Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation

Study information

Reviewed Marked as Reviewed by Lwaldron on 2021/06/26

study design

case-control
meta-analysis

Citation

PMID PubMed identifier for scientific articles.

30936548

DOI Digital object identifier for electronic documents.

10.1038/s41591-019-0405-7

URI

Authors

Thomas AM, Manghi P, Asnicar F, Pasolli E, Armanini F, Zolfo M, Beghini F, Manara S, Karcher N, Pozzi C, Gandini S, Serrano D, Tarallo S, Francavilla A, Gallo G, Trompetto M, Ferrero G, Mizutani S, Shiroma H, Shiba S, Shibata T, Yachida S, Yamada T, Wirbel J, Schrotz-King P, Ulrich CM, Brenner H, Arumugam M, Bork P, Zeller G, Cordero F, Dias-Neto E, Setubal JC, Tett A, Pardini B, Rescigno M, Waldron L, Naccarati A, Segata N

Journal

Nature medicine

Year

2019

Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.

Experiment 1

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Curated date: 2021/06/26

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Subjects

Location of subjects: Austria; Canada; China; France; Italy; 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: Colorectal carcinoma

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

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

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: colorectal cancer cases

Group 0 sample size Number of subjects in the control (unexposed) group: 308

Group 1 sample size Number of subjects in the case (exposed) group: 313

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).: raw counts

Statistical test: Linear Regression

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

Alpha Diversity

Richness Number of species: increased

Signature 1

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Source: Extended Data Fig. 4

Description: taxonomic meta-analysis of CRC cases vs controls

Abundance in Group 1: increased abundance in colorectal cancer cases

NCBI	Quality Control	Links
Alistipes onderdonkii
Alloprevotella tannerae
Anaerococcus obesiensis
Anaerococcus vaginalis
Anaerotruncus sp.
Bacteroides fragilis
Bacteroides salyersiae
Bilophila sp.
Bilophila wadsworthia
Campylobacter gracilis
Campylobacter showae
Campylobacter ureolyticus
Desulfovibrio desulfuricans
Eikenella corrodens
Escherichia coli
Eubacterium limosum
Flavonifractor plautii
Fusobacterium mortiferum
Fusobacterium necrophorum
Fusobacterium nucleatum
Gemella morbillorum
Granulicatella adiacens
Lachnospiraceae bacterium 3_1_57FAA_CT1
Lancefieldella rimae
Leptotrichia sp.
Methanobrevibacter smithii
Methanobrevibacter sp.
Parvimonas micra
Parvimonas sp.
Peptoniphilus harei
Peptostreptococcus anaerobius
Peptostreptococcus sp.
Peptostreptococcus stomatis
Porphyromonas asaccharolytica
Porphyromonas somerae
Porphyromonas uenonis
Prevotella intermedia
Schaalia cardiffensis
Selenomonas sputigena
Slackia exigua
Slackia sp.
Solobacterium moorei
Streptococcus constellatus
Streptococcus dysgalactiae
Streptococcus gallolyticus
Streptococcus oralis subsp. tigurinus
[Clostridium] symbiosum
[Eubacterium] infirmum
[Ruminococcus] torques

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Signature 2

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Source: Extended Data Fig. 4

Description: taxonomic meta-analysis of CRC cases vs controls

Abundance in Group 1: decreased abundance in colorectal cancer cases

NCBI	Quality Control	Links
Lachnospiraceae bacterium 1_1_57FAA
Ruminococcus sp. 5_1_39BFAA
Pseudomonas sp.
Bifidobacterium longum subsp. longum
Anaerobutyricum hallii
Adlercreutzia equolifaciens
Streptococcus thermophilus
Faecalibacterium prausnitzii
Roseburia intestinalis
Gordonibacter pamelaeae
Bifidobacterium catenulatum

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Signature 3

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Source: Extended Data Fig. 5

Description: putative oral species in CRC cases vs controls

Abundance in Group 1: increased abundance in colorectal cancer cases

NCBI	Quality Control	Links
Fusobacterium nucleatum
Parvimonas micra
Gemella morbillorum
Peptostreptococcus stomatis
Solobacterium moorei
Prevotella intermedia
Streptococcus constellatus
Granulicatella adiacens
Eikenella corrodens
Campylobacter showae
Alloprevotella tannerae
[Eubacterium] infirmum
Campylobacter gracilis
Prevotella nigrescens
Streptococcus oralis subsp. tigurinus