Pub Date : 2024-01-01DOI: 10.1016/S2352-345X(24)00049-3
{"title":"Cover - Crohn's Disease: Spotlight on the Mesenteric Lymph Node Immune Response","authors":"","doi":"10.1016/S2352-345X(24)00049-3","DOIUrl":"https://doi.org/10.1016/S2352-345X(24)00049-3","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000493/pdfft?md5=d8e50e08b331850ddada8ac47042c611&pid=1-s2.0-S2352345X24000493-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.02.015
Jessica M. Ferrell , Matthew Dilts , Sabita Pokhrel , Zachary Stahl , Shannon Boehme , Xinwen Wang , John Y.L. Chiang
Background & Aims
Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding.
Methods
After injection of adeno-associated virus-green fluorescent protein or AAV–FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge.
Results
Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfβ, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens.
Conclusions
Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.
{"title":"Fibroblast Growth Factor 19 Alters Bile Acids to Induce Dysbiosis in Mice With Alcohol-Induced Liver Disease","authors":"Jessica M. Ferrell , Matthew Dilts , Sabita Pokhrel , Zachary Stahl , Shannon Boehme , Xinwen Wang , John Y.L. Chiang","doi":"10.1016/j.jcmgh.2024.02.015","DOIUrl":"10.1016/j.jcmgh.2024.02.015","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding.</p></div><div><h3>Methods</h3><p>After injection of adeno-associated virus-green fluorescent protein or AAV–FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge.</p></div><div><h3>Results</h3><p>Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by <em>Il6</em>, <em>Tgfβ</em>, and <em>Tnfα</em>, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including <em>Enterococcus faecalis, Escherichia coli,</em> and <em>Clostridium perfringens</em>.</p></div><div><h3>Conclusions</h3><p>Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000432/pdfft?md5=613f4621d8bd3051c945bef5515e646d&pid=1-s2.0-S2352345X24000432-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139991960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.01.007
Wenjing Yang , Tianming Yu , Yingzi Cong
Intestinal inflammatory fibrosis is a severe consequence of inflammatory bowel diseases (IBDs). There is currently no cure for the treatment of intestinal fibrosis in IBD. Although inflammation is necessary for triggering fibrosis, the anti-inflammatory agents used to treat IBD are ineffective in preventing the progression of intestinal fibrosis and stricture formation once initiated, suggesting that inflammatory signals are not the sole drivers of fibrosis progression once it is established. Among multiple mechanisms involved in the initiation and progression of intestinal fibrosis in IBD, stromal cells play critical roles in mediating the process. In this review, we summarize recent progress on how stromal cells regulate intestinal fibrosis in IBD and how they are regulated by focusing on immune regulation and gut microbiota. We also outline the challenges moving forward in the field.
{"title":"Stromal Cell Regulation of Intestinal Inflammatory Fibrosis","authors":"Wenjing Yang , Tianming Yu , Yingzi Cong","doi":"10.1016/j.jcmgh.2024.01.007","DOIUrl":"10.1016/j.jcmgh.2024.01.007","url":null,"abstract":"<div><p>Intestinal inflammatory fibrosis is a severe consequence of inflammatory bowel diseases (IBDs). There is currently no cure for the treatment of intestinal fibrosis in IBD. Although inflammation is necessary for triggering fibrosis, the anti-inflammatory agents used to treat IBD are ineffective in preventing the progression of intestinal fibrosis and stricture formation once initiated, suggesting that inflammatory signals are not the sole drivers of fibrosis progression once it is established. Among multiple mechanisms involved in the initiation and progression of intestinal fibrosis in IBD, stromal cells play critical roles in mediating the process. In this review, we summarize recent progress on how stromal cells regulate intestinal fibrosis in IBD and how they are regulated by focusing on immune regulation and gut microbiota. We also outline the challenges moving forward in the field.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000080/pdfft?md5=12f9e2ae22065e001959192af5cd435d&pid=1-s2.0-S2352345X24000080-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139501421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.01.019
