The effects of pks+ Escherichia coli and bile acid in colorectal tumorigenesis among people with cholelithiasis or cholecystectomy.

BACKGROUND AND AIM: Patients with cholelithiasis (CL) or cholecystectomy (CE) would have more chances of getting colorectal adenoma (CRA) or cancer (CRC). We aimed to figure out the effects of gut microbiota and bile acid on colorectal neoplasm in CL and CE patients. METHODS: This was a retrospective observational study that recruited 514 volunteers, including 199 people with normal gallbladders (normal), 152 CL, and 163 CE patients. Discovery cohort was established to explore the difference in gut microbiota through 16S rRNA and metagenomics sequencing. Validation cohort aimed to verify the results through quantitative polymerase chain reaction (qPCR). RESULTS: Significant enrichment of Escherichia coli was found in patients with cholelithiasis or cholecystectomy both in the discovery cohort (16S rRNA sequencing, PNormal-CL = 0.013, PNormal-CE = 0.042; metagenomics sequencing, PNormal-CE = 0.026) and validation cohort (PNormal-CL < 0.0001, PNormal-CE < 0.0001). Pks+ E. coli was found enriched in CL and CE patients through qPCR (in discovery cohort: PNormal-CE = 0.018; in validation cohort: PNormal-CL < 0.0001, PNormal-CE < 0.0001). The differences in bile acid metabolism were found both through Tax4Fun analysis of 16S rRNA sequencing (Ko00120, primary bile acid biosynthesis, PNormal-CE = 0.014; Ko00121, secondary bile acid biosynthesis, PNormal-CE = 0.010) and through metagenomics sequencing (map 00121, PNormal-CE = 0.026). The elevation of serum total bile acid of CE patients was also found in validation cohort (PNormal-CE < 0.0001). The level of serum total bile acid was associated with the relative abundance of pks+ E. coli (r = 0.1895, P = 0.0012). CONCLUSIONS: E. coli, especially pks+ species, was enriched in CL and CE patients. Pks+ E. coli and bile acid metabolism were found associated with CRA and CRC in people after cholecystectomy.

Risk of colorectal cancer after appendectomy: A systematic review and meta-analysis.

BACKGROUND AND AIM: Appendectomy is associated with various diseases, but whether it increases the risk of colorectal cancer (CRC) remains uncertain. We conducted a systematic review and meta-analysis aimed at investigating the suggested correlation between appendectomy and CRC. METHODS: Systematic retrieval was performed using the PubMed, Embase, Cochrane library, Web of Science, and ClinicalTrials.gov databases up to May 4, 2022, for studies reported the influence of appendectomy on CRC, colon cancer (CC) or rectal cancer (RC). Odd ratios (ORs) and 95% confidence intervals (CIs) of CRC after appendectomy were pooled using the random effects model. Subgroup analyses were carried on by region, sex, and tumor location. RESULTS: Our search identified 1743 articles, of which 22 studies from three continents published between 1964 and 2022 were eligible for inclusion. Overall, people with appendectomy had a higher risk of CRC (OR = 1.31; 95% CI [1.05, 1.62]). But the risk for Europeans was not significant (OR = 0.94; 95% CI [0.87, 1.02]; I2  = 0%), while for Americans and Asians, appendectomy would increase the risk of CRC (OR = 1.68; 95% CI [1.15, 2.44]; I2  = 65% and OR = 1.46; 95% CI [1.04, 2.05]; I2  = 98%), especially in females and in developing countries. It is worth noting that appendectomy might be a protective factor for CC in European women (OR = 0.87; 95% CI [0.77, 0.98]; I2  = 0%). CONCLUSIONS: Appendectomy may be a risk factor for CRC, with varying degrees in different populations. More high-quality cross-regional studies are needed for better clinical decision making.

Peptidoglycan Recognition Protein 1 Attenuates Atherosclerosis by Suppressing Endothelial Cell Adhesion.

