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JOURNAL ARTICLE
Yalong Wang, Ronghui Tan, Ye-Guang Chen
The intestine comprises distinct segments, each characterized by unique cell populations and functions. Intestinal organoids faithfully replicate the cellular composition and functions of the intestine. Over the past decade, the organoid model has garnered considerable attention for its application in investigation of organ development, renewal and functional performance. While the organoid culture systems for mouse small intestine and human large intestine have widely adopted, a comparison summary for different segments of the human or mouse intestine is lacking...
April 23, 2024: Methods in Molecular Biology
#2
JOURNAL ARTICLE
Deborah Molehin, Jack Guinan, Brina Lopez
Organoid cell culture systems can recapitulate the complexity observed in tissues, making them useful in studying host-pathogen interactions, evaluating drug efficacy and toxicity, and tissue bioengineering. However, applying these models for the described reasons may be limited because of the three-dimensional (3D) nature of these models. For example, using 3D enteroid culture systems to study digestive diseases is challenging due to the inaccessibility of the intestinal lumen and its secreted substances. Indeed, stimulation of 3D organoids with pathogens requires either luminal microinjection, mechanical disruption of the 3D structure, or generation of apical-out enteroids...
April 5, 2024: Journal of Visualized Experiments: JoVE
#3
JOURNAL ARTICLE
Idil Apak Evans, Xingshen Sun, Bo Liang, Amber R Vegter, Lydia Guo, Thomas J Lynch, Yan Zhang, Yulong Zhang, Yaling Yi, Yu Yang, Zehua Feng, Soo Yeun Park, Amanita Shonka, Hannah McCumber, Lisi Qi, Peipei Wu, Guangming Liu, Allison Lacina, Kai Wang, Katherine N Gibson-Corley, David K Meyerholz, Dominique H Limoli, Bradley H Rosen, Ziying Yan, Douglas J Bartels, John F Engelhardt
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF...
April 22, 2024: JCI Insight
#4
Joseph Lee, Antoine Gleizes, Felipe Takaesu, Sarah F Webster, Taylor Hailstock, Adam D Gracz
Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we sought to model fISC activation in intestinal organoids with doxorubicin (DXR), a chemotherapeutic known to ablate Lgr5 + aISCs in vivo . We identified low and high doses of DXR compatible with long-term organoid survival. Similar fISC gene activation was observed between organoids treated with low vs high DXR, despite significantly decreased survival at the higher dose...
April 11, 2024: bioRxiv
#5
JOURNAL ARTICLE
Felix Haller, Kristine Jimenez, Maximilian Baumgartner, Michaela Lang, Anton Klotz, Manuela Jambrich, Georg Busslinger, Leonhard Müllauer, Vineeta Khare, Christoph Gasche
Lynch syndrome (LS) is the most prevalent heritable form of colorectal cancer (CRC). Its early onset and high lifetime risk for CRC emphasize the necessity for effective chemoprevention. NFE2L2 (NRF2) is often considered a potential druggable target, and many chemopreventive compounds do induce NRF2. However, while NRF2 counteracts oxidative stress, it is also overexpressed in CRC and may promote tumorigenesis. Herein, we evaluated the role of NRF2 in prevention of LS-associated neoplasia. We found an increased levels of NRF2 in intestinal epithelia of mice with intestinal epithelial-specific Msh2 deletion (MSH2ΔIEC) as compared to C57BL/6 (wild type) mice, as well as an increase in downstream NRF2 targets Nqo1 and Gclc...
April 22, 2024: Cancer Prevention Research
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JOURNAL ARTICLE
Simon Guignard, Mahmoud Saifeddine, Koichiro Mihara, Majid Motahhary, Magali Savignac, Laura Guiraud, David Sagnat, Mireille Sebbag, Sokchea Khou, Corinne Rolland, Anissa Edir, Barbara Bournet, Louis Buscail, Etienne Buscail, Laurent Alric, Caroline Camare, Mouna Ambli, Nathalie Vergnolle, Morley D Hollenberg, Céline Deraison, Chrystelle Bonnart
BACKGROUND AND PURPOSE: Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease-activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells. EXPERIMENTAL APPROACH: The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples...
April 18, 2024: British Journal of Pharmacology
#7
REVIEW
Zhengyang Wu, Hongyuan Liu, Xianli Wang
Bacterial enteritis has a substantial role in contributing to a large portion of the global disease burden and serves as a major cause of newborn mortality. Despite advancements gained from current animal and cell models in improving our understanding of pathogens, their widespread application is hindered by apparent drawbacks. Therefore, more precise models are imperatively required to develop more accurate studies on host-pathogen interactions and drug discovery. Since the emergence of intestinal organoids, massive studies utilizing organoids have been conducted to study the pathogenesis of bacterial enteritis, revealing new mechanisms and validating established ones...
