American journal of physiology. Gastrointestinal and liver physiology最新文献

{"title":"In silico integrative scRNA analysis of human colonic epithelium indicates four tuft cell subtypes.","authors":"Aydin I Herik, Sarthak Sinha, Rohit Arora, Caleb Small, Antoine Dufour, Jeff Biernaskie, Eduardo R Cobo, Derek M McKay","doi":"10.1152/ajpgi.00182.2024","DOIUrl":"10.1152/ajpgi.00182.2024","url":null,"abstract":"<p><p>This study integrated and analyzed human single-cell RNA sequencing data from four publicly available datasets to enhance cellular resolution, unveiling a complex landscape of tuft cell heterogeneity within the human colon. Four tuft subtypes (TC1-TC4) emerged, as defined by unique gene expression profiles, indicating potentially novel biological functions. Tuft cell 1 (TC1) was characterized by an antimicrobial peptide signature; TC2 had an increased transcription machinery gene expression profile consistent with a progenitor-like cell; TC3 expressed genes related to ganglion (neuronal) development; and TC4 expressed genes related to tight junctions. Our analysis of subtype-specific gene expression and pathway enrichment showed variances in tuft cell subtypes between healthy individuals and those with inflammatory bowel disease (IBD). The frequency of TC1 and TC2 differed between healthy controls and IBD. Relative to healthy controls, TC1 and TC2 in IBD tissue showed an upregulation of gene expression, favoring increased metabolism and immune function. These findings provide foundational knowledge about the complexity of the human colon tuft cell population and hint at their potential contributions to gut health. They provide a basis for future studies to explore the specific roles these cells may play in gut function during homeostasis and disease. We demonstrate the value of in silico approaches for hypothesis generation in relation to the putative functions of low-frequency gut cells for subsequent physiological analyses.<b>NEW & NOTEWORTHY</b> This study reveals the nuanced and novel landscape of human colonic tuft cells through integrative scRNA-seq analysis. Four distinct tuft cell subtypes were identified, varying markedly between healthy and individuals with IBD. We uncovered human colonic tuft cell subtypes with unexpected antimicrobial and progenitor-like gene expression signatures. These insights into tuft cell diversity offer new avenues for understanding gut health and disease pathophysiology.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G96-G109"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhamnogalacturonan promotes intestinal mucosal repair through increased cell migration.","authors":"Cristiane H Baggio, Judie Shang, Larissa L Périco, Raquel C Dos Santos, Marilyn H Gordon, Bruna B Da Luz, Matthew Stephens, Adamara M Nascimento, Maria Fernanda P Werner, Pierre-Yves von der Weid, Thales R Cipriani, Wallace K MacNaughton","doi":"10.1152/ajpgi.00170.2024","DOIUrl":"10.1152/ajpgi.00170.2024","url":null,"abstract":"<p><p>Mucosal healing is the primary goal for inflammatory bowel disease (IBD) treatment. We previously showed the direct beneficial effects of rhamnogalacturonan (RGal) on intestinal epithelial barrier function. Here, we aimed to evaluate the effect of RGal in intestinal epithelial wound healing. Confluent cancer cell lines and colonoid monolayers were wounded, treated with RGal for 48 h, and assessed using a live cell imaging system. Proliferation and apoptosis of cells were evaluated using 5-ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, respectively. Inhibitors were used to determine the receptor and signaling pathways involved. Female and male mice with DSS-induced colitis were treated orally with RGal for 7 days during the recovery phase. RGal enhanced wound healing in Caco-2, T84, and primary cells by increasing cell migration. Inhibition of pretranscriptional signaling pathways FAK, Src, PI3K, Rho family, and JNK reversed the RGal-induced wound healing. RNAseq data from Caco-2 and primary cells treated with RGal showed the upregulation of the NF-κB pathway at 12 h. Actinomycin D, Bay 11-7082 or JSH-23, and NS-398 treatment significantly reversed the effect of RGal on wound healing, confirming that the response was also transcriptionally dependent and involved NF-κB signaling and downstream COX-2 protein activity. RGal treatment of male mice enhanced recovery from DSS colitis. RGal promoted wound healing in cancer and primary cells by increasing cell migration and accelerated epithelial mucosal healing in male mice. Our findings show a novel mechanism of action of RGal in wound healing that could help in mucosal healing and the resolution of intestinal inflammation.