Abortive PDCoV infection triggers Wnt/β-catenin pathway activation, enhancing intestinal stem cell self-renewal and promoting chicken resistanceZhang, Cao, Huang
et alJ Virol (2025)
Abstract: Porcine deltacoronavirus (PDCoV) is an emerging coronavirus causing economic losses to swine industries worldwide. PDCoV can infect chickens under laboratory conditions, usually with no symptoms or mild symptoms, and may cause outbreaks in backyard poultry and wildfowl, posing a potential risk of significant economic loss to the commercial poultry industry. However, the reasons for such a subdued reaction after infection are not known. Here, using chicken intestinal organoid monolayers, we found that although PDCoV infects them nearly as well as porcine intestinal organoid monolayers, infection did not result in detectable amounts of progeny virus. In ex vivo and in vivo experiments using chickens, PDCoV infection failed to initiate interferon and inflammatory responses. Additionally, infection did not result in a disrupted intestinal barrier nor a reduced number of goblet cells and mucus secretion, as in pigs. In fact, the number of goblet cells increased as did the secreted mucus, thereby providing an enhanced protective barrier. Ex vivo PDCoV infection in chicken triggered activation of the Wnt/β-catenin pathway with the upregulation of Wnt/β-catenin pathway genes (Wnt3a, Lrp5, β-catenin, and TCF4) and Wnt target genes (Lgr5, cyclin D1, and C-myc). This activation stimulates the self-renewal of intestinal stem cells (ISCs), accelerating ISC-mediated epithelial regeneration by significant up-regulation of PCNA (transiently amplifying cells), BMI1 (ISCs), and Lyz (Paneth cells). Our data demonstrate that abortive infection of PDCoV in chicken cells activates the Wnt/β-catenin pathway, which facilitates the self-renewal and proliferation of ISCs, contributing to chickens' resistance to PDCoV infection.IMPORTANCEThe intestinal epithelium is the main target of PDCoV infection and serves as a physical barrier against pathogens. Additionally, ISCs are charged with tissue repair after injury, and promoting rapid self-renewal of intestinal epithelium will help to re-establish the physical barrier and maintain intestinal health. We found that PDCoV infection in chicken intestinal organoid monolayers resulted in abortive infection and failed to produce infectious virions, disrupt the intestinal barrier, reduce the number of goblet cells and mucus secretion, and induce innate immunity, but rather increased goblet cell numbers and mucus secretion. Abortive PDCoV infection activated the Wnt/β-catenin pathway, enhancing ISC renewal and accelerating the renewal and replenishment of shed PDCoV-infected intestinal epithelial cells, thereby enhancing chicken resistance to PDCoV infection. This study provides novel insights into the mechanisms underlying the mild or asymptomatic response to PDCoV infection in chickens, which is critical for understanding the virus's potential risks to the poultry industry.
Obese adipose tissue extracellular vesicles activate mitochondrial fatty acid β-oxidation to drive colonic stemnessHaque, Goodman, Kuusivuori-Robinson
et alCell Mol Gastroenterol Hepatol (2025)
Abstract: Patients with obesity and mouse models of obesity exhibit abnormalities in intestinal epithelial cells, including enhanced stemness. Adipose tissue (AT) is the largest endocrine organ secreting cytokines, hormones, and extracellular vesicles (EVs). Here, we characterized EV protein cargo from obese and non-obese AT and demonstrate the role of obese adipose-derived EVs in enhancing colonic stemness.EVs were isolated from visceral AT from mice fed high-fat diet to induce obesity or control matched-diet. EV cargo was characterized by unbiased proteomics. Mouse colonoids were treated with EVs and analyzed for fatty acid β-oxidation (FAO), expression of stem marker genes, stem function, and β-catenin expression and acetylation. Mice deficient in adipocyte-specific Tsg101 expression were generated to alter adipocyte EV protein cargo and colonic stemness was measured.EVs secreted from obese visceral AT (Ob EVs) were significantly enriched with acyl-CoA dehydrogenase long chain (ACADL), an initiator enzyme of FAO. Compared to non-obese EVs, colonoids treated with Ob EVs exhibited increased exogenous ACADL protein expression, FAO, growth, persistence of stem/progenitor function, and increased β-catenin protein expression and acetylation that was abolished by FAO inhibition. Mice deficient in adipocyte-specific Tsg101 expression exhibited Ob EVs with altered protein expression profiles and were protected from obesity-induced enhanced colonic stemness.The contents of Ob EVs are poised to fuel FAO and to promote obesity-induced stemness in the colon. Alteration of metabolism is a key mechanism of adipose-to-intestinal tissue communication elicited by EVs, thereby influencing basal colonic stem cell homeostasis during obesity.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