April 15, 2024: Molecular Biology Reports
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JOURNAL ARTICLE
Jinxia Liu, Jane MacNaughtan, Annarein J C Kerbert, Theo Portlock, Javier Martínez Gonzalez, Yi Jin, Frederick Clasen, Abeba Habtesion, Huoyan Ji, Qin Jin, Alexandra Phillips, Francesco De Chiara, Ganesh Ingavle, Cesar Jimenez, Giacomo Zaccherini, Katherine Husi, Miguel Angel Rodriguez Gandia, Paul Cordero, Junpei Soeda, Lynda McConaghy, Jude Oben, Karen Church, Jia V Li, Haifeng Wu, Aarti Jalan, Pere Gines, Elsa Solà, Simon Eaton, Carrie Morgan, Michal Kowalski, Daniel Green, Amir Gander, Lindsey A Edwards, I Jane Cox, Helena Cortez-Pinto, Thomas Avery, Reiner Wiest, Francois Durand, Paolo Caraceni, Roberto Elosua, Joan Vila, Marco Pavesi, Vicente Arroyo, Nathan Davies, Rajeshwar P Mookerjee, Victor Vargas, Susan Sandeman, Gautam Mehta, Saeed Shoaie, Julian Marchesi, Agustín Albillos, Fausto Andreola, Rajiv Jalan
OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro . Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied...
April 15, 2024: Gut
#9
JOURNAL ARTICLE
Priyanka Kanth, Mark W Hazel, John C Schell, Jared Rutter, Ruoxin Yao, Alyssa P Mills, Don A Delker
Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients...
April 12, 2024: Familial Cancer
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JOURNAL ARTICLE
Austin P Wright, Sydney Harris, Shelby Madden, Bryan Ramirez Reyes, Ethan Mulamula, Alexis Gibson, Isabella Rauch, David A Constant, Timothy J Nice
Intestinal epithelial cell (IEC) responses to interferon (IFN) favor antiviral defense with minimal cytotoxicity, but IEC-specific factors that regulate these responses remain poorly understood. Interferon regulatory factors (IRFs) are a family of nine related transcription factors, and IRF6 is preferentially expressed by epithelial cells, but its roles in IEC immunity are unknown. In this study, CRISPR screens found that Irf6 deficiency enhanced IFN-stimulated antiviral responses in transformed mouse IECs but not macrophages...
April 9, 2024: Mucosal Immunology
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JOURNAL ARTICLE
Claire Yung, Yang Zhang, Madeline Kuhn, Randall J Armstrong, Amy Olyaei, Molly Aloia, Brian Scottoline, Sarah F Andres
Human milk contains extracellular vesicles (HMEVs). Pre-clinical models suggest that HMEVs may enhance intestinal function and limit inflammation; however, it is unknown if HMEVs or their cargo survive neonatal human digestion. This limits the ability to leverage HMEV cargo as additives to infant nutrition or as therapeutics. This study aimed to develop an EV isolation pipeline from small volumes of human milk and neonatal intestinal contents after milk feeding (digesta) to address the hypothesis that HMEVs survive in vivo neonatal digestion to be taken up intestinal epithelial cells (IECs)...
April 2024: Journal of Extracellular Vesicles
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JOURNAL ARTICLE
R González, D Ceacero-Heras, M Tena-Garitaonaindia, A Álvarez-Mercado, R Gámez-Belmonte, W J Chazin, F Sánchez de Medina, O Martínez-Augustin
Calprotectin (CP), a heterodimer of S100A8 and S100A9, is expressed by neutrophils and a number of innate immune cells and is used widely as a marker of inflammation, particularly intestinal inflammation. CP is a ligand for toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE). In addition, CP can act as a microbial modulatory agent via a mechanism termed nutritional immunity, depending on metal binding, most notably Zn2+ . The effects on the intestinal epithelium are largely unknown...
April 8, 2024: Biomedicine & Pharmacotherapy
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JOURNAL ARTICLE
Beth B McConnell, Zhongxing Liang, Chad Xu, Yiran Han, C Chris Yun
Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice ( Lpar5f/f ) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine ( Lpar5IECKO ) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery...
April 9, 2024: American Journal of Physiology. Gastrointestinal and Liver Physiology
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JOURNAL ARTICLE
Clara Morral, Arshad Ayyaz, Hsuan-Cheng Kuo, Mardi Fink, Ioannis I Verginadis, Andrea R Daniel, Danielle N Burner, Lucy M Driver, Sloane Satow, Stephanie Hasapis, Reem Ghinnagow, Lixia Luo, Yan Ma, Laura D Attardi, Constantinos Koumenis, Andy J Minn, Jeffrey L Wrana, Chang-Lung Lee, David G Kirsch
Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs...
