Intraduodenal Fecal Microbiota Transplantation Ameliorates Gut Atrophy and Cholestasis in a Novel Parenteral Nutrition Piglet Model.

BACKGROUND Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. METHODS Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A) or TPN + intraduodenal fecal microbiota transplant (TPN-FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16s rRNA sequencing. PERMANOVA, Jaccard and Bray-Curtis metrics were performed. RESULTS Significant bilirubin elevation in TPN and TPN-A vs EN (p<0.0001) was prevented with FMT. IFN-G, TNF-alpha, IL-beta, IL-8 and LPS were significantly higher in TPN (p=0.009/0.001/0.043/0.011/<0.0001), with preservation upon FMT. Significant gut-atrophy by villous/crypt ratio in TPN (p<0.0001) and TPN-A (p=0.0001) vs EN was prevented by FMT (p=0.426 vs EN). Microbiota profiles using Principal Coordinate Analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN altered gut barrier was preserved upon FMT. Upregulated CYP7A1 and BSEP in TPN and TPN-A, and downregulatedFGFR4, EGF, FXR and TGR5 vs EN was prevented by FMT. CONCLUSION This study provides novel evidence of prevention of gut atrophy, liver injury and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores importance of gut microbes as prime targets for therapeutics and drug discovery.

• Publication year

  2024

• Venue

  American Journal of Physiology - Gastrointestinal and Liver Physiology

• Publication date

  2024-08-20

• Fields of study

  Medicine, Environmental Science

• Identifiers
  DOI 10.1152/ajpgi.00012.2024PMID 39163019PMCID PMC11559648
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Gut Microbiota to Microglia: Microbiome Influences Neurodevelopment in the CNS

  2023cited by this paper
• Role of Effective Policy and Screening in Managing Pediatric Nutritional Insecurity as the Most Important Social Determinant of Health Influencing Health Outcomes

  2023cited by this paper
• Research Progress of Fecal Microbiota Transplantation in Liver Diseases

  2023cited by this paper
• Food, gut barrier dysfunction, and related diseases: A new target for future individualized disease prevention and management

  2023cited by this paper
• Symbiotic Firmicutes establish mutualism with the host via innate tolerance and resistance to control systemic immunity.

  2023cited by this paper
• Farnesoid X Receptor, Bile Acid Metabolism, and Gut Microbiota

  2022cited by this paper
• Impact of Total Parenteral Nutrition on Gut Microbiota in Pediatric Population Suffering Intestinal Disorders

  2022cited by this paper
• Intestinal Fatty Acid Binding Protein (I-FABP) as a Prognostic Marker in Critically Ill COVID-19 Patients

  2022cited by this paper
• Integrity of the Intestinal Barrier: The Involvement of Epithelial Cells and Microbiota—A Mutual Relationship

  2022cited by this paper
• Carbamazepine Mitigates Total Parenteral Nutrition Associated Liver Disease in a Novel Ambulatory Piglet Model.

  2022cited by this paper
• Lower systemic inflammation is associated with gut firmicutes dominance and reduced liver injury in a novel ambulatory model of parenteral nutrition

  2022cited by this paper
• The Gut Microbiome of 54 Mammalian Species

  2022cited by this paper
• Parenteral Nutrition and Cardiotoxicity

  2021cited by this paper
• Antibiotics in critically ill children—a narrative review on different aspects of a rational approach

  2021cited by this paper
• The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease

  2021cited by this paper
• Gut microbiota and its diet‐related activity in children with intestinal failure receiving long‐term parenteral nutrition

  2021cited by this paper
• Dysbiosis and Intestinal Barrier Dysfunction in Pediatric Congenital Heart Disease Is Exacerbated Following Cardiopulmonary Bypass

  2021cited by this paper
• Inflammation Drives MicroRNAs to Limit Hepatocyte Bile Acid Transport in Murine Biliary Atresia.

  2020cited by this paper
• Mucus barrier, mucins and gut microbiota: the expected slimy partners?

  2020cited by this paper
• Role of Bile Acids and Gut Microbiota in Parenteral Nutrition Associated Injury

  2020cited by this paper
• Regulation of the intestinal barrier by nutrients: The role of tight junctions

  2020cited by this paper
• Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

  2020cited by this paper
• Current Explorations of Nutrition and the Gut Microbiome: A Comprehensive Evaluation of the Review Literature.

  2020cited by this paper
• Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis

  2020cited by this paper
• Intestinal permeability, microbial translocation, changes in duodenal and fecal microbiota, and their associations with alcoholic liver disease progression in humans

  2020cited by this paper
• Developing a Novel Ambulatory Total Parenteral Nutrition-Dependent Short Bowel Syndrome Animal Model.

  2019cited by this paper
• Mechanisms of Parenteral Nutrition-Associated Liver and Gut Injury.

  2019cited by this paper
• Treatment of Clostridioides (Clostridium) difficile infection

  2019cited by this paper
• Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial

  2019cited by this paper
• Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis.

  2019cited by this paper
• IL-10 produced by macrophages regulates epithelial integrity in the small intestine

  2019cited by this paper
• INFLAMMATION AND CELL DEATH DURING CHOLESTASIS: THE EVOLVING ROLE OF BILE ACIDS.

  2019cited by this paper
• Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis by Suppressing Caspase 3 Expression.

  2019cited by this paper
• Fecal Microbiota Transplantation

  2019cited by this paper
• What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases

  2019cited by this paper
• Intestinal Failure and Rehabilitation.