<b>NEW & NOTEWORTHY</b> RGal increases wound healing in colon cancer cell lines and primary cells through increased cell migration and participation of important pretranscriptional signaling pathways and the transcription factor NF-κB. In addition, RGal also accelerates intestinal mucosal healing of male mice with DSS-induced colitis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G152-G165"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered parasympathetic outflow and central sensitization response to continuous pain in cyclic vomiting syndrome: a functional magnetic resonance imaging study.","authors":"Andrew Bolender, Rowan Staley, Ronald G Garcia, Riccardo Barbieri, Ovidiu Andronesi, Shahar Castel, Andrea Thurler, Vitaly Napadow, Braden Kuo, Roberta Sclocco","doi":"10.1152/ajpgi.00011.2024","DOIUrl":"10.1152/ajpgi.00011.2024","url":null,"abstract":"<p><p>Cyclic vomiting syndrome (CVS) is a disorder of brain-gut interaction characterized by recurrent episodes of nausea and vomiting interspersed with asymptomatic periods and associated with autonomic nervous system dysfunction. We examined the dysautonomic response to noxious stimuli for patients with CVS using our previously validated approach to integrate peripheral autonomic outflow metrics, temporal summation of pain, and brain functional MRI (fMRI). Blood oxygen level-dependent (BOLD) fMRI and ECG were acquired from patients with CVS and healthy adults during both a rest condition and a sustained cuff pressure-pain stimulus at the leg. After the latter scan, participants rated pain for the first, middle, and last 2 min to calculate temporal summation. During sustained pain, patients, relative to healthy controls, exhibited greater reduction in heart rate variability within the high-frequency range (HF-HRV) and reduced anticorrelation between HF-HRV and fMRI signal in the anterior insula, pregenual anterior cingulate cortex, and ventrolateral and dorsolateral prefrontal cortex. Compared with healthy adults, patients also exhibited increasing pain intensity over the course of sustained cuff pressure. For healthy adults, seed-based functional connectivity analysis revealed pain sensitization correlated with pain-induced increases in connectivity between primary somatosensory cortex and regions of interest in both left anterior insula/posterior orbitofrontal cortex and right presupplementary motor area. These correlations were not seen in CVS, thus supporting a conclusion of altered central coding of nociceptive stimuli and autonomic responsivity of patients with CVS in key brain regions implicated in autonomic control and interoception.<b>NEW & NOTEWORTHY</b> Patients with cyclic vomiting syndrome exhibit multiple alterations in central function in response to a sustained pressure-pain stimulus, including altered high-frequency heart rate variability and associated changes in BOLD fMRI signal in key areas of the central autonomic and interoceptive networks, as well as abnormal temporal summation of pain associated with altered connectivity patterns between the primary somatosensory cortex and key regions associated with interoception.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G125-G135"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmenting anti-inflammatory macrophage function in colitis: a neuroimmune mechanism to drive intestinal wound repair.","authors":"Natalie Bhesania, Michael A Schumacher","doi":"10.1152/ajpgi.00368.2024","DOIUrl":"10.1152/ajpgi.00368.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G94-G95"},"PeriodicalIF":3.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duodenogastric Reflux in Health and Disease: Insights from a Computational Fluid Dynamics Model of the Stomach.","authors":"Sharun Kuhar, Jung Hee Seo, Pankaj Jay Pasricha, Michael Camilleri, Rajat Mittal","doi":"10.1152/ajpgi.00241.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00241.2024","url":null,"abstract":"<p><p>The stomach is responsible for physically and chemically processing the ingested meal before controlled emptying into the duodenum through the pyloric sphincter. An incompetent pylorus allows reflux from the duodenum back into the stomach, and if the amount of reflux is large enough, it could alter the low pH environment of the stomach and erode the mucosal lining of the lumen. In some cases, the regurgitated contents can also reach the esophagus leading to additional complications. In this work, \"StomachSim\", an <i>in-silico</i> model of the fluid dynamics of the stomach, is used to study the mechanism of duodenogastric reflux. The effects of variations in food properties and motility disorders on reflux are investigated. The simulations show that the primary driver of reflux is the relaxation of the antrum after a stomach contraction terminates near the pylorus. The region of the stomach walls exposed to the regurgitated contents depends significantly on the density of the stomach contents. For stomach contents of higher viscosity, the increased pressure required to maintain gastric emptying reduces the amount of duodenogastric reflux. Concomitant stomach motility disorders that weaken the relaxation of the walls also affect the amount of reflux. The study illustrates the utility of <i>in-silico</i> models in analyzing the factors at play in gastrointestinal diseases.