Size selectivity of intestinal mucus to diffusing particulates is dependent on surface chemistry and exposure to lipids.

Intestinal mucus provides a significant barrier to transport of orally delivered drug carriers, as well as other particulates (e.g. food, microbes). The relative significance of particle size, surface chemistry, and dosing medium to mucus barrier properties is not well characterized, but important in designing delivery systems targeted to the intestinal mucosa. In this study, multiple particle tracking (MPT) was used to study diffusion of 20-500 nm diameter carboxylate- and polyethylene glycol-(PEG-)functionalized polystyrene model carriers through intestinal mucus. The impact of exposure to mucus in buffer versus a partially digested triglyceride mixture was explored. Effective diffusivity of particles in intestinal mucus decreased with an increasing particle size less than and more than theoretically (Stokes-Einstein) expected in a homogenous medium when dosed in buffer and model-fed state intestinal contents, respectively. For example, effective diffusivity decreased 2.9- versus 20-fold with increase in the particle size from 100 to 500 nm when dosed to mucus in buffer versus lipid-containing medium. Functionalization with PEG dramatically decreased sensitivity to lipids in a dosing medium. The results indicate that reduction of particle size may increase particle transport through intestinal mucus barriers, but these effects are strongly dependent on intestinal contents and particle surface chemistry.

Food-associated stimuli enhance barrier properties of gastrointestinal mucus.

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.

Mucus Barriers to Microparticles and Microbes are Altered in Hirschsprung's Disease.

Mucus forms a protective hydrogel layer over the intestinal epithelium, presenting a selective and robust barrier to the uptake of particulates and microbe invasion. Disease can alter mucus production and composition, thus potentially modifying mucosal barrier properties. Hirschsprung's disease (HD) is a developmental abnormality of the nervous system often complicated by intestinal infection. An investigation of colonic mucus barrier properties in an HD animal model, endothelin receptor B mutant mice, revealed significantly reduced microsphere (passive) and microbe (active) transport rates (7-fold and 3.6-fold, respectively, in proximal colonic mucus) relative to wild-type. Transport differences were evident in both the ganglionic and aganglionic colon segments, in agreement with the risk of HD-associated enterocolitis after surgery to remove aganglionic colon segments. The development of therapies aimed at altering colonic mucus barrier properties could be explored towards preventing the onset of enterocolitis in HD.