Transport and absorption of nutrients in the gastrointestinal tract

Adam Macierzanka Adam.Macierzanka@ifr.ac.uk

Transport of food/nutrients in the gastrointestinal tract

Transport of food along the GI tract, Roles of the individual parts of the

GI tract, Transport across the GI tract mucosa Role of the mucus layer, Role of the chemical compounds e.g.

bile salts, phospholipids, Absorption of nutrients.

The digestive system includes many organs, and each organ has many various regions. The main tract through the digestive system (from the mouth, through the stomach and intestines) is called the gastrointestinal tract (GI) or the alimentary canal.

The Mouth

breaking large pieces into small pieces, resulting in a massive increase in surface area, which is where digestive enzymes work,

warming or cooling of the food, softening of food and transformation into a size conducive to

swallowing, lubrication of food by mixing it with saliva.

Mastication (grounding, chewing) is the first step in the breakdown of complex foods and serves several functions, including:

Lubrication and binding: the mucus (mucins) in saliva is effective in binding masticated food into a slippery bolus that slides easily through the esophagus without inflicting damage to the mucosa.

Coats the oral cavity and esophagus: food basically never directly touches the epithelial cells of those tissues.

Solubilizes dry food: in order to be tasted, the molecules in food must be solubilized.

Oral hygiene: Saliva contains lysozyme, an enzyme that lyses many bacteria and prevents overgrowth of oral microbial populations.

Initiates digestion: Saliva contains an alpha-amylase which can begin to digest dietary starch into maltose.

Saliva is a watery substance in the mouths secreted by the salivary glands. Human saliva is composed of 99.5% water; the other 0.5% consists of electrolytes, mucus, enzymes, and antibacterial compounds.

adapted from: R. Bowen, Colorado State University ©

Mouth → Stomach

The Stomach

The wet mass of broken up food and digestive chemicals is called chyme.

• It serves as a short-term storage reservoir, allowing a meal to be consumed quickly and dealt with over an extended period of time.

• In the stomach a substantial enzymatic digestion is initiated, particularly of proteins by pepsin. Low pH (pH 2-3).

• Contractions of gastric smooth muscle mix food with gastric secretions, resulting in liquefaction of food, a prerequisite for delivery of the ingesta to the small intestine.

• As food is liquefied, it is slowly released into the small intestine for further processing.

The Stomach

MRI images of the human stomach immediately prior to (left) and immediately after (right) consumption of a liquid meal. Also shown is a schematic representation of the process in which the area of the green region (gastric secretion) is the same in both shapes. A. R. Mackie, A. N. Round, N. M. Rigby, A. Macierzanka; Food Digestion (2012) 3:8–15

The Stomach

The thicknesses of the loosely adherent and firmly adherent mucus layers in vivo in the rat gastrointestinal tract (from C. Atuma et al., Am. J. Physiol. Gastrointest. Liver 280 (2001) G922–G929).

The Stomach

Possible role of an extracellular lining of zwitterionic phospholipids in generating the hydrophobic barrier of the stomach to luminal acid.

From: L.M. Lichtenberger, Annu. Rev. Physiol., 1995, 57, 565–583, and L. M. Ensign, R. Cone, J. Hanes; Advanced Drug Delivery Reviews, 2012, 64, 557-570.

Phospholipid Interactions Protect the Milk α-Lactalbumin from Pepsinolysis during in vitro Digestion

SDS-PAGE analysis of α-La subjected to gastric digestion over 120 min in the absence (A) or presence (B) of phosphatidylcholine (PC) F. J. Moreno et al., J. Agric. Food Chem. 2005, 53, 9810-9816

The Stomach

The Small Intestine

The average length in an adult human male is 7 m.

It is approximately 2.5–3 cm in diameter.

The small intestine is the main site for digestion and absorption of nutrients.

Enzymatic Transport into the Duodenum

Most digestion occurs in the upper portion of the small intestine, called the duodenum.

