Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites.
HFD or ...control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography–mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy.
HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet–fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression.
HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.
High-fat diet drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated oncogenic lysophosphatidic acid, and gut epithelial barrier impairment in mice.
The detection of molecular markers in stool samples is a potential strategy for colorectal cancer (CRC) screening. This study evaluated the feasibility of detecting miR-21 and miR-92a in stool ...samples of patients with CRC or polyps.
The reproducibility of detection and stability of stool-based microRNA were evaluated. Stool samples were collected from 88 patients with CRC, 57 patients with colorectal polyps and 101 healthy controls. MiRNA levels in CRC tissues and stool samples were detected by real-time quantitative reverse transcription PCR. Stool miR-21 and miR-92a levels were compared before and after the removal of tumour or advanced adenoma.
The study demonstrated that stool-based miRNA were stable with highly reproducible detection. The expression of miR-21 and miR-92a was significantly higher in CRC tissues compared with their adjacent normal tissues (p<0.0001). Patients with CRC had a significantly higher stool miR-21 level (p<0.01) and miR-92a level (p<0.0001) compared with normal controls. Stool miR-92a, but not miR-21, was significantly higher in patients with polyps than in controls (p<0.0001). At a cut-off value of 435 copies/ng of stool RNA, miR-92a had a sensitivity of 71.6% and 56.1% for CRC and polyp, respectively, and a specificity of 73.3%. In addition, the stool miR-92a level demonstrated a higher sensitivity for distal CRC than proximal CRC (p<0.05), and a higher sensitivity for advanced adenoma than minor polyps (p<0.05). Removal of tumour resulted in reduced stool miR-21 and miR-92a levels (p<0.01), and the removal of advanced adenoma resulted in a reduction of the stool miR-92a level (p<0.05).
Stool miRNA are useful for screening CRC and polyps.
Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because discrepant results have been reported in different ethnic groups.
To determine whether intravenous ...esomeprazole prevents recurrent peptic ulcer bleeding better than placebo in a multiethnic patient sample.
Randomized trial conducted between October 2005 and December 2007; patients, providers, and researchers were blinded to group assignment.
91 hospital emergency departments in 16 countries.
Patients 18 years or older with peptic ulcer bleeding from a single gastric or duodenal ulcer showing high-risk stigmata.
Intravenous esomeprazole bolus, 80 mg, followed by 8-mg/h infusion, over 72 hours or matching placebo, each given after successful endoscopic hemostasis. Intervention was allocated by computer-generated randomization. After infusion, both groups received oral esomeprazole, 40 mg/d, for 27 days.
The primary end point was rate of clinically significant recurrent bleeding within 72 hours. Recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety were also assessed.
Of 767 patients randomly assigned, 764 provided data for an intention-to-treat analysis (375 esomeprazole recipients and 389 placebo recipients). Fewer patients receiving intravenous esomeprazole (22 of 375) had recurrent bleeding within 72 hours than those receiving placebo (40 of 389) (5.9% vs. 10.3%; difference, 4.4 percentage points 95% CI, 0.6% to 8.3%; P = 0.026). The difference in bleeding recurrence remained significant at 7 days and 30 days (P = 0.010). Esomeprazole also reduced endoscopic re-treatment (6.4% vs. 11.6%; difference, 5.2 percentage points 95% CI of difference, 1.1 percentage points to 9.2 percentage points; P = 0.012), surgery (2.7% vs. 5.4%), and all-cause mortality rates (0.8% vs. 2.1%) more than placebo, although differences for the latter 2 comparisons were not significant. About 10% and 40% of patients in both groups reported serious and nonserious adverse events, respectively.
Endoscopic therapy was not completely standardized; some patients received epinephrine injection, thermal coagulation, or hemoclips alone, whereas others received combination therapy, but there were similar proportions with single therapy in each group.
High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days.
AstraZeneca Research and Development.
is associated with gastric inflammation, precancerous gastric atrophy (GA) and intestinal metaplasia (IM). We aimed to identify microbes that are associated with progressive inflammation, GA and IM 1 ...year after
eradication.
A total of 587
-positive patients were randomised to receive
eradication therapy (295 patients) or placebo (292 patients). Bacterial taxonomy was analysed on 404 gastric biopsy samples comprising 102 pairs before and after 1 year
eradication and 100 pairs before and after 1 year placebo by 16S rRNA sequencing.
Analysis of microbial sequences confirmed the eradication of
in treated group after 1 year. Principal component analysis revealed distinct microbial clusters reflected by increase in bacterial diversity (p<0.00001) after
eradication. While microbial interactions remained largely unchanged after placebo treatment, microbial co-occurrence was less in treated group.
,
and
were enriched while
and
were depleted in patients with persistent inflammation 1 year after
eradication. A distinct cluster of oral bacteria comprising
,
,
,
and
were associated with emergence and persistence of GA and IM. Probiotic
was depleted in subjects who developed GA following
eradication. Functional pathways including amino acid metabolism and inositol phosphate metabolism were enriched while folate biosynthesis and NOD-like receptor signalling decreased in atrophy/IM-associated gastric microbiota.
This study identified that gastric microbes contribute to the progression of gastric carcinogenesis after
eradication.
Living in an urban environment may increase the risk of developing inflammatory bowel disease (IBD). It is unclear if this observation is seen globally. We conducted a population-based study to ...assess the relationship between urbanization and incidence of IBD in the Asia-Pacific region.
Newly diagnosed IBD cases between 2011 and 2013 from 13 countries or regions in Asia-Pacific were included. Incidence was calculated with 95% confidence interval (CI) and pooled using random-effects model. Meta-regression analysis was used to assess incidence rates and their association with population density, latitude, and longitude.
