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

Abstract

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.

Albuca Bracteata Polysaccharides Attenuate AOM/DSS Induced Colon Tumorigenesis via Regulating Oxidative Stress, Inflammation and Gut Microbiota in Mice

“…The heat map and LEfSe analysis showed that ABP decreased the relative abundance of some potentially pathogenic bacteria ( g_Streptococcus, g_Proteus, g_Corynebacterium, g_Anaeroplasma, g_Acinetobacter, and g_Ralstonia ) ( Wu et al, 2018 ; Liu et al, 2019 ; Xia X. et al, 2020 ; Zorron Cheng Tao Pu et al, 2020 ; Marongiu et al, 2021 ; Zhang et al, 2021 ). GC-MS results revealed that ABP increased the levels of SCFAs in AOM/DSS induced CAC mice.…”

Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial)

“…The biological heterogeneity of CRLM arises from different clones of cancer cells with their own genomic profile [ 30 ]. However, this evolution could be modulated by the effect of host factors and external influences such as diet, tumor immune microenvironment [ 21 , 31 ], cancer and gut microbiome [ 32 , 33 ], and systemic treatment [ 21 , 28 , 31 ]. A retrospective study [ 34 ] on 73 patients with multiple CRLM ( n = 300) reported an association between bevacizumab treatment and homogeneous pathological response.…”

Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia

“…Interestingly, inflammation has been noted to supply bioactive molecules (growth factors, survival factors, and extracellular-modifying enzymes) to the tumor microenvironment to allow angiogenesis, invasion, and metastasis of the tumor [ 128 , 206 , 207 , 208 ]. Marongiu et al [ 209 ] described how phage-induced bacteriolysis drives inflammation through the release of cellular debris into the microenvironment. This change in the microenvironment is followed by a pathogen-associated molecular pattern to further stimulate the immune environment.…”

“…Marongiu et al [ 209 ], in a metagenomic analysis of primary colorectal carcinomas and their metastases, analyzed whole-genome sequences of CRC primary tumors and their corresponding metastasis sites for sequences of viral, phage, and bacterial species. While multiple bacterial species were shown to be enriched at the primary tumor, only enrichment of E. coli strains was observed in metastasis sites.…”

“…Few published experiments include other sites besides the liver to draw comparisons between the tumor microenvironments and bacterial colonization after colorectal cancer metastasis, likely because the liver is by far the most common site of metastasis. Marongiu et al [ 209 ] found no bacterial species in lung metastases of CRC. However, a relationship between gut microbiome dysbiosis and lung cancer has been established [ 232 ], suggesting that similar mechanisms may be at play.…”