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Mucosal microbiome dysbiosis in gastric carcinogenesis.
Coker, OO, Dai, Z, Nie, Y, Zhao, G, Cao, L, Nakatsu, G, Wu, WK, Wong, SH, Chen, Z, Sung, JJY, et al
Gut. 2018;67(6):1024-1032
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Gastric cancer (GC) is the 4th most common cancer and a leading cause of cancer-related deaths worldwide. Infection with Helicobacter pylori is an important risk factor for GC and other changes in gastric microbial composition are thought to play role in gastric carcinogenesis. This observational study aimed to elucidate the microbial changes that are characteristic for the different stages of gastric tumor development. The authors found significant changes in microbial composition in stomach cancer patients compared to patients with pre-cancerous mucosal changes, with an increase of some and a depletion of other bacteria, in particular an increase in oral bacteria, which is also found in other gastrointestinal cancers. They also found that interactions between the depleted and enriched bacterial species progressively increased with progressing carcinogenesis. Whilst there was no difference in the diversity of bacteria between H. pylori-positive and negative samples, more bacterial interactions were observed in H. pylori-negative samples. The authors conclude that significant gastric dysbiosis can be seen in samples of stomach cancer patients, however, they point out that from their study it is impossible to tell whether the bacteria increased in GC are “drivers” or “passengers” of gastric carcinogenesis. Their call for more research focusses on using this knowledge to develop better diagnostic biomarkers, rather than using this information for prevention or treatment of stomach cancer.
Abstract
OBJECTIVES We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. DESIGN We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. RESULTS We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori-negative samples compared with H. pylori-positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. CONCLUSIONS In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis, D. pneumosintes, S. exigua, P. micra and S. anginosus in GC progression.
2.
Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes.
Nakatsu, G, Zhou, H, Wu, WKK, Wong, SH, Coker, OO, Dai, Z, Li, X, Szeto, CH, Sugimura, N, Lam, TY, et al
Gastroenterology. 2018;155(2):529-541.e5
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Whilst research shows that patients with colorectal cancer (CRC) have a different microbiome composition to those without, little is known about differences in the virome, the collection of viruses in and on the human body. The authors investigated the viromes of faecal samples of patients with CRC and found that the gut virome differed between CRC patients and controls. Differences were also seen between early and late stage CRC patients, and certain virome profiles were associated with disease prognosis. The authors conclude that these virome “signatures” associated with CRC may be used for diagnostic purposes and to predict outcomes.
Abstract
BACKGROUND & AIMS Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. METHODS We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. RESULTS The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10-6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. CONCLUSIONS 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.