2. Academic Validation
  3. Quantifying Forms and Functions of Enterohepatic Bile Acid Pools in Mice

Quantifying Forms and Functions of Enterohepatic Bile Acid Pools in Mice

  • Cell Mol Gastroenterol Hepatol. 2024 Aug 22;18(6):101392. doi: 10.1016/j.jcmgh.2024.101392.
Koichi Sudo 1,  Amber Delmas-Eliason 2,  Shannon Soucy 3,  Kaitlyn E Barrack 4,  Jiabao Liu 5,  Akshaya Balasubramanian 4,  Chengyi Jenny Shu 6,  Michael J James 6,  Courtney L Hegner 7,  Henry D Dionne 1,  Alex Rodriguez-Palacios 8,  Henry M Krause 9,  George A O'Toole 4,  Saul J Karpen 10,  Paul A Dawson 11,  Daniel Schultz 4,  Mark S Sundrud 12
Affiliations

Affiliations

  • 1 Center for Digestive Health, Dartmouth Health, Lebanon, New Hampshire.
  • 2 Department of Immunology and Microbiology, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida.
  • 3 Department of Biomedical Data Science, Geisel School of Medicine, Hanover, New Hampshire.
  • 4 Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire.
  • 5 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
  • 6 Synlogic Therapeutics, Cambridge, Massachusetts.
  • 7 The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida.
  • 8 Division of Gastroenterology and Liver Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Research and Education Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio.
  • 9 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 10 Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia; Stravitz-Sanyal Liver Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
  • 11 Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia.
  • 12 Center for Digestive Health, Dartmouth Health, Lebanon, New Hampshire; Department of Immunology and Microbiology, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida; Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida; Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire; Dartmouth Cancer Center, Lebanon, New Hampshire. Electronic address: mark.sundrud@dartmouth.edu.
PMID: 39179177 DOI: 10.1016/j.jcmgh.2024.101392
Abstract

Backgrounds & aims: Bile acids (BAs) are core gastrointestinal metabolites with dual functions in lipid absorption and cell signaling. BAs circulate between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with host intestinal cells in vivo remain poorly understood. Because ileal absorption is rate-limiting in determining which BAs in the intestinal lumen gain access to host intestinal cells and receptors, and at what concentrations, we hypothesized that defining the rates and routes of ileal BA absorption in vivo would yield novel insights into the physiological forms and functions of mouse enterohepatic BA pools.

Methods: Using ex vivo mass spectrometry, we quantified 88 BA species and metabolites in the intestinal lumen and superior mesenteric vein of individual wild-type mice, and cage-mates lacking the ileal BA transporter, Asbt/Slc10a2.

Results: Using these data, we calculated that the pool of BAs circulating through ileal tissue (i.e., the ileal BA pool) in fasting C57BL/6J female mice is ∼0.3 μmol/g. Asbt-mediated transport accounted for ∼80% of this pool and amplified size. Passive permeability explained the remaining ∼20% and generated diversity. Compared with wild-type mice, the ileal BA pool in Asbt-deficient mice was ∼5-fold smaller, enriched in secondary BA species and metabolites normally found in the colon, and elicited unique transcriptional responses on addition to exvivo-cultured ileal explants.

Conclusions: This study defines quantitative traits of the mouse enterohepatic BA pool and reveals how aberrant BA metabolism can impinge directly on host intestinal physiology.

Keywords

ASBT; Bile Acids; Enterohepatic Circulation; Intestinal Absorption.

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