title: Food-associated stimuli enhance barrier properties of gastrointestinal mucus.
abstract: Orally delivered drugs and nutrients must diffuse through mucus to enter the circulatory system, but the barrier properties of mucus and their modulation by physiological factors are generally poorly characterized. The main objective of this study was to examine the impact of physicochemical changes occurring upon food ingestion on gastrointestinal (GI) mucus barrier properties. Lipids representative of postprandial intestinal contents enhanced mucus barriers, as indicated by a 10-142-fold reduction in the transport rate of 200 nm microspheres through mucus, depending on surface chemistry. Physiologically relevant increases in [Ca(2+)] resulted in a 2-4-fold reduction of transport rates, likely due to enhanced cross-linking of the mucus gel network. Reduction of pH from 6.5 to 3.5 also affected mucus viscoelasticity, reducing particle transport rates approximately 5-10-fold. Macroscopic visual observation and micro-scale lectin staining revealed mucus gel structural changes, including clumping into regions into which particles did not penetrate. Histological examination indicated food ingestion can prevent microsphere contact with and endocytosis by intestinal epithelium. Taken together, these results demonstrate that GI mucus barriers are significantly altered by stimuli associated with eating and potentially dosing of lipid-based delivery systems; these stimuli represent broadly relevant variables to consider upon designing oral therapies.
authors.affiliation: Department of Chemical Engineering, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Hasan M
authors.initials: HM
authors.lastname: Yildiz
authors.affiliation: Department of Bioengineering, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Speciner
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Cafer
authors.initials: C
authors.lastname: Ozdemir
authors.affiliation: Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: Department of Chemical Engineering, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA. Electronic address: r.carrier@neu.edu.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Carrier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004063:Digestion / Q000502:physiology; D055119:Elastic Modulus / Q000502:physiology; D005502:Food; D005766:Gastrointestinal Contents / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D009093:Mucus / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014783:Viscosity
chemical_list: D002118:Calcium
keywords: Diffusion; Food effect; Mucosal barriers; Mucus; Oral drug delivery