Absorption of nutrients

The structure of the small intestine, in place to aid absorption of nutrients, consists of three levels: on the macro-scale, folds or plicae intrude into the lumen; on the meso-scale villi cover the surface; and on the micro-scale microvilli cover the villi on a cellular level.

• The surface area of the intestine is well suited to its function: the structural adaptations of mucosal folds, villi and microvilli give a total absorptive area for the small intestine of 200-500 m² (600-fold increase over the projected surface area of a smooth-surfaced tube of equivalent length). The small intestine normally absorbs far in excess of body needs – the major portion of this organ can be removed without deleterious effect.

• The major function of the small intestine is absorption of nutrients, water, electrolytes, etc.

• ~ 90% of nutrients from ingested food are absorbed in the small intestine

About five million villi (up to 1mm long) line the small intestine

Intestinal Motility

• contractions of small intestine serve three functions: – to mix chyme with intestinal juice, bile, and pancreatic juice

• to neutralize acid • digest nutrients more effectively

– to churn chyme and bring it in contact with the mucosa for contact digestion and nutrient absorption – to move residue toward large intestine

Intestinal Motility Segmentation & Peristalsis

Segmentation – the movement in which stationary ringlike constrictions appear in several places along the intestine – they relax and new constrictions form elsewhere – most common kind of intestinal contraction – pacemaker cells in muscularis externa set rhythm of segmentation • contractions about 12 times per minute in the duodenum • 8 to 9 times per minute in the ileum

Peristalsis – The Migrating Motor Complex

• gradual movement of contents towards colon • peristaltic wave begins in the duodenum, travels 10 to 70 cm and dies out • followed by another wave starting further down the tract

• migrating motor complex – successive, overlapping waves of contraction

• move chyme toward colon over a period of two hours • ileocecal valve usually closed

• food in stomach triggers gastroileal reflex that enhances segmentation in the ileum and relaxes the valve

• as cecum fills with residue, pressure pinches the valve shut (prevents reflux of cecal contents into the ileum)

The terminal ileum

Silva A C et al. Radiographics 2007;27:1039-1054

Food bolus propelled through the intestine via peristaltic contractions

Mucins adhere to the food, wrapping it in a ‘blanket’ of mucus.

The shear thinning properties of the mucus allow the bolus to pass without perturbing the epithelium.

Enzymes that can pass through the mucus will begin to digest the food, extracting nutrients.

PERISTALSIS

from L. M. Ensign, R. Cone, J. Hanes; Advanced Drug Delivery Reviews, 2012, 64, 557-570.

Pig small intestine (jejunum)

Mucus Lamina propria

Pig small intestine (jejunum)

Glycoprotein MUCIN monomer consisting of glycosylated regions flanked by regions with relatively little glycosylation.

from R. Bansil, B. S. Turner; Current Opinion in Colloid & Interface Science 11 (2006) 164 – 170

The cellular assembly of mucin MUC2, showing the main domains in the primary sequence. The monomer shows the highly variable main tandem repeat region also known as the proline, threonine, and serine (PTS)-rich region in yellow. Also shown in various colors are the terminal domains that are so similar to vWF, all of which are disulfide-rich. In the Golgi and granule, the heavy glycation of the PTS regions are shown in green. This also highlights the formation of dimers, trimers, and higher oligomers. A. R. Mackie, A. N. Round, N. M. Rigby, A. Macierzanka; Food Digestion (2012) 3:8–15

Small intestinal MUC2 mucins form trimers

Biomacromolecules (2012) 13, 3253

Andrew Round University of east Anglia

AFM data

250 nm

Columnar epithelial cells

Goblet cell

VILLUS

Electron micrograph of a goblet cell from the small intestine secreting mucus to the extracellular space.

Mucin monomer length (nm)

Small intestinal mucins (MUC2) form a network

A. N. Round et al., Biomacromolecules 2012, 13, 3253−3261

250 nm

A correct expansion of mucin granules requires a fast pH increase and Ca2+ removal (mucins are packed inside the goblet cell granule by Ca2+ -dependent cross-linking).