Markus F. Neurath
{"title":"The Proteomic Signature of Tissue Remodeling in Chronic Intestinal Inflammation","authors":"Markus F. Neurath","doi":"10.1016/j.jcmgh.2024.01.019","DOIUrl":"10.1016/j.jcmgh.2024.01.019","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24000225/pdfft?md5=a8308a52935daaea2a8fc884c285fdd0&pid=1-s2.0-S2352345X24000225-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139708660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.11.005
Tao Cheng, Yun Cheng, Dong-Yan Jin
{"title":"Oncostatin M for Anti-HBV Therapy: Can a Foe Be Turned Into a Friend?","authors":"Tao Cheng, Yun Cheng, Dong-Yan Jin","doi":"10.1016/j.jcmgh.2023.11.005","DOIUrl":"10.1016/j.jcmgh.2023.11.005","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300200X/pdfft?md5=c01c5cd6b0e85a89e7c963b0b5bb1ef7&pid=1-s2.0-S2352345X2300200X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138453205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.12.008
David A. Rudnick
{"title":"New Insights About Epigenetic Mechanisms That Influence Risk of Transgenerational Fatty Liver Disease","authors":"David A. Rudnick","doi":"10.1016/j.jcmgh.2023.12.008","DOIUrl":"10.1016/j.jcmgh.2023.12.008","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002217/pdfft?md5=502b3e403c89717a1cdd7ada85505e3f&pid=1-s2.0-S2352345X23002217-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139064961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.12.009
Udayan Apte
{"title":"Modulation of Hepatocyte Nuclear Factor 4 Alpha (HNF4α): A Critical Mechanism of Disease Progression in Liver Cirrhosis","authors":"Udayan Apte","doi":"10.1016/j.jcmgh.2023.12.009","DOIUrl":"10.1016/j.jcmgh.2023.12.009","url":null,"abstract":"","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X23002229/pdfft?md5=95c721e18f5b63b6bc56146d77c1b206&pid=1-s2.0-S2352345X23002229-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139051648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2023.12.012
Sai Wang , Frederik Link , Mei Han , Roohi Chaudhary , Anastasia Asimakopoulos , Roman Liebe , Ye Yao , Seddik Hammad , Anne Dropmann , Marinela Krizanac , Claudia Rubie , Laura Kim Feiner , Matthias Glanemann , Matthias P.A. Ebert , Ralf Weiskirchen , Yoav I. Henis , Marcelo Ehrlich , Steven Dooley
Background & Aims
Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction–associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction–associated steatohepatitis and hepatocellular carcinoma. However, the reciprocal regulation of TGF-β1 signaling and cholesterol metabolism in MASLD is yet unknown.
Methods
Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA sequencing of murine hepatocyte cell line (alpha mouse liver 12/AML12) and mouse primary hepatocytes treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment [CE] or cholesterol depletion [CD]), and on mice injected with adenovirus-associated virus 8–control/TGF-β1.
Results
TGF-β1 inhibited messenger RNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, mouse primary hepatocytes, and adenovirus-associated virus–TGF-β1–treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue also were reduced upon TGF-β1 treatment. Smad2/3 phosphorylation after 2 hours of TGF-β1 treatment persisted after CE or CD and was mildly increased after CD, whereas TGF-β1–mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 hours of incubation with TGF-β1, including epithelial–mesenchymal transition, actin polymerization, and apoptosis. CD mimicked the outcome of long-term TGF-β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. In addition, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells.