We identified 1175 ulcerative colitis (UC), 656 Crohn's disease (CD), and 37 IBD undetermined (IBD-U). Mean annual IBD incidence per 100 000 was 1.50 (95% CI: 1.43-1.57). India (9.31; 95% CI: 8.38-10.31) and China (3.64; 95% CI, 2.97-4.42) had the highest IBD incidence in Asia. Incidence of overall IBD (incidence rate ratio IRR: 2.19; 95% CI: 1.01-4.76) and CD (IRR: 3.28; 95% CI: 1.83-9.12) was higher across 19 areas of Asia with a higher population density. In China, incidence of IBD (IRR: 2.37; 95% CI: 1.10-5.16) and UC (IRR: 2.63; 95% CI: 1.2-5.8) was positively associated with gross domestic product. A south-to-north disease gradient (IRR: 0.94; 95% CI: 0.91-0.98) was observed for IBD incidence and a west-to-east gradient (IRR: 1.14; 95% CI: 1.05-1.24) was observed for CD incidence in China. This study received IRB approval.
Regions in Asia with a high population density had a higher CD and UC incidence. Coastal areas within China had higher IBD incidence. With increasing urbanization and a shift from rural areas to cities, disease incidence may continue to climb in Asia.
TGF-β/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific ...genes. In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy. In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction. In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-β(1)-induced downregulation of miR-29 by binding to the promoter of miR-29. Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-β/Smad3-mediated fibrosis. In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-β(1)-induced expression of collagens I and III by renal tubular cells. Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis. In conclusion, miR-29 is a downstream inhibitor of TGF-β/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis.
Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models ...of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic‐ and asparagine‐ treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS‐induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.—Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.‐F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J. 32, 37‐51 (2018). www.fasebj.org
In this randomized study of patients with upper gastrointestinal bleeding, infusion of omeprazole, as compared with placebo, before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. ...28.4%, P=0.007) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases. These findings suggest that infused omeprazole is beneficial for patients with upper gastrointestinal bleeding who are awaiting endoscopy.
In patients with upper gastrointestinal bleeding, infusion of omeprazole before endoscopy reduced the incidence of endoscopic treatment (19.1% vs. 28.4%) and, among patients with peptic ulcers, resulted in fewer actively bleeding ulcers and more ulcers with clean bases.
In patients with bleeding peptic ulcers, we previously showed that infusion of a high-dose proton-pump inhibitor after hemostasis had been achieved during endoscopy reduced recurrent bleeding and improved clinical outcomes.
1
The adjuvant use of high-dose proton-pump inhibitors in endoscopic therapy has also been endorsed in two consensus statements
2
,
3
and confirmed in two meta-analyses.
4
,
5
Clot formation over arteries is pH dependent; a gastric pH above 6 is thought to be critical for platelet aggregation.
6
When given intravenously and at a high dose, proton-pump inhibitors can be used to maintain a neutral gastric pH.
7
In clinical practice, treatment with proton-pump . . .
Yes-associated protein 1 (YAP1) is a multifunctional protein that can interact with different transcription factors to activate gene expression. The role of YAP1 in tumorigenesis is unclear. We aimed ...to investigate the functional role of YAP1 in tumorigenesis of gastric cancer.
YAP1 expression in gastric adenocarcinoma was evaluated. The biological function was determined by proliferation assay, colony formation, cell invasion, and flow cytometric analysis through knocking down or ectopic expressing YAP1 in gastric cancer cell lines coupled with in vivo study. The possible downstream effectors of YAP1 were investigated by expression microarray.
YAP1 protein expression was upregulated in gastric cancer. Nuclear accumulation of YAP1 was associated with poor disease-specific survival (P = 0.021), especially in patients with early-stage diseases (P < 0.001). Knockdown YAP1 resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion, and cell motility. Ectopic YAP1 expression promoted anchorage-independent colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK (mitogen-activated protein kinase) pathway by YAP1. We confirmed a constitutive activation of RAF/MEK/ERK (extracellular signal-regulated kinase) in YAP1-expressing MKN45 cells and further showed that YAP1 enhanced serum/epidermal growth factor-induced c-Fos expression in gastric cancer cells.
Our findings supported that YAP1 exhibits oncogenic property in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early-response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer.
The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in ...Asia-Pacific examined risk factors prior to patients developing IBD.
442 incident cases (186 Crohn's disease (CD); 256 UC; 374 Asians) diagnosed between 2011 and 2013 from eight countries in Asia and Australia and 940 controls (frequency-matched by sex, age and geographical location; 789 Asians) completed an environmental factor questionnaire at diagnosis. Unconditional logistic regression models were used to estimate adjusted ORs (aOR) and 95% CIs.
In multivariate model, being breast fed >12 months (aOR 0.10; 95% CI 0.04 to 0.30), antibiotic use (aOR 0.19; 0.07 to 0.52), having dogs (aOR 0.54; 0.35 to 0.83), daily tea consumption (aOR 0.62; 0.43 to 0.91) and daily physical activity (aOR 0.58; 0.35 to 0.96) decreased the odds for CD in Asians. In UC, being breast fed >12 months (aOR 0.16; 0.08 to 0.31), antibiotic use (aOR 0.48; 0.27 to 0.87), daily tea (aOR 0.63; 0.46 to 0.86) or coffee consumption (aOR 0.51; 0.36 to 0.72), presence of hot water tap (aOR 0.65; 0.46 to 0.91) and flush toilet in childhood (aOR 0.71; 0.51 to 0.98) were protective for UC development whereas ex-smoking (aOR 2.02; 1.22 to 3.35) increased the risk of UC.
This first population-based study of IBD risk factors in Asia-Pacific supports the importance of childhood immunological, hygiene and dietary factors in the development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.
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