With the strong evidence displayed by multi-direction proofs, the stomach cancer associated pathogenetic bacterium (Helicobactor pylori) has been identified and recognized internationally as the level one carcinogen. Likewise, with a more complicated microbial community covering the inner surface of the colon, this earlier discovery enlightens the researchers to seek for a similar pathogen to explain the initiation and development of CRC. To explore the possible role of microbiota in the etiology of CRC, the researchers first separate and culture several bacteria in various media. However, less supportive evidence can illustrate the role of microbiota in the CRC development. Along with an improvement in detection technology, more and more studies utilize the next sequencing technology to explore the candidate carcinogenetic pathogen in the gut among population with distinct differing disease phenotypes.
The first report that links the gut microbiota with CRC is published by Weisburger and his colleagues [
21]. Later, more and more studies confirm the relationships between pathogenetic bacteria and colorectal cancer. For example, infection with
Streptococcus bovis, a group of gram-positive cocci, has been reported to be a risky sign for colon tumors [
22]. Kostic and his team identify high enrichment of Fusobacteria sequence in colorectal carcinoma tissue using whole genome sequencing, and confirm the result in a large scale study of colorectal cancer tissue samples [
23]. Similarly, Enterotoxigenic
Bacteroides fragilis and
Fusobacterium nucletum are identified to be highly expressed in colorectal cancer tissue compared to the matched tissue, and
Fusobacterium nucletum is proved to be associated with high microsatellite instability [
24]. Our previous study also identifies a discrepancy in tissue-associated gut microbiota between colorectal cancer patients and healthy volunteers [
25]. In addition, mucosa-associated
E.coli belonging to the B2 phylogroup is found to be more prevalent in CRC tissues, and is identified to encode cyclomodulin which is vital for colon epithelia cell mutation [
26].To explore subsequently,
Fusobacterium nucleatum, which belongs to Fusobacteria, has been isolated from tumor tissue and proved to be invasive in the in-vitro experiments. In addition,
Fusobacterium nucleatum also has a positive correlation with lymph node metastasis in CRC [
27].Furthermore, Zhao and his colleagues study the stool samples of CRC patients in China, and found find that
Bacteroides fragilis,
Enterococcus,
Escherichia/Shigella,
Klebsiella,
Streptococcus, and
Peptostreptococcus display a higher relative abundance in CRC patients, while
Roseburia- and Lachnospiraceae-related OTUs dominat a high load in the healthy controls [
28]. In another study, researchers also compare stool samples and find that the CRC patients have a lower microbiota diversity and
Clostridia abundance, but a high abundance of
Fusobacterium and
Porphyromonas at genus level [
29]. The lumen and tissue microbiota are obviously different in microbial structure. In the tissue samples, beneficial microbes such as
Bifidobacterium,
Faecalibacterium, and
Blautia were are significantly reduced, while
Fusobacterium is enriched in the CRC patients [
30]. However, the stool samples show a significant different microbial landscape with
Paraprevotella,
Eubacterium, and several other bacteria enriched in CRC patients [
30]. Inflammation is also an important factor that contributed to CRC progress via gut microbiota. Arthur finds that
E.coli NC101 will increase the colon tumor load in AOM treated IL10
-/- mice. When he deletes the polyketide synthase (
pks) Genotoxic Island in
E.coli NC101, a significant decrease of tumor load and invasion capacity are observed [
31]. Clinical study also revealeds a close connection between
E.coli and advanced stages, and animal experiment shows a high tumor load under incubation with
E.coli [
32,
33]. To better understand adenoma-carcinoma sequence-related gut microbiota and functional genes, sequential continuous detection is performed in the stool samples. By metagenomic analysis, the researchers find that a total of 130,000 genes are different in any two-group comparison among the healthy, adenoma, and CRC patients [
34]. And further analysis including the diet pattern concludes that fruit and vegetable consumption are related to the healthy group, while high level of red meat consumption and C-reation protein are associated with the carcinoma phenotype. In addition to these findings, the study also show that sugar transporter and a couple of amino acids consist of histidine, lysine, methionine, cysteine, and leucine are enriched in the healthy when compared with adenoma or in adenoma in comparison with carcinoma patients. Despite the stool microbiota change, the architecture of gut microbiota is also altered in the tissue samples by the sequencing. By 16S ribosomal RNA sequencing, researchers identify that
Fusobacterium,
Parvimonas,
Gemella, and
Leptotrichia are enriched and anti-inflammatory
F. prausnitzii loses its abundance in early-stage colorectal cancer [
35]. Furthermore, current studies also demonstrates that the
Fusobacterium nucletum is strongly associated with CpG island methylator phenotype [
36]. A recent study explores the gut microbiota in matched tissue and stool samples, host genes, and immune system together. The results show that firstly the fecal microbiota only has partial similarity with the tissue microbiota. Then a new cluster set is proposed and named co-abundance groups (CAGs) which is similar to enterotypes, and identified decreased Bacteroidetes cluster 1 and Firmicutes cluster 1, also cluster 2 of Bacteroidetes and Firmicutes as well as pathogen and
Prevotella cluster in the colorectal cancer tissue community [
37]. The study also identifies that CAGs are also associated with human immune responses such as IL17a, myc, and STAT3.
To illustrate the relationships between CRC and gut microbiota, several typical rodent models which simulate the CRC development are also performed. In a dimethylhydrazine-induced model, a obvious separated lumen gut microbiota is observed [
38]. APC
min/+ mice raised in a germ-free environment display a reduced tumor load after that in the SPF condition [
39]. When the germ-free mice are delivered with gut microbiota from tumor burden mice, they display more and larger tumors. To verify that the increased tumor burden that appears in germ-free mice are derived from the harmful microbiota, antibiotics are applied to the receptor mice which, as a result, did slow down the carcinogenesis process [
40]. These experiments show us the critical role of gut microbiota in colorectal cancer and also plausible causality of gut microbiota for the rodent models. However, gut microbiota in the rodent models differ significantly from the human beings, so it is not certain whether the same ideal results will re-emerge in the human-derived gut microbiota. Nielson and his partners transplant human donor stool into the mice, and results show that the tumor burden is apparently associated with the gut microbiota structure at baseline in the germ-free mice [
41]. These results sufficiently confirm that dysbiosis in the gut is one of the reasons that caused colorectal cancer.