{"title":"The Interplay of TGF-β1 and Cholesterol Orchestrating Hepatocyte Cell Fate, EMT, and Signals for HSC Activation","authors":"Sai Wang , Frederik Link , Mei Han , Roohi Chaudhary , Anastasia Asimakopoulos , Roman Liebe , Ye Yao , Seddik Hammad , Anne Dropmann , Marinela Krizanac , Claudia Rubie , Laura Kim Feiner , Matthias Glanemann , Matthias P.A. Ebert , Ralf Weiskirchen , Yoav I. Henis , Marcelo Ehrlich , Steven Dooley","doi":"10.1016/j.jcmgh.2023.12.012","DOIUrl":"10.1016/j.jcmgh.2023.12.012","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction–associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction–associated steatohepatitis and hepatocellular carcinoma. However, the reciprocal regulation of TGF-β1 signaling and cholesterol metabolism in MASLD is yet unknown.</p></div><div><h3>Methods</h3><p>Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA sequencing of murine hepatocyte cell line (alpha mouse liver 12/AML12) and mouse primary hepatocytes treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment [CE] or cholesterol depletion [CD]), and on mice injected with adenovirus-associated virus 8–control/TGF-β1.</p></div><div><h3>Results</h3><p>TGF-β1 inhibited messenger RNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, mouse primary hepatocytes, and adenovirus-associated virus–TGF-β1–treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue also were reduced upon TGF-β1 treatment. Smad2/3 phosphorylation after 2 hours of TGF-β1 treatment persisted after CE or CD and was mildly increased after CD, whereas TGF-β1–mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 hours of incubation with TGF-β1, including epithelial–mesenchymal transition, actin polymerization, and apoptosis. CD mimicked the outcome of long-term TGF-β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. In addition, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells.</p></div><div><h3>Conclusions</h3><p>TGF-β1 inhibits cholesterol metabolism whereas cholesterol attenuates TGF-β1 downstream effects in hepatocytes.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X2300228X/pdfft?md5=bec8bc778b26a42b61823131c5e3d8ac&pid=1-s2.0-S2352345X2300228X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139051674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.05.005
James D. Lewis , Scott G. Daniel , Hongzhe Li , Fuhua Hao , Andrew D. Patterson , Aaron L. Hecht , Colleen M. Brensinger , Gary D. Wu , Kyle Bittinger
Background & Aims
Crohn’s disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn’s disease surgery.
Methods
Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn’s Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with 1H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry.
Results
Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, Egerthella lenta, Adlercreutzia equalofaciens, and Gordonibacter pamelaeae were lower in abundance among patients with prior surgery in both cohorts.
Conclusions
In 2 different populations, prior surgery in Crohn’s disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria E lenta and related actinobacteria and secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.
{"title":"Surgery for Crohn’s Disease Is Associated With a Dysbiotic Microbiome and Metabolome: Results From Two Prospective Cohorts","authors":"James D. Lewis , Scott G. Daniel , Hongzhe Li , Fuhua Hao , Andrew D. Patterson , Aaron L. Hecht , Colleen M. Brensinger , Gary D. Wu , Kyle Bittinger","doi":"10.1016/j.jcmgh.2024.05.005","DOIUrl":"10.1016/j.jcmgh.2024.05.005","url":null,"abstract":"<div><h3>Background & Aims</h3><p>Crohn’s disease is associated with alterations in the gut microbiome and metabolome described as dysbiosis. We characterized the microbial and metabolic consequences of ileal resection, the most common Crohn’s disease surgery.</p></div><div><h3>Methods</h3><p>Patients with and without intestinal resection were identified from the Diet to Induce Remission in Crohn’s Disease and Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease studies. Stool samples were analyzed with shotgun metagenomics sequencing. Fecal butyrate was measured with <sup>1</sup>H nuclear magnetic resonance spectroscopy. Fecal bile acids and plasma 7α-hydroxy-4-cholesten-3-one (C4) was measured with mass spectrometry.</p></div><div><h3>Results</h3><p>Intestinal resection was associated with reduced alpha diversity and altered beta diversity with increased Proteobacteria and reduced Bacteroidetes and Firmicutes. Surgery was associated with higher representation of genes in the KEGG pathway for ABC transporters and reduction in genes related to bacterial metabolism. Surgery was associated with reduced concentration of the But gene but this did not translate to reduced fecal butyrate concentration. Surgery was associated with decreased abundance of bai operon genes, with increased plasma C4 concentration, increased primary bile acids and reduced secondary bile acids, including isoLCA. Additionally, <em>Egerthella lenta</em>, <em>Adlercreutzia equalofaciens</em>, and <em>Gordonibacter pamelaeae</em> were lower in abundance among patients with prior surgery in both cohorts.</p></div><div><h3>Conclusions</h3><p>In 2 different populations, prior surgery in Crohn’s disease is associated with altered fecal microbiome. Patients who had undergone ileal resection had reduction in the potentially beneficial bacteria <em>E lenta</em> and related actinobacteria and secondary bile acids, including isoLCA, suggesting that these could be biomarkers of patients at higher risk for disease progression.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001115/pdfft?md5=8b01a3690506672a2d116b54b365b90e&pid=1-s2.0-S2352345X24001115-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-01DOI: 10.1016/j.jcmgh.2024.101377
Background and Aims
Transcriptome sequencing revealed high expression of DDR2 in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC.