A lamellar model for the mucus barrier

AFM data show unpacking

and expansion of MUC2 mucin granules

MUC2 mucin forms porous

flat lamellar networks, linked

by covalent trimeric bonds

rather than by physical entanglement

There is little interaction between

lamellae. In vivo this predicts the

existence of transient channels forming between lamellae

Andrew Round et al. Biomacromolecules (2012) 13, 3253

Surface of the small intestine

50 um 100 um

100 um

Mucin DNA

Numerous pores that open into tubular glands on the floor of the small intestine between the bases of the villi. – similar to gastric glands – in upper half, have enterocytes and goblet cells like the villi – in lower half, dominated by dividing stem cells

• life span of 3 to 6 days • new epithelial cells migrate up the

crypt to the tip of the villus where it is sloughed off

– a few Paneth Cells are clustered at the base of each crypt

• secrete lysozyme, phospholipase, and defensins (defensive proteins that resist bacterial invasion of the mucosa)

Intestinal Crypts

The intestinal epithelium undergoes continuous self-renewal to maintain tissue homeostasis (stability) and eliminate damaged cells. The epithelial cells are constantly renewed through a process in which stem cells generated in the crypts migrate to the tip of the villi and ultimately peel off into the lumen. from H. Ashida et al., Nature Chemical Biology, 8, 36–45 (2012)

The epithelial cells shedding

Surface of the small intestine

J. Hanes et al., Adv. Drug Delivery Rev., 61 (2009) 158

Administration of particles to a mucosal

surface

Is the mucus layer a continuous homogenous barrier?

If not how does that affect transport of particulates?

TRANSPORT through the intestinal mucus

Mucin DNA Merge

31.25 x 31.25 μm

Confocal microscopy of the porcine small intestine mucus

The small intestinal mucus contains mucin and DNA

Mucin DNA Merge

62.5 x 62.5 um

Mucus from the small intestine of piglet

PIG vs. PIGLET

Transport of probe particles (latex beads) in the intestinal mucus

Enzymatic Transport into the Duodenum

Food particulate covered with bile salts (negative charge)

- - - -

Diffusion of solid particles (500 nm) coated with BS; 37oC)

100 μm

bile salt

Maldano-Valderrama J., Wilde P., Macierzanka A., Mackie A.R. (2011) The role of bile salts in digestion. Advances in Colloid and Interface Science, 165 36-46

The role of BILE SALTS (BS) in the transport through the small intestine mucus

Diffusion of solid particles in the small intestine mucus

Ensemble mean-squared displacements (MSD)

- Distance travelled by the diffusing particles

+BS ζ-potential -50 mV

-BS ζ-potential -15 mV

Diffusion was driven by high negative charged provided by bile salts (BS) adsorbed to latex beads

The role of BILE SALTS (BS) in the transport through the small intestine mucus

CONFOCAL MICROSCOPY (diffusion of latex beads)

All three sizes of latex particles show the same viscosity distribution in

the presence of bile salts

A. Macierzanka et al., Soft Matter (2011) 7 8077-8084

In vitro gastro-duodenal digestion (proteolysis) of NaCas stabilised O/W emulsion in the presence or absence of bile salts (BS).

Transport of post-digestion emulsion droplets

Gastro-duodenal emulsions (GDEs), +/- BS

In vitro gastro-duodenal digestion (proteolysis) of NaCas stabilised O/W emulsion in the presence or absence of bile salts (BS).

(A) Gastro-duodenal emulsion (GDE) droplet size distributions

(B) ζ-potential of GDEs

(C) GDE droplets interacting with intestinal ex vivo mucus in the presence or

absence of BS adsorbed onto the surface of droplets. Images 1 and 2 show

droplets in the absence of BS after 15-min and 3-h incubation, respectively.

Image 3 shows emulsion droplets in the presence of BS (30-min incubation).

