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.
Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and ...mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in Apc
mice. In vitro assays and transmission electron microscopy revealed that P. anaerobius selectively adheres to CRC cell lines (HT-29 and Caco-2) compared to normal colonic epithelial cells (NCM460). We identified a P. anaerobius surface protein, putative cell wall binding repeat 2 (PCWBR2), which directly interacts with colonic cell lines via α
/β
integrin, a receptor frequently overexpressed in human CRC tumours and cell lines. Interaction between PCWBR2 and integrin α
/β
induces the activation of the PI3K-Akt pathway in CRC cells via phospho-focal adhesion kinase, leading to increased cell proliferation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. NF-κB in turn triggers a pro-inflammatory response as indicated by increased levels of cytokines, such as interleukin-10 and interferon-γ in the tumours of P. anaerobius-treated Apc
mice. Analyses of tumour-infiltrating immune cell populations in P. anaerobius-treated Apc
mice revealed significant expansion of myeloid-derived suppressor cells, tumour-associated macrophages and granulocytic tumour-associated neutrophils, which are associated with chronic inflammation and tumour progression. Blockade of integrin α
/β
by RGDS peptide, small interfering RNA or antibodies all impair P. anaerobius attachment and abolish P. anaerobius-mediated oncogenic response in vitro and in vivo. Collectively, we show that P. anaerobius drives CRC via a PCWBR2-integrin α
/β
-PI3K-Akt-NF-κB signalling axis and identify the PCWBR2-integrin α
/β
axis as a potential therapeutic target for CRC.
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.
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.
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.
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.
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The colorectal cancer (CRC) and polyps incidentally found in autopsies represent the lesions that have not actually caused problems throughout the lifetime and thus may not need to be removed during ...screening. This study aimed to investigate the prevalence of incidental CRC (iCRC) and polyps in autopsies of different populations. A systematic search was performed on 19 August 2022 to identify autopsy studies that provided data on prevalence of iCRC, adenomatous polyps, hyperplastic polyps, and/or all polyps combined. The prevalence was pooled with the random-effects model. Subgroup and multivariable meta-regression analyses were conducted to investigate the heterogeneity. Forty-three eligible studies including 59,656 autopsies were identified, with 94% conducted before 1990 when CRC screening was uncommon or not available. The pooled prevalence was 0.7% (95% confidence interval CI, 0.3–1.2%) for iCRC, 18.4% (95% CI, 13.3–24.1%) for adenomatous polyps, 16.4% (95% CI, 8.7–25.9%) for hyperplastic polyps, 26.3% (95% CI, 15.4–38.8%) for all polyps combined, and 29.9% (95% CI, 14.8–47.6%) for iCRC plus polyps. The prevalence of iCRC was higher (1.2%) in white-predominant populations but lower (0.4%) after excluding low-quality studies. Multivariable analyses showed that the prevalence of polyps was higher in white-predominant populations and higher-quality studies, increased with age, and showed a downward trend from “before 1975” through “after 1985”. In conclusion, the prevalence of iCRC in autopsies was not low, considering the average lifetime risk of CRC, while incidental polyps were common. Both varied greatly in different populations. These findings may have implications when weighing the benefits and harms of screening.
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.
There is a need for early detection of colorectal cancer (CRC) at precancerous-stage adenoma. Here, we identified novel faecal bacterial markers for diagnosing adenoma.
This study included 1012 ...subjects (274 CRC, 353 adenoma and 385 controls) from two independent Asian groups. Candidate markers were identified by metagenomics and validated by targeted quantitative PCR.
Metagenomic analysis identified '
' from a
sp.,
(
) and
(
) to be significantly enriched in adenoma. Faecal
and
were significantly increased from normal to adenoma to CRC (p<0.0001, linear trend by one-way ANOVA) in group I (n=698), which was further confirmed in group II (n=313; p<0.0001). Faecal
may perform better than
in distinguishing adenoma from controls (areas under the receiver operating characteristic curve (AUROCs)
=0.675 vs
=0.620, p=0.09), while
performed better in diagnosing CRC (AUROCs
=0.862 vs
=0.741, p<0.0001). At 78.5% specificity,
and
showed sensitivities of 48.3% and 33.8% for adenoma, and 62.1% and 77.8% for CRC, respectively. In a subgroup tested with faecal immunochemical test (FIT; n=642),
performed better than FIT in detecting adenoma (sensitivities for non-advanced and advanced adenomas of 44.2% and 50.8% by
(specificity=79.6%) vs 0% and 16.1% by FIT (specificity=98.5%)). Combining with FIT improved sensitivity of
for advanced adenoma to 56.8%. The combination of
with
,
,
and FIT performed best for diagnosing CRC (specificity=81.2% and sensitivity=93.8%).