ABSTRACT: Peptidoglycan recognition protein 1 (PGLYRP1) has long been believed to play an important role in infectious and immune diseases. We hypothesized that it might be involved in the pathophysiology of atherosclerotic diseases, which are regarded as chronic inflammatory diseases. Serum PGLYRP1 concentrations were measured in 240 patients with coronary artery disease (CAD) and 209 age-matched and gender-matched individuals with normal coronary arteries using enzyme-linked immunosorbent assay. The expression of PGLYRP1 in atherosclerotic plaques was quantified using western blotting and immunostaining. ApoE-/- mice, fed a high-fat diet, were randomly given intraperitoneal injections of saline or recombinant PGLYRP1 protein for 12 weeks. The effects of PGLYRP1 on human umbilical vein endothelial cells were investigated by western blotting. Higher concentrations of PGLYRP1 were significantly associated with a higher risk of CAD. The odd ratio for upper quartile versus lower quartile was 2.24 (95% confidence interval: 1.21-4.13) after adjustment for sex, age, smoking, body mass index, lipid profile, blood pressure, fasting glucose, and estimated glomerular filtration rate. PGLYRP1 was highly expressed in murine atherosclerotic plaques. Recombinant PGLYRP1 protein alleviated the progress of atherosclerosis in vivo and reduced the expression of endothelial cells' adhesion molecules in vitro. In conclusion, our study suggested that PGLYRP1 is upregulated in patients with CAD and atherosclerotic plaques. PGLYRP1 may participate in the pathophysiological process of atherosclerosis.

Oxidized low-density lipoprotein promotes macrophage lipid accumulation via the toll-like receptor 4-Src pathway.

BACKGROUND: Uptake of oxidized low-density lipoprotein (oxLDL) by macrophages is recognized as a crucial step in the development of atherosclerosis, whereas the precise molecular mechanisms involving it remain to be elucidated. METHODS AND RESULTS: This study focused on determining the role of toll-like receptor 4 (TLR4) and Src kinase in macrophage lipid accumulation. oxLDL significantly enhanced Src kinase activity and intracellular lipid contents in RAW264.7 macrophages, whereas the small interference RNA-mediated knockdown of TLR4 and Src or chemical inhibition of Src activity blocked oxLDL-induced lipid accumulation. Immunoprecipitation and immunofluorescence studies demonstrated that TLR4 was associated with Src on the plasma membrane upon oxLDL stimulation. CONCLUSIONS: The results of the present study suggest an essential role of TLR4-Src signaling in macrophages in the pathogenesis of atherosclerosis.

BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism.

Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.

Differences in D-dimer blood concentration in atrial fibrillation patients with left atrial thrombus or severe left atrial spontaneous echo contrast.

PURPOSE: Severe left atrial spontaneous echo contrast (SLASEC) is considered the prior stage to thrombosis and a high-risk factor for thrombotic events. Studies have suggested an effect of D-dimer blood concentration on exclusion of left atrial thrombus (LAT), but it remains unclear whether D-dimer concentrations differ between atrial fibrillation (AF) patients with SLASEC or LAT. METHODS: Nonvalvular AF patients scheduled to undergo catheter ablation or cardioversion in Shanghai Ruijin Hospital between January 2017 and July 2020 were screened for this prospective study. All patients underwent transesophageal echocardiography (TEE) to detect SLASEC or LAT. D-dimer concentrations were measured at the time of TEE. Clinical data including CHA2DS2-VASc score were evaluated. Major complications with thromboembolism in the SLASEC group were followed up at least 6 months after therapy. RESULTS: Among 920 consecutively enrolled nonvalvular AF patients, 30 patients with SEC grade 0, 35 patients with SLASEC, and 22 patients with LAT were included. D-dimer concentration and CHA2DS2-VASc score were significantly lower in the SLASEC group compared with the LAT group (D-dimer, 0.26±0.13 vs. 0.86±0.9 mg/L, P<0.05; CHA2DS2-VASc score, 2.3±0.9 vs. 3.1±1.5, P=0.02). The cut-off value for D-dimer concentration (0.285 mg/L) had sensitivity of 77.3% and specificity of 80.0% for prediction of LAT. D-dimer concentration showed a decreasing trend with a significant difference (0.42±0.22 vs. 0.33±0.18 mg/L, P=0.03) for 9 patients in the LAT group after complete thrombus resolution by anticoagulation treatment. No major or fatal bleeding, ischemic stroke, or systemic thromboembolism events occurred in the SLASEC group during the 6-month follow-up. CONCLUSIONS: This study demonstrated a significantly lower D-dimer concentration and CHA2DS2-VASc score in AF patients with SLASEC than in those with LAT. The D-dimer cut-off value (0.285 mg/L) can be used as an effective reference index to distinguish the pre-thrombotic state of LAT from LAT. D-dimer blood concentration may be a predictor of LAT thrombolysis.