April 8, 2024: Nature Communications
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JOURNAL ARTICLE
Brooke Wang, Lilianne Iglesias-Ledon, Matthew Bishop, Anushka Chadha, Sara E Rudolph, Brooke N Longo, Dana M Cairns, Ying Chen, David L Kaplan
The development of patient-derived intestinal organoids represents an invaluable model for simulating the native human intestinal epithelium. These stem cell-rich cultures outperform commonly used cell lines like Caco-2 and HT29-MTX in reflecting the cellular diversity of the native intestinal epithelium after differentiation. In our recent study examining the effects of polystyrene (PS), microplastics (MPs), and nanoplastics (NPs), widespread pollutants in our environment and food chain, on the human intestinal epithelium, these organoids have been instrumental in elucidating the absorption mechanisms and potential biological impacts of plastic particles...
April 2024: Current protocols
#16
JOURNAL ARTICLE
J Guillermo Sanchez, Scott Rankin, Emily Paul, Heather A McCauley, Daniel O Kechele, Jacob R Enriquez, Nana-Hawa Jones, Siri A W Greeley, Lisa Letourneau-Friedberg, Aaron M Zorn, Mansa Krishnamurthy, James M Wells
The gastrointestinal tract is complex and consists of multiple organs with unique functions. Rare gene mutations can cause congenital malformations of the human GI tract, although the molecular basis of these has been poorly studied. We identified a patient with compound-heterozygous mutations in RFX6 presenting with duodenal mal-rotation and atresia, implicating RFX6 in development of the proximal intestine. To identify how mutations in RFX6 impact intestinal patterning and function, we derived iPSCs from this patient to generate human intestinal organoids (HIOs)...
April 8, 2024: Development
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JOURNAL ARTICLE
Wenping Ma, Yi Zheng, Guangzhen Yang, Hongjian Zhang, Mingxia Lu, Hongshi Ma, Chengtie Wu, Hongxu Lu
Organoids, which are 3D multicellular constructs, have garnered significant attention in recent years. Existing organoid culture methods predominantly utilize natural and synthetic polymeric hydrogels. This study explored the potential of a composite hydrogel mainly consisting of calcium silicate (CS) nanowires and methacrylated gelatin (GelMA) as a substrate for organoid formation and functionalization, specifically for intestinal and liver organoids. Furthermore, the research delved into the mechanisms by which CS nanowires promote the structure formation and development of organoids...
April 8, 2024: Materials Horizons
#18
JOURNAL ARTICLE
Eun-Jung Kang, Jae-Hoon Kim, Young Eun Kim, Hana Lee, Kwang Bo Jung, Dong-Ho Chang, Youngjin Lee, Shinhye Park, Eun-Young Lee, Eun-Ji Lee, Ho Bum Kang, Moon-Young Rhyoo, Seungwoo Seo, Sohee Park, Yubin Huh, Jun Go, Jung Hyeon Choi, Young-Keun Choi, In-Bok Lee, Dong-Hee Choi, Yun Jeong Seo, Jung-Ran Noh, Kyoung-Shim Kim, Jung Hwan Hwang, Ji-Seon Jeong, Ha-Jeong Kwon, Hee Min Yoo, Mi-Young Son, Yeon-Gu Kim, Dae-Hee Lee, Tae-Young Kim, Hyo-Jung Kwon, Myung Hee Kim, Byoung-Chan Kim, Yong-Hoon Kim, Dukjin Kang, Chul-Ho Lee
Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A...
April 6, 2024: Nature Communications
#19
JOURNAL ARTICLE
Yu Jia, Ge Zhu, Cheng Qiu, Jun-Mei Lai, Ye Shen, Shu-Wen Jin, Xue Yang, Hai-Ping Zhu, Bang-Chuan Hu, Xiang-Ming Ye, Shi-Jing Mo
AIMS: Intestinal barrier dysfunction is the initial and propagable factor of sepsis in which acute kidney injury (AKI) has been considered as a common life-threatening complication. Our recent study identifies the regulatory role of Pellino1 in tubular death under inflammatory conditions in vitro. The objective of our current study is to explore the impact of Pellino1 on gut-kidney axis during septic AKI and uncover the molecular mechanism (s) underlying this process. MATERIALS AND METHODS: Immunohistochemistry (IHC) was conducted to evaluate Pellino1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels in renal biopsies from critically ill patients with a clinical diagnosis of sepsis...
April 3, 2024: Life Sciences
#20
JOURNAL ARTICLE
Michael McPhee, Jonghwa Lee, Jayme Salsman, Marinella Pinelli, Francesca Di Cara, Kirill Rosen, Graham Dellaire, Neale D Ridgway
Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid droplets (nLDs) are present in intestinal cells but their origin and relationship to cytoplasmic TAG synthesis and secretion is unknown. nLDs and related lipid-associated promyelocytic leukemia (PML) structures (LAPS) were abundant in oleate-treated Caco2 but less frequent in other human colorectal cancer cell lines and mouse intestinal organoids...
April 1, 2024: Journal of Lipid Research
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