Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

Yu, Jun; Feng, Qiang; Wong, Sunny H.; Zhang, Dongya; Liang, Qiao Yi; Qin, Youwen; Tang, Longqing; Zhao, Hui; Stenvang, Jan; Li, Yanli; Wang, Xiaokai; Xu, Xiaoqiang; Chen, Ning; Wu, William Ka Kei; Al‐Aama, Jumana Y.; Nielsen, Hans Jørgen; Kiilerich, Pia; Jensen, Benjamin Anderschou Holbech; Yau, Tung On; Lan, Zhou; Jia, Huijue; Li, Junhua; Xiao, Liang; Lam, Thomas Y.; Cheng, Alfred S.L.; Wong, Vincent Wai‐Sun; Chan, Francis K.L.; Xu, Xun; Yang, Huanming; Madsen, Lise; Datz, Christian; Tilg, Herbert; Wang, Jian; Brünner, Nils; Kristiansen, Karsten; Arumugam, Manimozhiyan; Sung, Joseph J.Y.; Wang, Jun

doi:10.1136/gutjnl-2015-309800

Cited by 871 publications

(919 citation statements)

References 44 publications

(50 reference statements)

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“…Specifically, we used 239 stool samples from the HMP (Huttenhower et al , 2012) collected from 139 US American individuals, as well as 676 oral samples from the same individuals; 156 samples from as many Austrian individuals (Yu et al , 2015); 368 Chinese samples (Qin et al , 2012); 387 Danish samples from the MetaHIT cohort; 156 French and 40 German samples (Zeller et al , 2014); 126 novel German samples collected from 26 individuals; 172 novel Kazakh samples from 86 individuals; 359 Spanish samples from MetaHIT; and 145 Swedish samples (Karlsson et al , 2013; Table EV1). Informed consent was obtained from the German individuals through the my.microbes project (http://my.microbes.eu).…”

Section: Methodsmentioning

confidence: 99%

Subspecies in the global human gut microbiome

Costea

Coelho

Sunagawa

et al. 2017

Molecular Systems Biology

126

143

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Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.

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Section: Methodsmentioning

confidence: 99%

Subspecies in the global human gut microbiome

Costea

Coelho

Sunagawa

et al. 2017

Molecular Systems Biology

126

143

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“…Detection of molecular biomarkers in fecal samples for the noninvasive diagnosis of colorectal cancer may be a more promising alternative than blood/plasma biomarkers to be implemented in present clinical settings. With the widespread application of pyrosequencing and metagenome sequencing in the field of microbiota, an increasing number of colorectal cancer-associated bacteria have been identified, including those identified by us (12). There is an urgent need to validate these candidate markers and to evaluate their clinical application values by targeted quantification methods.…”

Section: Discussionmentioning

confidence: 99%

“…These candidates were identified by eliminating confounding effects of colonoscopy using blocked independent Wilcoxon rank-sum tests with colonoscopy as a stratifying factor in our previous metagenome study (12). Fn has also been identified to be enriched in colorectal cancer patients by others (3,5,8), while the other four have not associated with colorectal cancer by other researchers.…”

Section: Design Of Primers and Probesmentioning

confidence: 99%

“…Fecal samples from 97 Hong Kong patients with adenoma (60.5 AE 4.7 years; 50 males and 47 females) were further included in this study. Subjects recruited for fecal sample collection included individuals presenting symptoms such as change of bowel habit, rectal bleeding, abdominal pain or anemia, and asymptomatic individuals aged 50 or above undergoing screening colonoscopy as in our previous metagenomics study (12). Samples were collected before or one month after colonoscopy, when gut microbiome should have recovered to baseline (13).…”

Section: Human Fecal Sample Collectionmentioning

confidence: 99%

“…In our recent study, using 16S rRNA sequencing to catalog the microbial communities in human gut mucosa at different stages of colorectal tumorigenesis, Fusobacterium was also found to be enriched in colorectal tumors (11). Then by using metagenomics analysis to compare the fecal microbiome of 74 colorectal cancer patients and 54 healthy subjects, we have identified bacterial candidates that may serve as noninvasive biomarkers for colorectal cancer (12), including Fn, Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), one undefined species (labeled as m7). Unlike Fn, the other bacteria have not yet been associated with colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

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Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Liang

Chiu

Chen

et al. 2017

Clinical Cancer Research

Self Cite

242

251

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Purpose: Gut microbiota have been implicated in the development of colorectal cancer. We evaluated the utility of fecal bacterial marker candidates identified by our metagenome sequencing analysis for colorectal cancer diagnosis.Experimental Design: Subjects (total 439; 203 colorectal cancer and 236 healthy subjects) from two independent Asian cohorts were included. Probe-based duplex quantitative PCR (qPCR) assays were established for the quantification of bacterial marker candidates.Results: Candidates identified by metagenome sequencing, including Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Roseburia intestinalis (Ri), Clostridium hathewayi (Ch), and one undefined species (labeled as m7), were examined in fecal samples of 203 colorectal cancer patients and 236 healthy controls by duplex-qPCR. Strong positive correlations were demonstrated between the quantification of each candidate by our qPCR assays and metagenomics approach (r ¼ 0.801-0.934, all P < 0.0001). Fn was significantly more abundant in colorectal cancer than controls (P < 0.0001), with AUROC of 0.868 (P < 0.0001). At the best cut-off value maximizing sum of sensitivity and specificity, Fn discriminated colorectal cancer from controls with a sensitivity of 77.7%, and specificity of 79.5% in cohort I. A simple linear combination of four bacteria (Fn þ Ch þ m7-Bc) showed an improved diagnostic ability compared with Fn alone (AUROC ¼ 0.886, P < 0.0001) in cohort I. These findings were further confirmed in an independent cohort II. In particular, improved diagnostic performances of Fn alone (sensitivity 92.8%, specificity 79.8%) and four bacteria (sensitivity 92.8%, specificity 81.5%) were achieved in combination with fecal immunochemical testing for the detection of colorectal cancer.Conclusions: Stool-based colorectal cancer-associated bacteria can serve as novel noninvasive diagnostic biomarkers for colorectal cancer.

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Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors

et al. 2021

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The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial co-factors of colorectal cancer (CRC) carcinogenesis or progression. We analyzed whole-genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs.The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. λ48. Enrichment of Escherichia coli strains IAI1, SE11, K-12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast-confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR-validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues,and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t-test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co-)risk factors of CRC, and extend putative suggestions on critical microbiome species in CRC metastasis.

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Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer

Cited by 871 publications

References 44 publications

Subspecies in the global human gut microbiome

Subspecies in the global human gut microbiome

Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer

Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors

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