C and E) or cladrogram (B, D and F). All listed bacterial groups were significantly (P b .05, Kruskal-Wallis test) enriched for their respective groups (responder versus progressive).

Abundance in Group 1: increased abundance in Responders

NCBI	Quality Control	Links
Bacteroides caccae
Bacteroides thetaiotaomicron
Dorea formicigenerans
Faecalibacterium prausnitzii
Holdemania filiformis
Streptococcus parasanguinis

Revision editor(s): Sharmilac, Aiyshaaaa

Signature 2

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-18

Curated date: 2023/04/16

Curator: Sharmilac

Revision editor(s): Sharmilac, Peace Sandy

Source: Figure 2, text

Description: MSS identifies specific bacterial species that are enriched in the gut microbiomes of melanoma patients who are responding to ICT therapy. Relative abundance of gut bacterial taxa as determined by MetaPhlAn analysis of MSS data generated from fecal specimens collected from melanoma patients prior to receiving ipilimumab/nivolumab, pembrolizumab, ipilimumab alone, or nivolumab alone.Differential taxonomic abundance was analyzed by linear discriminate analysis coupled with effect size measurements (LEfSe) projected as a histogram (A, C and E) or cladrogram (B, D and F). All listed bacterial groups were significantly (P b .05, Kruskal-Wallis test) enriched for their respective groups (responder versus progressive).

Abundance in Group 1: decreased abundance in Responders

NCBI	Quality Control	Links
Actinomyces viscosus
Anaerococcus vaginalis
Bacteroides eggerthii
Lactobacillus gasseri
Lancefieldella parvula
Leuconostoc gasicomitatum
Leuconostoc mesenteroides
Peptoniphilus
Schaalia odontolytica
Slackia exigua
Streptococcus infantarius
Streptococcus mutans
Coriobacteriaceae
Coriobacteriales
Acidaminococcaceae
Atopobium
Actinomycetales
Campylobacter
Campylobacteraceae
Actinomyces
Lactobacillus
Lactobacillaceae
unclassified Peptoniphilus

Revision editor(s): Sharmilac, Peace Sandy