To explore the potential combined treatment strategy for colorectal cancer: inhibition of cancer stem cells and enhancement of intestinal immune microenvironmentXu, Geng, Gao
et alEur J Pharmacol (2025)
Abstract: The antibiotic salinomycin, a well-known cancer stem cell inhibitor, may impact the diversity of the intestinal microbiota in colorectal cancer (CRC) mice, which plays a pivotal role in shaping the immune system. This study explores the anti-cancer effects and mechanisms of combining salinomycin and fecal microbiota transplantation (FMT) in treating CRC.FMT was given via enema, while salinomycin was injected intraperitoneally into the CRC mouse model induced by azoxymethane/dextran sodium sulfate.In CRC mice, a large number of LGR5-labeled cancer stem cells and severe disturbances in the intestinal microbiota were observed. Interestingly, salinomycin inhibited the proliferation of cancer stem cells without exacerbating the microbial disorder as expected. In comparison to salinomycin treatment, the combination of salinomycin and FMT significantly improved pathological damage and restored intestinal microbial diversity, which is responsible for shaping the anti-cancer immune microenvironment. The supplementation of FMT significantly increased the levels of propionic acid and butyric acid while also promoting the infiltration of CD8+ T cells and Ly6G+ neutrophils, as well as reducing F4/80+ macrophage recruitment. Notably, cytokines that were not impacted by salinomycin exhibited robust reactions to alterations in the gut microbiota. These included pro-inflammatory factors (IL6, IL12b, IL17, and IL22), chemokine-like protein OPN, and immunosuppressive factor PD-L1.Salinomycin plays the role of "eliminating pathogenic qi," targeting cancer stem cells; FMT plays the role of "strengthening vital qi," reversing the intestinal microbiota disorder and enhancing anti-cancer immunity. They have a synergistic effect on the development of CRC.Copyright © 2025. Published by Elsevier B.V.
Modulation of intestinal signal transduction pathways: Implications on gut health and diseaseVerma, Garg, Yadav
et alEur J Pharmacol (2025) 998, 177531
Abstract: The gastrointestinal (GI) tract is essential for nutrient absorption and protection against pathogens and toxins. Its epithelial lining undergoes continuous renewal every 3-5 days, driven by intestinal stem cells (ISCs). ISCs are primarily of two types: actively proliferating crypt base columnar cells (CBCs), marked by Lgr5 expression, and quiescent label-retaining cells (+4 LRCs), which act as reserves during stress or injury. Key signaling pathways, such as Wnt/β-catenin, Notch, bone morphogenetic proteins (BMPs), and epidermal growth factor (EGF), are crucial in maintaining epithelial homeostasis. These pathways regulate ISCs proliferation and their differentiation into specialized epithelial cells, including goblet cells, paneth cells, enteroendocrine cells, and enterocytes. Disruptions in ISCs signaling can arise from extrinsic factors (e.g., dietary additives, heavy metals, pathogens) or intrinsic factors (e.g., genetic mutations, metabolic changes). Such disruptions impair tight junction integrity, induce inflammation, and promote gut dysbiosis, often perpetuating a cycle of intestinal dysfunction. Chronic ISCs dysregulation is linked to severe intestinal disorders, including colorectal cancer (CRC) and inflammatory bowel disease (IBD). This review emphasizes the critical role of ISCs in maintaining epithelial renewal and how various factors disrupt their signaling pathways, jeopardizing intestinal health and contributing to diseases. It also underscores the importance of protecting ISCs function to mitigate the risk of inflammation-related disorders. It highlights how understanding these regulatory mechanisms could guide therapeutic strategies for preserving GI tract integrity and treating related conditions.Copyright © 2025 Elsevier B.V. All rights reserved.
膜杰作
Star Staining
