We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis.
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.
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
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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
-negative samples compared with
-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.
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
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in GC progression.
Gut microbiota contributes to colorectal cancer (CRC) pathogenesis through microbes and their metabolites. The importance of microbiota-associated metabolites in colorectal carcinogenesis highlights ...the need to investigate the gut metabolome along the adenoma-carcinoma sequence to determine their mechanistic implications in the pathogenesis of CRC. To date, how and which microbes and metabolites interactively promote early events of CRC development are still largely unclear. We aim to determine gut microbiota-associated metabolites and their linkage to colorectal carcinogenesis.
We performed metabolomics and metagenomics profiling on fecal samples from 386 subjects including 118 CRC patients, 140 colorectal adenomas (CRA) patients and 128 healthy subjects as normal controls (NC). We identified differences in the gut metabolite profiles among NC, CRA and CRC groups by partial least squares-discriminant and principal component analyses. Among the altered metabolites, norvaline and myristic acid showed increasing trends from NC, through CRA, to CRC. CRC-associated metabolites were enriched in branched-chain amino acids, aromatic amino acids and aminoacyl-tRNA biosynthesis pathways. Moreover, metabolites marker signature (twenty metabolites) classified CRC from NC subjects with an area under the curve (AUC) of 0.80, and CRC from CRA with an AUC of 0.79. Integrative analyses of metabolomics and metagenomics profiles demonstrated that the relationships among CRC-associated metabolites and bacteria were altered across CRC stages; certain associations exhibited increasing or decreasing strengths while some were reversed from negative to positive or vice versa. Combinations of gut bacteria with the metabolite markers improved their diagnostic performances; CRC vs NC, AUC: 0.94; CRC vs CRA, AUC 0.92; and CRA vs NC, AUC: 0.86, indicating a potential for early diagnosis of colorectal neoplasia.
This study underscores potential early-driver metabolites in stages of colorectal tumorigenesis. The Integrated metabolite and microbiome analysis demonstrates that gut metabolites and their association with gut microbiota are perturbed along colorectal carcinogenesis. Fecal metabolites can be utilized, in addition to bacteria, for non-invasive diagnosis of colorectal neoplasia. Video Abstract.
Alterations of gut microbiota are associated with colorectal cancer (CRC) in different populations and several bacterial species were found to contribute to the tumorigenesis. The potential use of ...gut microbes as markers for early diagnosis has also been reported. However, cohort specific noises may distort the structure of microbial dysbiosis in CRC and lead to inconsistent results among studies. In this regard, our study targeted at exploring changes in gut microbiota that are universal across populations at species level.
Based on the combined analysis of 526 metagenomic samples from Chinese, Austrian, American, and German and French cohorts, seven CRC-enriched bacteria (Bacteroides fragilis, Fusobacterium nucleatum, Porphyromonas asaccharolytica, Parvimonas micra, Prevotella intermedia, Alistipes finegoldii, and Thermanaerovibrio acidaminovorans) have been identified across populations. The seven enriched bacterial markers classified cases from controls with an area under the receiver-operating characteristics curve (AUC) of 0.80 across the different populations. Abundance correlation analysis demonstrated that CRC-enriched and CRC-depleted bacteria respectively formed their own mutualistic networks, in which the latter was disjointed in CRC. The CRC-enriched bacteria have been found to be correlated with lipopolysaccharide and energy biosynthetic pathways.
Our study identified potential diagnostic bacterial markers that are robust across populations, indicating their potential universal use for non-invasive CRC diagnosis. We also elucidated the ecological networks and functional capacities of CRC-associated microbiota.
Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA ...gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria.
Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice.
Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria. Video abstract.
The gastrointestinal tract houses millions of microbes collectively referred to as the gut microbiome. The gut microbes comprise of bacteria, viruses, fungi, archaea, and microscopic eukaryotes, ...which co‐evolved or colonize the gut forming complex symbiotic and mutualistic relationships. A state of homeostasis is required between host and gut microbiome relationship to maintain several host beneficial processes. Alterations in the taxonomic and functional composition of the gut microbes are associated with several human diseases including gastrointestinal cancers. Owed to their overwhelming abundance and ease of characterization, several studies focus on the role of bacteria in gastrointestinal cancers. There is however growing evidence that non‐bacteria gut microbes are associated with the pathogenesis of gastrointestinal cancers. This review details the association of non‐bacteria gut microbes including fungi, viruses, and archaea and their potential manipulation in the prevention and treatment of human gastrointestinal cancers.
Sepsis is a life-threatening illness caused by the dysregulated host response to infection. Nevertheless, our current knowledge of the microbial landscape in the blood of septic patients is still ...limited. Next-generation sequencing (NGS) is a sensitive method to quantitatively characterize microbiomes at various sites of the human body. In this study, we analyzed the blood microbial DNA of 22 adult patients with sepsis and 3 healthy subjects. The presence of non-human DNA was identified in both healthy and septic subjects. Septic patients had a markedly altered microbial DNA profile compared to healthy subjects over α- and β-diversity. Unexpectedly, the patients could be further divided into two subgroups (C1 and C2) based on β-diversity analysis. C1 patients showed much higher bacteria, viruses, fungi, and archaea abundance, and a higher level of α-diversity (Chao1, Observed and Shannon index) than both C2 patients and healthy subjects. The most striking difference was seen in the case of Streptomyces violaceusniger, Phenylobacterium sp. HYN0004, Caulobacter flavus, Streptomyces sp. 11-1-2, and Phenylobacterium zucineum, the abundance of which was the highest in the C1 group. Notably, C1 patients had a significantly poorer outcome than C2 patients. Moreover, by analyzing the patterns of microbe-microbe interactions in healthy and septic subjects, we revealed that C1 and C2 patients exhibited distinct co-occurrence and co-exclusion relationships. Together, our study uncovered two distinct microbial signatures in the blood of septic patients. Compositional and ecological analysis of blood microbial DNA may thus be useful in predicting mortality of septic patients.
The gastrointestinal tract represents one of the largest interfaces between the host and environmental factors. It contains a vast and complex community of microbes, forming what is collectively ...known as the microbiota. This gut microbiota plays a pivotal role in the maintenance of health, and 'dysbiosis' of the gut microbiota, commonly considered as perturbation of microbiota diversity and composition, has been associated with intestinal and extra-intestinal diseases, including non-alcoholic fatty liver disease (NAFLD) and its associated hepatocellular carcinoma (NAFLD-HCC).
In this review, we highlight microbiota dysbiosis and the microbiota-host interactions that link to the pathogenesis of NAFLD and NAFLD-HCC. We discuss the potential therapeutic implications of the gut microbiota in the progression of NAFLD-HCC.
•Gut microbiota plays a mechanistic role in non-alcoholic fatty liver disease (NAFLD). .•Gut microbiota profile is associated with HCC development in NAFLD patients.•Microbe-generated metabolites contribute to NAFLD and NAFLD-HCC pathogenesis. .•Host immune response is involved in gut microbiota-regulated NAFLD and NAFLD-HCC. .•Gut microbiota acts as a potential therapeutic target for NAFLD.
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