e595629dbfcba24a25da849c69c565f3 pmc_9175091.pdf a7420a403ee9ceeeda6bcbbc61a8aa2d7234e645 pmc_9175091.pdf 4c234337da406442c3b6c3521798e5d32b7946fa693a5336bbe7954b7043eca5 pmc_9175091.pdf Title: A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo Subject: The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression. Keywords: NAFLD; gut microbiome; bacterial consortium; portal hypertension; fibrosis Author: Iris Pinheiro, Aurora Barberá, Imma Raurell, Federico Estrella, Marcel de Leeuw, Selin Bolca, Davide Gottardi, Nigel Horscroft, Sam Possemiers, María Teresa Salcedo, Joan Genescà, María Martell and Salvador Augustin Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue May 24 09:36:05 2022 CEST ModDate: Tue May 24 09:48:50 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 20 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2102280 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OTZEDH+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 AEITLL+VnURWPalladioL Type 1 Custom yes yes no 15 0 EUGQQA+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 RUAPWY+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 EOIQIO+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 46 0 QFPRYD+CMSY10 Type 1 Builtin yes yes no 68 0 VVSYYB+EURM10 Type 1 Builtin yes yes no 75 0 WABLSD+SFRM1000 Type 1 Custom yes yes no 88 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 96 0 DUJUUF+PazoMath-Italic Type 1 Builtin yes yes no 100 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 107 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-08-22 02:25:53 CEST RepresentationInformation: pmc_9175091.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-08-11 02:17:36 CEST Size: 2102280 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 388 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Rat NASH Model of Portal Hypertension (PHT) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: STAM™ Mouse Model of NASH Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Blood Biochemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Histological Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Liver Hemodynamics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Western Blot Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Real-Time PCR Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Biological Parameter Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Children: Item: Title: The Nine-Strain Bacterial Consortium Improves Portal Hypertension (PHT), Endothelial Dysfunction (ED), and Fibrotic Markers in the Rat NASH Model of PHT Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Microbiota-Based Treatments Significantly Improved Body Weight Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: The Metabolic Profile Improved in the Treatment Groups Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: No Treatment Group Significantly Reversed the NASH Histological Pattern Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Microbiota-Based Treatments Significantly Reduced Portal Pressure and Improved Liver Hemodynamics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Features of ED Were Improved in Animals after Receiving Microbiota-Based Treatments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Microbiota-Based Treatments Improved Cecal Species Diversity and Induced Composition Shifts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: The Nine-Strain Bacterial Consortium Induced Functional Microbiome Shifts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Microbiota-Based Treatments Induced Differential Hepatic Gene Expression Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: The Nine-Strain Bacterial Consortium Delays Disease Progression and Improves NAFLD Disease Markers in the STAM™ Mouse Model Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Children: Item: Title: The Consortium of Nine Gut Commensals Improved NAS at Histopathology at 9 Weeks of Age Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: The Consortium of Nine Gut Commensals Improved Fibrosis, and Showed Reduced Hepatic Expression of F4/80 and Serum CK-18 Levels Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Discussions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Info: Title: A Nine-Strain Bacterial Consortium Improves Portal Hypertension and Insulin Signaling and Delays NAFLD Progression In Vivo Author: Iris Pinheiro, Aurora Barberá, Imma Raurell, Federico Estrella, Marcel de Leeuw, Selin Bolca, Davide Gottardi, Nigel Horscroft, Sam Possemiers, María Teresa Salcedo, Joan Genescà, María Martell and Salvador Augustin Subject: The gut microbiome has a recognized role in Non-alcoholic fatty liver disease (NAFLD) and associated comorbidities such as Type-2 diabetes and obesity. Stool transplantation has been shown to improve disease by restoring endothelial function and insulin signaling. However, more patient-friendly treatments are required. The present study aimed to test the effect of a defined bacterial consortium of nine gut commensal strains in two in vivo rodent models of Non-alcoholic steatohepatitis (NASH): a rat model of NASH and portal hypertension (PHT), and the Stelic animal (mouse) model (STAM™). In both studies the consortium was administered orally q.d. after disease induction. In the NASH rats, the consortium was administered for 2 weeks and compared to stool transplant. In the STAM™ study administration was performed for 4 weeks, and the effects compared to vehicle or Telmisartan at the stage of NASH/early fibrosis. A second group of animals was followed for another 3 weeks to assess later-stage fibrosis. In the NASH rats, an improvement in PHT and endothelial function was observed. Gut microbial compositional changes also revealed that the consortium achieved a more defined and richer replacement of the gut microbiome than stool transplantation. Moreover, liver transcriptomics suggested a beneficial modulation of pro-fibrogenic pathways. An improvement in liver fibrosis was then confirmed in the STAM™ study. In this study, the bacterial consortium improved the NAFLD activity score, consistent with a decrease in steatosis and ballooning. Serum cytokeratin-18 levels were also reduced. Therefore, administration of a specific bacterial consortium of defined composition can ameliorate NASH, PHT, and fibrosis, and delay disease progression. 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