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is LPAR5 agonist a new treatment for microvilli inclusion disease?","authors":"C Chris Yun","doi":"10.1152/ajpgi.00355.2024","DOIUrl":"10.1152/ajpgi.00355.2024","url":null,"abstract":"","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G49-G50"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesogenic cafeteria diet induces dynamic changes in gut microbiota, reduces myenteric neuron excitability, and impairs gut contraction in mice.","authors":"Luis M Ramírez-Maldonado, Julio Guerrero-Castro, José L Rodríguez-Mejía, Yair Cárdenas-Conejo, Edgar O Bonales-Alatorre, Georgina Valencia-Cruz, Paulina T Anguiano-García, Irving I Vega-Juárez, Adán Dagnino-Acosta, Jessica Ruvalcaba-Galindo, Eduardo E Valdez-Morales, Fernando Ochoa-Cortes, Alma Barajas-Espinosa, Raquel Guerrero-Alba, Andrómeda Liñán-Rico","doi":"10.1152/ajpgi.00198.2024","DOIUrl":"10.1152/ajpgi.00198.2024","url":null,"abstract":"<p><p>The cafeteria diet (CAF) is a superior diet model in animal experiments compared with the conventional high-fat diet (HFD), effectively inducing obesity, metabolic disturbances, and multi-organ damage. Nevertheless, its impact on gut microbiota composition during the progression of obesity, along with its repercussions on the enteric nervous system (ENS) and gastrointestinal motility has not been completely elucidated. To gain more insight into the effects of CAF diet in the gut, C57BL/6 mice were fed with CAF or a standard diet for 2 or 8 wk. CAF-fed mice experienced weight gain, disturbed glucose metabolism, dysregulated expression of colonic IL-6, IL-22, TNFα, and TPH1, and altered colon morphology, starting at <i>week 2</i>. Fecal DNA was isolated and gut microbiota composition was monitored by sequencing the V3-V4 16S rRNA region. Sequence analysis revealed that <i>Clostridia</i> and <i>Proteobacteria</i> were specific biomarkers associated with CAF-feeding at <i>week 2</i>, while <i>Bacteroides</i> and <i>Actinobacteria</i> were prominent at <i>week 8</i>. In addition, the impact of CAF diet on ENS was investigated (<i>week 8</i>), where HuC/D+ neurons were measured and counted, and their biophysical properties were evaluated by patch clamp. Gut contractility was tested in whole-mount preparations. Myenteric neurons in CAF-fed mice exhibited reduced body size, incremented cell density, and decreased excitability. The amplitude and frequency of the rhythmic spontaneous contractions in the colon and ileum were affected by the CAF diet. Our findings demonstrate, for the first time, that CAF diet gradually changes the gut microbiota and promotes low-grade inflammation, impacting the functional properties of myenteric neurons and gut contractility in mice.<b>NEW & NOTEWORTHY</b> The gut microbiota changes gradually following the consumption of CAF diet. An increase in <i>Clostridia</i> and <i>Proteobacteria</i> is a hallmark of dysbiosis at the early onset of gut inflammation and obesity. The CAF diet was effective in inducing intestinal low-grade inflammation and alterations in myenteric neuronal excitability in mice. CAF diet is a reliable strategy to study the interplay between gut dysbiosis and low-grade inflammation, in addition to the mechanisms underlying gastrointestinal dysmotility associated with obesity.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G32-G48"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EMC3 is critical for CFTR function and calcium mobilization in the mouse intestinal epithelium.","authors":"Sarah Penrod, Xiaofang Tang, Changsuk Moon, Jeffrey A Whitsett, Anjaparavanda P Naren, Yunjie Huang","doi":"10.1152/ajpgi.00066.2024","DOIUrl":"10.1152/ajpgi.00066.2024","url":null,"abstract":"<p><p>Membrane proteins, such as the cystic fibrosis transmembrane-conductance regulator (CFTR), play a crucial role in gastrointestinal functions and health. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins' processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3^ΔIEC). EMC3^ΔIEC mice were viable but notably smaller compared with their wild-type littermates. Although the intestinal structure was generally maintained, EMC3^ΔIEC crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3^ΔIEC enteroids. CFTR-mediated organoid swelling in EMC3^ΔIEC mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC.<b>NEW & NOTEWORTHY</b> We generated mice in which endoplasmic reticulum membrane protein complex (EMC) subunit 3 was deleted from intestinal epithelium cells and studied the molecular functions of EMC in vivo. Our findings demonstrate the importance of intestinal EMC in the biogenesis of membrane proteins in vivo, including CFTR, and highlight its critical role in maintaining intracellular calcium homeostasis and, consequently, in calcium-dependent functions in the intestine and beyond.