  2018cited by this paper
• Intestine farnesoid X receptor agonist and the gut microbiota activate G‐protein bile acid receptor‐1 signaling to improve metabolism

  2018cited by this paper
• Role of the Gut–Liver Axis in Driving Parenteral Nutrition-Associated Injury

  2018cited by this paper
• Actinobacteria: A relevant minority for the maintenance of gut homeostasis.

  2018cited by this paper
• Administration of antibiotics contributes to cholestasis in pediatric patients with intestinal failure via the alteration of FXR signaling

  2018cited by this paper
• No Gut No Gain! Enteral Bile Acid Treatment Preserves Gut Growth but Not Parenteral Nutrition–Associated Liver Injury in a Novel Extensive Short Bowel Animal Model

  2018cited by this paper
• Mechanisms regulating intestinal barrier integrity and its pathological implications

  2018cited by this paper
• Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

  2017cited by this paper
• Gut microbiota functions: metabolism of nutrients and other food components

  2017cited by this paper
• Intestinal epithelial claudins: expression and regulation in homeostasis and inflammation

  2017cited by this paper
• Proteobacteria: A Common Factor in Human Diseases

  2017cited by this paper
• Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection – fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy

  2017cited by this paper
• Fecal Microbiota Transplantation.

  2017cited by this paper
• Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile Acid–Treated Animals Receiving Parenteral Nutrition

  2017cited by this paper
• The role of I-FABP as a biomarker of intestinal barrier dysfunction driven by gut microbiota changes in obesity

  2016cited by this paper
• Epidermal Growth Factor and Intestinal Barrier Function

  2016cited by this paper
• Oleanolic Acid Improves Gut Atrophy Induced by Parenteral Nutrition.

  2016cited by this paper
• Parenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines.

  2016cited by this paper
• Liver Disease, Systemic Inflammation, and Growth Using a Mixed Parenteral Lipid Emulsion, Containing Soybean Oil, Fish Oil, and Medium Chain Triglycerides, Compared With Soybean Oil in Parenteral Nutrition-Fed Neonatal Piglets.

  2016cited by this paper
• The role of intestinal epithelial barrier function in the development of NEC

  2015cited by this paper
• Validating hyperbilirubinemia and gut mucosal atrophy with a novel ultramobile ambulatory total parenteral nutrition piglet model.

  2015cited by this paper
• IL-10 Production in Macrophages Is Regulated by a TLR-Driven CREB-Mediated Mechanism That Is Linked to Genes Involved in Cell Metabolism

  2015cited by this paper
• Taxonomy, Physiology, and Natural Products of Actinobacteria

  2015cited by this paper
• The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.

  2015cited by this paper
• Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review.

  2014cited by this paper
• Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.

  2014cited by this paper
• Distinct Interactions with Cellular E-Cadherin of the Two Virulent Metalloproteinases Encoded by a Bacteroides fragilis Pathogenicity Island

  2014cited by this paper
• Immunohistochemical study for the origin of ductular reaction in chronic liver disease.

  2014cited by this paper
• The bile acid TGR5 membrane receptor: from basic research to clinical application.

  2014cited by this paper
• Metabolic effects of bile acids in the gut in health and disease.

  2014cited by this paper
• The gut microbiota and the liver. Pathophysiological and clinical implications.

  2013cited by this paper
• Standardized Frozen Preparation for Transplantation of Fecal Microbiota for Recurrent Clostridium difficile Infection

  2012cited by this paper
• Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs.

  2012cited by this paper
• Probiotic treatment with Probioflora in patients with predicted severe acute pancreatitis without organ failure.

  2012cited by this paper
• Environmental and Gut Bacteroidetes: The Food Connection

  2011cited by this paper
• Depletion of Murine Intestinal Microbiota: Effects on Gut Mucosa and Epithelial Gene Expression

  2011cited by this paper
• Bacteroides fragilis Enterotoxin Induces Human β-Defensin-2 Expression in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase/IκB Kinase/NF-κB-Dependent Pathway

  2010cited by this paper
• Intestinal bile acid physiology and pathophysiology.

  2008cited by this paper
• The role of FXR in disorders of bile acid homeostasis.

  2008cited by this paper
• Bile Acid Transporters: Structure, Function, Regulation and Pathophysiological Implications

  2007cited by this paper
• Total Parenteral Nutrition Causes Circumferential Intestinal Atrophy, Remodeling of the Intestinal Wall, and Redistribution of Eosinophils in the Rat Gastrointestinal Tract

  2007cited by this paper
• Mechanisms of Disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis

  2007cited by this paper
• Increased CXCR3 expression associated with CD3-positive lymphocytes in the liver and biliary remnant in biliary atresia.

  2006cited by this paper
• Regulation of Complement C3 Expression by the Bile Acid Receptor FXR*

  2005cited by this paper
• The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism.

  2005cited by this paper
• Onset of small intestinal atrophy is associated with reduced intestinal blood flow in TPN-fed neonatal piglets.

  2004cited by this paper
• Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

  2004cited by this paper
• Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway.

  2004cited by this paper
• Early developments and clinical applications of total parenteral nutrition.

  2003cited by this paper
• Identification of a nuclear receptor for bile acids.

  1999cited by this paper
• Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

  1998cited by this paper
• Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin.

  1998cited by this paper
• Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents.

  1996cited by this paper
• Total parenteral nutrition-associated cholestasis in infants: clinical and liver histologic studies.

  1993cited by this paper

• No citing papers are available for this paper.