Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes

Nakatsu, Geicho; Zhou, Haokui; Wu, William Ka Kei; Wong, Sunny H.; Coker, Olabisi Oluwabukola; Dai, Zhenwei; Li, Xiangchun; Szeto, Chun Ho; Sugimura, Naoki; Lam, Thomas Y.; Yu, Allen Chi Shing; Wang, Xiansong; Chen, Zigui; Wong, Martin C.S.; Chan, Matthew Tak Vai; Chan, Paul Kay Sheung; Chan, Francis K.L.; Sung, Joseph J.Y.; Yu, Jun

doi:10.1053/j.gastro.2018.04.018

Cited by 279 publications

(244 citation statements)

References 81 publications

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“…Treatment of mice transplanted with patient‐derived colorectal carcinoma xenografts with metronidazole has been shown to decrease F nucleatum, cancer cell proliferation and tumour growth. Interestingly, the gut virome has been associated with CRC survival outcomes independent of tumour stage and CRC has been associated with an increase in phage richness and diversity . Phages targeting F nucleatum have already been described with clinical trials planned utilising these viruses…”

Section: The Future Of Phage Therapy In Gastrointestinal Diseasesmentioning

confidence: 99%

“…91 The interaction between the gut microbiota and the human 98 Interestingly, the gut virome has been associated with CRC survival outcomes independent of tumour stage and CRC has been associated with an increase in phage richness and diversity. 99 Phages targeting F nucleatum have already been described 100 with clinical trials planned utilising these viruses. 101 Phage therapy could be applied together with other strategies to modulate gut microbiota.…”

Section: Temperate Phagementioning

confidence: 99%

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Review article: bacteriophages in gastroenterology—from biology to clinical applications

Sabino

Hirten

Colombel

2019

Aliment Pharmacol Ther

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Summary Background The gut microbiota plays an important role in the pathogenesis of several gastrointestinal diseases. Its composition and function are shaped by host‐microbiota and intra‐microbiota interactions. Bacteriophages (phages) are viruses that target bacteria and have the potential to modulate bacterial communities. Aims To summarise phage biology and the clinical applications of phages in gastroenterology Methods PubMed was searched to identify relevant studies. Results Phages induce bacterial cell lysis, integration of viral DNA into the bacteria and/or coexistence in a stable equilibrium. Bacteria and phages have co‐evolved and their dynamic interactions are yet to be fully understood. The increasing need to modulate microbial communities (e.g., gut microbiota, multidrug‐resistant bacteria) has been a strong stimulus for research in phages as an antibacterial therapy. In gastroenterology, phage therapy has been mainly studied in infectious diseases such as cholera. However, it is currently being explored in several other circumstances such as treating Clostridioides difficile colitis, targeting adherent‐invasive Escherichia coli in Crohn's disease or eradicating Fusobacterium nucleatum in colorectal cancer. Overall, phage therapy has a favourable and acceptable safety profile. Presently, trials with phage therapy are ongoing in Crohn's disease. Conclusions Phage therapy is a promising therapeutic tool against pathogenic bacteria in the fields of infectious diseases and gastroenterology. Randomised, placebo‐controlled trials with phage therapy for gastroenterological diseases are ongoing.

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Section: The Future Of Phage Therapy In Gastrointestinal Diseasesmentioning

confidence: 99%

Section: Temperate Phagementioning

confidence: 99%

Review article: bacteriophages in gastroenterology—from biology to clinical applications

Sabino

Hirten

Colombel

2019

Aliment Pharmacol Ther

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“…Undoubtedly, bacteriophages are account for a main portion of virome in the human gut. Previous studies have demonstrated that the abundance of intestinal phages varied with different disease status (i.e., health or carcinoma) [28,58]. However, the consequences of change on phages in the gut remain poorly known.…”

Section: Discussionmentioning

confidence: 99%

“…Although several studies have considered the effects of different factors such as diet, age, geography and host genetics on structural variation of the gut microbiome [25,26], the effects of virus-bacteria interaction in the gut have been paid more and more attention by researchers [27]. Recently, the metagenome-wide association study of gut virome in CRC has demonstrated that virome profile differentiated individuals at healthy controls, early and late stages of CRC patients [28].Moreover, statistical comparison between gut phage and bacterial communities provide the evidences that there could be a close and dynamic relationship between these phages and bacterial population. Their significant correlation suggests that phages, to a certain extents, play roles in reshaping microbial ecosystems and consequently affect the health or disease status of the individuals.…”

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confidence: 99%

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confidence: 99%

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The virus integrations in gut microbes associated with dysbiosis of microbial community in tumorigenesis of colorectal carcinoma

Cui

Wang

et al. 2019

Preprint

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Patients with colorectal cancer (CRC) have a different gut microbial and viral communities from healthy individuals. But little is known about the ways and functions of interaction of virus-bacteria, let alone its correlation with the aetiology of CRC. In this study we aimed to identify the association between the genetic integration of virusbacteria and the expansion of some microbial population during tumorigenesis of human colorectum. Using a gut metagenomics sequencing data of healthy controls, advanced adenoma and carcinoma patients, to our knowledge, we demonstrate for the first time that the viral genetic integrations in gut microbes tend to occur in CRC patients and are potentially associated with the carcinogenesis. We found that almost all of the genetic integrations were happened between bacteriophages and bacteria, which could be influenced by the abundance of the phage communities. Importantly, the integrations of phage-carried positive effective genes offered selective advantages to the commensal and potential pathogenic bacteria, as a result, potentially led to a microbial dysbiosis along with the increasing bacterial diversity in carcinoma patients.Consequently, our work opens a new way to understand the carcinogenicity in complex intestinal ecosystems.Colorectal cancer (CRC) is among the top three most common cause of cancer mortality in the world. Most of the CRC cases are referred to as the order of adenoma-carcinoma that could progress into malignant forms [1][2][3]. The accumulation of genetic mutations for many years is the most important reason for the development of CRC, which is affected by many factors such as lifestyle and environment including the gut microbiota [4-6]. The human gut microbiome is composed of a large number of bacterial cells, along with a minority of virus, archaeal and eukaryotic cells, together forming a very complex intestinal microbial ecosystem [7]. The virus is primarily made up of bacteriophages and also includes rarer eukaryotic viruses and endogenous retroviruses [8-10].Accumulating data have demonstrated that the composition of gut microbiota in CRC patients are distinct from healthy individuals [11,12]. On the one hand, emerging evidences have indicated that several bacteria, such as Bacteroides fragilis [13], Fusobacterium nucleatum (F. nucleatum) [6,14] and a strain of Escherichia coli [4], are more abundant in the gut of CRC patients or CRC tissues and have been found to be associated with CRC development by promoting colorectal carcinogenesis. These microbes can accelerate carcinoma development through secretion of oncogenic virulence factors [15], generation of carcinogenic microbial metabolites [16,17] or recruitment of immune cells [18,19] and so on. On the other hand, an increasing number of studies suggest that the human intestinal microbiota contributes to CRC via the influence of the whole microbial community, especially the dysbiosis of the bacterial population that is a result of symbiotic, commensal, and pathobiont interactions among microorgan...

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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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Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes

Abstract: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.

Cited by 279 publications

References 81 publications

Review article: bacteriophages in gastroenterology—from biology to clinical applications

Review article: bacteriophages in gastroenterology—from biology to clinical applications

The virus integrations in gut microbes associated with dysbiosis of microbial community in tumorigenesis of colorectal carcinoma

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

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