Paracellular transport explained

Paracellular transport refers to the transfer of substances across an epithelium by passing through the intercellular space between the cells.^[1] It is in contrast to transcellular transport, where the substances travel through the cell, passing through both the apical membrane and basolateral membrane.^{[2] [3]}

The distinction has particular significance in renal physiology and intestinal physiology. Transcellular transport often involves energy expenditure whereas paracellular transport is unmediated and passive down a concentration gradient,^[4] or by osmosis (for water) and solvent drag for solutes.^[5] Paracellular transport also has the benefit that absorption rate is matched to load because it has no transporters that can be saturated.

In most mammals, intestinal absorption of nutrients is thought to be dominated by transcellular transport, e.g., glucose is primarily absorbed via the SGLT1 transporter and other glucose transporters. Paracellular absorption therefore plays only a minor role in glucose absorption,^[6] although there is evidence that paracellular pathways become more available when nutrients are present in the intestinal lumen.^[7] In contrast, small flying vertebrates (small birds and bats) rely on the paracellular pathway for the majority of glucose absorption in the intestine.^{[8] [9]} This has been hypothesized to compensate for an evolutionary pressure to reduce mass in flying animals, which resulted in a reduction in intestine size and faster transit time of food through the gut.^{[10] [11]}

Capillaries of the blood–brain barrier have only transcellular transport, in contrast with normal capillaries which have both transcellular and paracellular transport.

The paracellular pathway of transport is also important for the absorption of drugs in the gastrointestinal tract. The paracellular pathway allows the permeation of hydrophilic molecules that are not able to permeate through the lipid membrane by the transcellular pathway of absorption. This is particularly important for hydrophilic pharmaceuticals, which may not have affinity for membrane-bound transporters, and therefore may be excluded from the transcellular pathway.The vast majority of drug molecules are transported through the transcellular pathway, and the few which rely on the paracellular pathway of transportation typically have a much lower bioavailability; for instance, levothyroxine has an oral bioavailability of 40 to 80%, and desmopressin of 0.16%.

Structure of paracellular channels

Some claudins form tight junction-associated pores that allow paracellular ion transport.^[12]

The tight junctions have a net negative charge, and are believed to preferentially transport positively charged molecules. Tight junctions in the intestinal epithelium are also known to be size-selective, such that large molecules (with molecular radii greater than about 4.5Å) are excluded.^{[13] [14] [15]} Larger molecules may also pass the intestinal epithelium via the paracellular pathway, although at a much slower rate and the mechanism of this transport via a "leak" pathway is unknown but may include transient breaks in the epithelial barrier.

Paracellular transport can be enhanced through the displacement of zona occludens proteins from the junctional complex by the use of permeation enhancers. Such enhancers include medium chain fatty acids (e.g. capric acid), chitosans, zona occludens toxin, etc.

Notes and References

1. Web site: Calcium Adsorption . https://web.archive.org/web/20060307095305/http://www.citracal.com/gfx/dyk_absorption.gif . 2006-03-07 . Citracal . Bayer .
2. Web site: Blystone R . Trinity University . Epithelial Transcellular Transport . https://web.archive.org/web/20070209063321/http://www.trinity.edu/rblyston/MicroA/Lectures/L07pt2-html/sld022.htm . 9 February 2007 .
3. Book: Essentials of Human Physiology. Nosek TM . Transport Across a Cell Layer: Transcellular Transport . http://humanphysiology.tuars.com/program/section1/1ch2/s1ch2_37.htm . https://web.archive.org/web/20160324124828/http://humanphysiology.tuars.com/program/section1/1ch2/s1ch2_37.htm. 2016-03-24.
4. Web site: Barac-Nieto M . Renal Physiology Tutorial Web Site . Department of Physiology. Kuwait University . Tubular Transport . https://web.archive.org/web/20060214165532/http://www.acbrown.com/renal/OutTubl.htm . 14 February 2006 .
5. Book: Hall . John E. . Guyton and Hall textbook of medical physiology. . 2020 . Amsterdam . 9780323640039 . Fourteenth . Passive Water Reabsorption by Osmosis Coupled Mainly to Sodium Reabsorption.
6. Schwartz RM, Furne JK, Levitt MD . Paracellular intestinal transport of six-carbon sugars is negligible in the rat . Gastroenterology . 109 . 4 . 1206–1213 . October 1995 . 7557087 . 10.1016/0016-5085(95)90580-4 . free .
7. Pappenheimer JR, Reiss KZ . Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat . The Journal of Membrane Biology . 100 . 2 . 123–136 . 1987 . 3430569 . 10.1007/BF02209145 . 20716486 .
8. Lavin SR, Karasov WH . Allometry of paracellular absorption in birds . Physiological and Biochemical Zoology . 81 . 5 . 551–560 . 2008 . 18752419 . 10.1086/588176 . 12228465 .
9. Price ER, Rott KH, Caviedes-Vidal E, Karasov WH . Paracellular nutrient absorption is higher in bats than rodents: integrating from intact animals to the molecular level . The Journal of Experimental Biology . 217 . Pt 19 . 3483–3492 . October 2014 . 25063860 . 10.1242/jeb.105619 . free . 11336/14502 . free .
10. Caviedes-Vidal E, McWhorter TJ, Lavin SR, Chediack JG, Tracy CR, Karasov WH . The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts . Proceedings of the National Academy of Sciences of the United States of America . 104 . 48 . 19132–19137 . November 2007 . 18025481 . 2141920 . 10.1073/pnas.0703159104 . 2007PNAS..10419132C . free .
11. Price ER, Brun A, Caviedes-Vidal E, Karasov WH . Digestive adaptations of aerial lifestyles . Physiology . 30 . 1 . 69–78 . January 2015 . 25559157 . 10.1152/physiol.00020.2014 . 11336/14497 . free .
12. Anderson JM, Van Itallie CM . Physiology and function of the tight junction . Cold Spring Harbor Perspectives in Biology . 1 . 2 . a002584 . August 2009 . 20066090 . 2742087 . 10.1101/cshperspect.a002584 .
13. Chediack JG, Caviedes-Vidal E, Fasulo V, Yamin LJ, Karasov WH . Intestinal passive absorption of water-soluble compounds by sparrows: effect of molecular size and luminal nutrients . Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology . 173 . 3 . 187–197 . April 2003 . 12743721 . 10.1007/s00360-002-0314-8 . 26845857 .
14. Turner JR, Buschmann MM, Romero-Calvo I, Sailer A, Shen L . The role of molecular remodeling in differential regulation of tight junction permeability . Seminars in Cell & Developmental Biology . 36 . 204–212 . December 2014 . 25263012 . 4253049 . 10.1016/j.semcdb.2014.09.022 .
15. Caviedes-Vidal E, McWhorter TJ, Lavin SR, Chediack JG, Tracy CR, Karasov WH . The digestive adaptation of flying vertebrates: high intestinal paracellular absorption compensates for smaller guts . Proceedings of the National Academy of Sciences of the United States of America . 104 . 48 . 19132–19137 . November 2007 . 18025481 . 2141920 . 10.1073/pnas.0703159104 . 2007PNAS..10419132C . free .