A. Macierzanka et al., Soft Matter (2011) 7 8077-8084

Bile salts are key in transport of food particulates through mucus

Interaction of bacteria with the ex vivo

intestinal mucus GFP E. coli (non-flagellated)

+ Bile Salts ζ ≈ -19mV

10 min

30 min

100 μm

- Bile Salts ζ ≈ -18mV

Weak negative charge of bacteria cells - no diffusion into the mucus!

Food Digestion, 2012, in press

Mucus: + Bile Salts, ζ ≈ -11mV - Bile Salts, ζ ≈ -10mV

Bacteria:

Fluorescence recovery after photobleaching (FRAP)

Aggregated networks of seed storage globulins from peanut and soybean render them resistant to proteolysis

Gelation of peanut 7S at 100 oC

15 min

30 min

Confocal microscopy (FRAP method): diffusion of FITC-labelled pepsin in the protein gels

Peanut 7S gel:

D = 0.49 ± 0.14 μm2/s

Soybean 7S gel:

D = 0.75 ± 0.11 μm2/s

Digestion kinetics can be altered by structuring of colloids !

Slow diffusion of pepsin:

Peanut Soybean

Large majority of nutrients from the diet are absorbed through the epithelial cells lining the small intestine. In addition, the intestine absorbs water and electrolytes, thus playing a critical role in maintenance of body water and acid-base balance.

Absorption in the small intestine

Columnar Epithelial Cells (Enterocytes)

Goblet cell

Villus

Microvilli

40 μm

• The epithelial cells of the villi transport nutrients from the lumen of the intestine into capillaries (amino acids and carbohydrates) and lacteals (lipids).

• Each villus has a network of capillaries and fine lymphatic vessels (lacteals) close to its surface.

• The absorbed substances are transported via the blood vessels to different organs of the body where they are used to build complex substances such as the proteins required by our body.

• The food that remains undigested and unabsorbed passes into the large intestine. adapted from: Rhoades, R. and Pflanzer R., Eds. The Gastrointestinal System.

Human Physiology, 2nd Ed. Saunders College Publishing; 1992: 777-822

• The small intestine must absorb massive quantities of water. A normal person takes in 1 – 2 liters of dietary fluid every day. Another 6 – 7 liters of fluid is received by the small intestine as secretions from salivary glands, stomach, pancreas, liver and the small intestine itself.

• By the time the ingesta enters the large intestine,

approximately 80% of this fluid has been absorbed. • The absorption of water is absolutely dependent on

absorption of solutes, particularly sodium.

Absorption of Water and Electrolytes

• Sodium is absorbed into the cell by several mechanisms, but mainly by cotransport with glucose and amino acids - this means that efficient sodium absorption is dependent on absorption of these organic solutes.

• Absorbed sodium is rapidly exported from the cell via sodium pumps - when a lot of sodium is entering the cell, a lot of sodium is pumped out of the cell, which establishes a high osmolarity in the small intercellular spaces between adjacent enterocytes.

• Water diffuses in response to the osmotic gradient established by sodium - in this case into the intercellular space. It seems that the bulk of the water absorption is transcellular, but some also diffuses through the tight junctions.

• Water, as well as sodium, then diffuses into capillary blood within the villus.

Absorption of Water and Electrolytes

The key concepts involved in assimilation of carbohydrates (such as starch, lactose and sucrose) are:

• Polysaccharides and disaccharides must be digested to monosaccharides prior to absorption. • The final enzymatic digestion that releases monosaccharides is

conducted by integral membrane enzymes of absorptive enterocytes (so-called "brush border hydrolases").

Absorption of Monosaccharides

Epithelial cell

Microvilli • Fructose enters the cell from the intestinal lumen via facilitated diffusion. • Glucose generated by digestion is

absorbed in the small intestine only by co-transport with sodium using the sodium-dependent hexose transporter.

The transport by the sodium-dependent hexose transporter involves a series of conformational changes induced by binding and release of sodium and glucose: 1. The transporter is initially oriented facing into

the lumen - at this point it is capable of binding sodium, but not glucose.