Methods
Oxaliplatin-resistant HCC cell lines were established. The interaction between DDR2 and STAT3 was investigated, along with the mechanisms involved in DDR2/STAT3-mediated PD-L1 upregulation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) accumulation both in vitro and in vivo.
Results
DDR2 was found to induce the phosphorylation of STAT3, leading to its nuclear translocation. Conversely, the activation of STAT3 enhanced DDR2 expression. A positive feedback loop involving DDR2/STAT3 was identified in oxaliplatin-resistant HCC, which was associated with PD-L1 upregulation and PMN-MDSCs accumulation. Knockdown of DDR2 and STAT3 sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in decreased PMN-MDSCs and increased CD8+ T cells in the tumor microenvironment. Enzyme-linked immunosorbent array and MDSC transwell migration assays indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through CCL20. Dual luciferase reporter assays demonstrated that STAT3 can directly enhance the transcription of PD-L1 and CCL20. Furthermore, treatment with a PD-L1 antibody in combination with CCL20 blockade had significant antitumor effects on oxaliplatin-resistant HCC.
Conclusions
Our findings revealed a positive feedback mechanism involving DDR2 and STAT3 that mediates the immunosuppressive microenvironment and promotes oxaliplatin resistance and immune evasion via PD-L1 upregulation and PMN-MDSC recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.
{"title":"DDR2/STAT3 Positive Feedback Loop Mediates the Immunosuppressive Microenvironment by Upregulating PD-L1 and Recruiting MDSCs in Oxaliplatin-Resistant HCC","authors":"","doi":"10.1016/j.jcmgh.2024.101377","DOIUrl":"10.1016/j.jcmgh.2024.101377","url":null,"abstract":"<div><h3>Background and Aims</h3><p>Transcriptome sequencing revealed high expression of DDR2 in oxaliplatin-resistant hepatocellular carcinoma (HCC). This study aimed to explore the role of DDR2 in oxaliplatin resistance and immune evasion in HCC.</p></div><div><h3>Methods</h3><p>Oxaliplatin-resistant HCC cell lines were established. The interaction between DDR2 and STAT3 was investigated, along with the mechanisms involved in DDR2/STAT3-mediated PD-L1 upregulation and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) accumulation both in vitro and in vivo.</p></div><div><h3>Results</h3><p>DDR2 was found to induce the phosphorylation of STAT3, leading to its nuclear translocation. Conversely, the activation of STAT3 enhanced DDR2 expression. A positive feedback loop involving DDR2/STAT3 was identified in oxaliplatin-resistant HCC, which was associated with PD-L1 upregulation and PMN-MDSCs accumulation. Knockdown of DDR2 and STAT3 sensitized oxaliplatin-resistant HCC cells to oxaliplatin and resulted in decreased PMN-MDSCs and increased CD8<sup>+</sup> T cells in the tumor microenvironment. Enzyme-linked immunosorbent array and MDSC transwell migration assays indicated that oxaliplatin-resistant HCC cells recruited PMN-MDSCs through CCL20. Dual luciferase reporter assays demonstrated that STAT3 can directly enhance the transcription of PD-L1 and CCL20. Furthermore, treatment with a PD-L1 antibody in combination with CCL20 blockade had significant antitumor effects on oxaliplatin-resistant HCC.</p></div><div><h3>Conclusions</h3><p>Our findings revealed a positive feedback mechanism involving DDR2 and STAT3 that mediates the immunosuppressive microenvironment and promotes oxaliplatin resistance and immune evasion via PD-L1 upregulation and PMN-MDSC recruitment. Targeting the DDR2/STAT3 pathway may be a promising therapeutic strategy to overcome immune escape and chemoresistance in HCC.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":null,"pages":null},"PeriodicalIF":7.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001322/pdfft?md5=650df56321cc36d1fa173c7863141062&pid=1-s2.0-S2352345X24001322-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}