This study identifies a novel bacterial marker
for the non-invasive diagnosis of colorectal adenoma.
Emerging evidence suggests that long non-coding RNA (lncRNA) plays important roles in the regulation of gene expression. We determine the role of using urinary lncRNA as a non-invasive biomarker for ...lupus nephritis.
We studied three cohorts of lupus nephritis patients (31, 78, and 12 patients, respectively) and controls (6, 7, and 24 subjects, respectively). The urinary sediment levels of specific lncRNA targets were studied using real-time quantitative polymerase chain reactions.
The severity of proteinuria inversely correlated with urinary maternally expressed gene 3 (MEG3) (r = -0.423,
= 0.018) and ANRIL levels (r = -0.483,
= 0.008). Urinary MEG3 level also inversely correlated with the SLEDAI score (r = -0.383,
= 0.034). Urinary cancer susceptibility candidate 2 (CASC2) levels were significantly different between histological classes of nephritis (
= 0.026) and patients with pure class V nephritis probably had the highest levels, while urinary metastasis-associated lung carcinoma transcript 1 (MALAT1) level significantly correlated with the histological activity index (r = -0.321,
= 0.004). Urinary taurine-upregulated gene 1 (TUG1) level was significantly lower in pure class V lupus nephritis than primary membranous nephropathy (
= 0.003) and minimal change nephropathy (
= 0.04), and urinary TUG1 level correlated with eGFR in class V lupus nephritis (r = 0.706,
= 0.01).
We identified certain urinary lncRNA targets that may help the identification of lupus nephritis and predict the histological class of nephritis. Our findings indicate that urinary lncRNA levels may be developed as biomarkers for lupus nephritis.
To investigate the relationship between disease-related parameters and joint space width (JSW) on high-resolution peripheral quantitative computed tomography (HR-pQCT) in psoriatic arthritis (PsA) ...patients.
PsA patients who underwent HR-pQCT examination of the second to fourth metacarpophalangeal joint (MCPJ 2-4) were recruited in this cross-sectional study. The joint space metrics included joint space volume (JSV), mean, minimum, and maximum JSW, JSW asymmetry, and distribution. Correlation analysis and multivariable linear regression models were used to determine the association between disease-related variables and JSW.
Sixty-seven patients 37 (55.2%) males; median (IQR) age: 57.0 (53.0, 63.0); median disease duration: 21 (16, 28) years were included in this analysis. Multivariable linear regression analysis demonstrated that males had larger JSV (MCPJ 2-4), mean (MCPJ 4), and maximum JSW (MCPJ 3). Longer disease duration (MCPJ 2-3) and higher ESR values (MCPJ 3) were negatively associated with mean and maximum JSW, while higher damage joint count was negatively associated with mean and minimum JSW (MCPJ 2). Use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) was negatively associated with minimum JSW (MCPJ 3) while use of biologic DMARDs (bDMARDs) was positively associated with minimum JSW (MCPJ 2).
Higher inflammatory burden as reflected by longer disease duration, higher ESR levels, and damage joint count was negatively associated with mean, maximum, and minimum JSW, while suppression of inflammation using bDMARDs seems to limit the decline in JSW.
Objective
This study aimed to evaluate the short-term patient satisfaction, compliance, disease control, and infection risk of telemedicine (TM) compared with standard in-person follow-up (FU) for ...patients with lupus nephritis (LN) during the COVID-19 pandemic.
Method
This was a single-center open-label randomized controlled study. Consecutive patients followed at the LN clinic were randomized to either TM or standard FU (SF) group in a 1:1 ratio. Patients in the TM group received FU via videoconferencing. SF group patients continued conventional in-person outpatient care. The 6-month data were compared and presented.
Results
From June to December 2020, 122 patients were randomized (TM: 60, SF: 62) and had at least 2 FUs. There were no baseline differences, including SLEDAI-2k and proportion of patients in lupus low disease activity state (LLDAS), between the two groups except a higher physician global assessment score (PGA) in the TM group. After a mean FU of 19.8 ± 4.5 weeks, the overall patient satisfaction score was higher in the TM group. More patients in the TM group had hospitalization (15/60, 25.0% vs 7/62, 11.3%; p = .049) with higher baseline PGA (OR = 1.17; 95% CI, 1.08–1.26) being the independent predictor. The proportions of patients remained in LLDAS were similar in the two groups (TM: 75.0% vs SF: 74.2%, p = .919). None of the patients had COVID-19.
Conclusions
TM FU resulted in better patient satisfaction and similar short-term disease control in patients with LN compared to standard care. However, it was associated with more hospitalizations and might need to be complemented by in-person visits especially in patients with higher PGA.
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