Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis.

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

Deficiency of immunoglobulin IgSF6 enhances antibacterial effects by promoting endoplasmic reticulum stress and the inflammatory response in intestinal macrophages.

Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. Igsf6 expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking Igsf6 displayed resistance to Salmonella typhimurium challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of Igsf6 enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of Igsf6 deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.

Combination of PI-RADS score and PSAD can improve the diagnostic accuracy of prostate cancer and reduce unnecessary prostate biopsies.

Objectives: The purpose of this study is to evaluate the diagnostic accuracy of the clinical variables of patients with prostate cancer (PCa) and to provide a strategy to reduce unnecessary biopsies. Patients and methods: A Chinese cohort that consists of 833 consecutive patients who underwent prostate biopsies from January 2018 to April 2022 was collected in this retrospective study. Diagnostic ability for total PCa and clinically significant PCa (csPCa) was evaluated by prostate imaging-reporting and data system (PI-RADS) score and other clinical variables. Univariate and multivariable logistic regression analyses were performed to figure out the independent predictors. Diagnostic accuracy was estimated by plotting receiver operating characteristic curves. Results: The results of univariate and multivariable analyses demonstrated that the PI-RADS score (P < 0.001, OR: 5.724, 95% CI: 4.517-7.253)/(P < 0.001, OR: 5.199, 95% CI: 4.039-6.488) and prostate-specific antigen density (PSAD) (P < 0.001, OR: 2.756, 95% CI: 1.560-4.870)/(P < 0.001, OR: 4.726, 95% CI: 2.661-8.396) were the independent clinical factors for predicting total PCa/csPCa. The combination of the PI-RADS score and PSAD presented the best diagnostic performance for the detection of PCa and csPCa. For the diagnostic criterion of "PI-RADS score ≥ 3 or PSAD ≥ 0.3", the sensitivity and negative predictive values were 94.0% and 93.1% for the diagnosis of total PCa and 99.2% and 99.3% for the diagnosis of csPCa, respectively. For the diagnostic criterion "PI-RADS score >3 and PSAD ≥ 0.3", the specificity and positive predictive values were 96.8% and 92.6% for the diagnosis of total PCa and 93.5% and 82.4% for the diagnosis of csPCa, respectively. Conclusions: The combination of the PI-RADS score and PSAD can implement the extraordinary diagnostic performance of PCa. Many patients may safely execute active surveillance or take systematic treatment without prostate biopsies by stratification according to the PI-RADS score and the value of PSAD.