2. Sodium binds, inducing a conformational change that opens the glucose-binding pocket.

3. Glucose binds and the transporter reorients in the membrane such that the pockets holding sodium and glucose are moved inside the cell (two sodium ions are transported for each glucose).

4. Sodium dissociates into the cytoplasm, causing glucose binding to destabilize.

5. Glucose dissociates into the cytoplasm and the unloaded transporter reorients back to its original, outward-facing position.

Absorption of Glucose

Alan R. Mackie and Adam Macierzanka; Current Opinion in Colloid & Interface Science 15 (2010) 102–108

The key concepts involved in assimilation of dietary proteins are: • Through the action of gastric and

pancreatic proteases, dietary proteins are hydrolysed predominantly into medium and small peptides (oligopeptides).

• Oligopeptides are further

hydrolysed by the brush border peptidases to free amino acids and very small peptides.

Absorption of Amino Acids and Peptides

Epithelial cell

Microvilli

• There is virtually no absorption of peptides longer than four amino acids. However, there is abundant absorption of di- and tripeptides in the small intestine. These small peptides are absorbed into the epithelial cell by cotransport with H+ ions via a transporter called PepT1.

• Once inside the cell, most of di- and tripeptides are digested into amino

acids by cytoplasmic peptidases and exported from the cell into blood.

Absorption of Peptides

• The mechanism by which amino acids are absorbed is conceptually identical to that of monosaccharides (i.e. sodium-dependent transporters).

• Thus, absorption of amino acids, like that of monosaccharides, contributes

to generating the osmotic gradient that drives water absorption.

Absorption of Amino Acids

In order for lipids to be absorbed, two processes must occur:

• Large aggregates of dietary triglycerides, which are virtually insoluble in an aqueous environment, must be broken down physically and held in suspension - a process called emulsification.

• Triglyceride molecules must be

enzymatically digested to yield monoglyceride and fatty acids, both of which can efficiently diffuse or be transported into the enterocyte

Absorption of Fats/Lipids (Triglycerides)

• The major products of lipid digestion - fatty acids (FA) and 2-monoglycerides (MG) - enter the enterocyte by simple diffusion or via a specific fatty acid transporter protein in the membrane.

• FA and MG are transported into the endoplasmic reticulum, where they are used to synthesize triglyceride. Continuing in the Golgi, triglyceride is packaged with cholesterol, lipoproteins and other lipids into particles called chylomicrons.

Absorption of Fats/Lipids (Triglycerides)

• Chylomicrons are transported first into the lymphatic vessel (lacteal) that penetrates into each villus. Chylomicron-rich lymph then drains into the lymphatic system, which rapidly flows into blood.

, R. a

• The ileocecal valve of the ileum (small intestine) passes material into the large intestine at the cecum.

• Partly digested food moves through the cecum into the colon, where water and some nutrients and electrolytes are removed.

• The colon is responsible for reabsorption of 1.0 to 1.5 liters of electrolyte-rich fluid entering it each day from the proximal intestine.

• The remaining material, solid waste called stool, moves through the colon, is stored in the rectum, and leaves the body through the anal canal and anus.

The Large Intestine

• The large intestine is about 1.5 m long.

• It absorbs mainly water and minerals and produces and eliminates fecal matter.

versus

The large intestine primarily absorbs water, and compacts and dries out the fecal bolus: villi would be a hindrance to movement of the semi-solid fecal mass, and would likely be injured by its passage. Hence there are no villi in the large intestine, and in addition, there are numerous goblet cells whose secretions (mucins) act as lubrication for the moving material.

The Large Intestine

Section of large intestine showing goblet cells secreting mucus to the extracellular space of the intestinal crypt. Goblet cell are in larger numbers than in the small intestine.

Epithelial cell Goblet cell

Johansson et al., PNAS 2008, 105, 15064–15069

Thank you

Transport and absorption of nutrients in the gastrointestinal tract

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