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G72-G82"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11901349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcitonin gene-related peptide promotes epithelial reparative and anticolitic functions of IL-4 educated human macrophages.","authors":"Blanca E Callejas, James A Sousa, Kyle L Flannigan, Arthur Wang, Eve Higgins, Aydin I Herik, Shuhua Li, Sruthi Rajeev, Ryan Rosentreter, Remo Panaccione, Derek M McKay","doi":"10.1152/ajpgi.00159.2024","DOIUrl":"10.1152/ajpgi.00159.2024","url":null,"abstract":"<p><p>Interleukin-4 activated human macrophages [M(IL4)s] promote epithelial wound healing and exert an anticolitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn's disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, receptor activity modifying protein-1 (RAMP1), raising the issue of neural modulation of the M(IL4)s reparative function. Thus, human M(IL4)s were treated with CGRP and the cells' phagocytotic, epithelial wound repair and anticolitic functions were assessed. Initial studies confirmed upregulation of expression of the CGRP receptor, which was localized to the cell surface and was functional as determined by CGRP-evoked increases in cAMP. M(IL4,CGRP)s had increased mannose receptor (CD206) and FcγRIIa (CD32a) mRNA expression, a subtle, but significant, increase in phagocytosis and decreased chemokine production following the exposure to <i>Escherichia coli</i>. When delivered systemically (10⁶ cells IP) to oxazolone-treated <i>rag1^-/-</i> mice, M(IL4,CGRP) had an anticolitic effect superior to M(IL4)s from the same blood donor. Conditioned medium (CM) from M(IL4,CGRP) had increased amounts of transforming growth factor (TGF)-β and increased wound-healing capacity compared with matched M(IL4)-CM in the human CaCo₂ epithelial cell line in-vitro wounding assay. Moreover, M(IL4,CGRP)s displayed increased cyclooxygenase (COX)-1 and prostaglandin D₂ (PGD₂), and CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX-1 activity failed to promote repair of wounded CaCo₂ cell monolayers. These data confirm the human M(IL4)s' anticolitic effect that was enhanced by CGRP and may be partially dependent on macrophage COX-1/PGD₂ activity. Thus, input from neurone-derived molecules is a local modifier capable of boosting the anticolitic effect of autologous M(IL4) transfer.<b>NEW & NOTEWORTHY</b> A novel pathway is identified whereby interleukin-4-educated human macrophages [M(IL4)s] exposed to calcitonin gene-related peptide (CGRP) reduce oxazolone-induced colitis and promote epithelial wound healing in vitro through COX1-dependent signaling. Support is provided for the concept of macrophage transfer to treat enteric inflammation where neuroimmune interaction, in this case CGRP neuropeptide, produced under inflammatory conditions will reinforce the anticolitic and wound repair capacity of M(IL4) autologous-based therapy for IBD treatment.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G1-G16"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of six clinical drugs and dietary intervention in the nonobese CDAA-HFD mouse model of MASH and progressive fibrosis.","authors":"Malte Hasle Nielsen, Jacob Nøhr-Meldgaard, Mathias Bonde Møllerhøj, Denise Oró, Susanne E Pors, Maja Worm Andersen, Ioannis Kamzolas, Evangelia Petsalaki, Michele Vacca, Lea Mørch Harder, James W Perfield, Sanne Veidal, Henrik H Hansen, Michael Feigh","doi":"10.1152/ajpgi.00110.2024","DOIUrl":"10.1152/ajpgi.00110.2024","url":null,"abstract":"<p><p>The choline-deficient l-amino acid defined-high-fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat, and resmetirom. Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 wk and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat, or resmetirom were profiled as treatment intervention for 8 wk, starting after 6 wk of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 wk, starting 3 wk after CDAA-HFD diet feeding. In addition, benefits of dietary intervention (chow reversal) for 8 wk were characterized following 6 wk of CDAA-HFD feeding. CDAA-HFD mice demonstrated a nonobese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 wk of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention but not as treatment intervention. Elafibranor was the only interventional drug therapy to improve fibrosis. In comparison, chow-reversal resulted in complete regression of steatosis with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model.<b>NEW & NOTEWORTHY</b> The CDAA-HFD mouse model is widely used in preclinical MASH research, but validation of the model is lacking. This study presents the longitudinal characterization of disease progression. Furthermore, late-stage clinical compounds and dietary intervention (chow reversal) display distinct hepatoprotective effects in the model. Collectively, the study provides critical information guiding the use of the CDAA-HFD mouse model in preclinical drug discovery for MASH and fibrosis.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G51-G71"},"PeriodicalIF":3.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}