Digestion and Absorption

Digestion refers to the process of the mechanical and chemical breakdown of food into smaller particles, which can then be absorbed and utilized by the body. Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates, proteins, lipids, and micronutrients are digested and absorbed differently and require several enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and transport proteins to complete the process.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview of Digestion and Absorption

  • Digestion and absorption are complex processes that begin in the mouth but largely occur in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine.
  • Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates:
    • Must be broken down into monosaccharides to be absorbed
    • Primary enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
      • Amylase
      • Brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Absorbed via:
      • Apical side: sodium–glucose-linked transporter (SGLT) 1, glucose transporter (GLUT) 5
      • Basolateral side: GLUT2
  • Proteins:
    • Broken down into peptides and individual amino acids (AAs)
    • Primary enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
      • Pepsin
      • Trypsin
      • Chymotrypsin
      • Carboxypeptidase
      • Elastase
    • Absorbed by specialized cotransporters
  • Lipids:
    • Broken down into its constituents (e.g., triacylglycerides (TAGs) → glycerol + free fatty acids)
    • Primary enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
      • Lipases
      • Cholesterol esterase
      • Phospholipase A2
    • Lipids are reassembled in enterocytes before being released into the interstitial space.
    • Absorbed into the lymphatic circulation
  • Vitamin and mineral absorption varies and depends on the nutrient.
Overview of macromolecule digestion and absorption

Overview of macromolecule digestion and absorption
AA: amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids

Image by Lecturio.

Digestion and Absorption of Carbohydrates

Digestion

Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates are primarily digested by amylases and brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates can only be absorbed as monosaccharides; accordingly, enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes hydrolyze large starch molecules to monosaccharides.

Amylases:

  • Cleavage of α-1,4-glycosidic bonds in sugar molecules
  • Creation of smaller and smaller polysaccharide chains until most α-1,4-glycosidic bonds are broken, leaving behind:
    • Monosaccharides: individual sugar molecules
    • Disaccharides: starches with 2 sugar molecules
    • Oligosaccharides: starches with 3‒10 sugar molecules
    • Indigestible starches: sugars joined by other types of bonds
  • Active at higher pH:
    • Active in the mouth and small intestines
    • Inactivated in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
  • Types and location of amylase:
    • Salivary amylase: secreted in the mouth by the salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands
    • Pancreatic amylase: secreted into the duodenum by the exocrine pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas
Amylopectin

Amylopectin is partially digested by amylase. Amylopectin molecules are chains of glucose, joined together by α-1,4-glycosidic bonds (creation of a straight chain of glucose molecules) and α-1,6-glycosidic bonds (creation of a branch from the straight chain). Amylase breaks the α-1,4-glycosidic bonds.

Image by Lecturio.

Brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:

Brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are membrane-bound proteins on the luminal surface of enterocytes in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine. There are 4 major brush border enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in carbohydrate digestion.

  • Isomaltase: cleaves the α-1,6-glycosidic bonds
  • Maltase:
    • Hydrolyzes maltose → glucose + glucose
    • Hydrolyzes maltotriose → glucose + glucose + glucose
  • Lactase: hydrolyzes lactose → glucose + galactose
  • Sucrase: 
    • Hydrolyzes sucrose → glucose + fructose
    • Hydrolyzes other small oligosaccharides

Absorption

Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates are absorbed as monosaccharides by the enterocytes in the small intestines and transported via blood to the portal circulation. Carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates that cannot be broken down into monosaccharides are not absorbed (e.g., fibers). Monosaccharides are:

  • Moved into the enterocytes by 1 set of transport proteins in the apical membrane:
    • SGLT1:
      • Found in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
      • Transports 2 Na+, 1 glucose or galactose, and water
      • Uses the chemical Na+ gradient generated by the Na+/K+ ATPase pump on the basolateral membrane (keeps intracellular Na+ concentration low)
      • Leads to secondary active transport
    • GLUT5: transports fructose into the cell down its concentration gradient via facilitated diffusion
  • Moved out into the interstitial space by a different transport protein located in the basolateral membrane:
    • GLUT2:
      • Can move all 3 primary monosaccharides: glucose, galactose, and fructose
      • Works via facilitated diffusion
  • Absorbed into the capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries from the interstitial space
  • Capillaries drain into veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins → portal vein → liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver for metabolism
Absorption of monosaccharides

Absorption of monosaccharides across enterocytes
SGLT: sodium–glucose-linked transporter
GLUT: glucose transporter

Image by Lecturio.

Digestion and Absorption of Proteins

Digestion

  • Protein digestion mainly occurs in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and duodenum.
  • Recall: Peptide bonds join the amino terminus of AA to the carboxy terminus of the next AA.
  • Protein digestion occurs via enzymatic hydrolysis of peptide bonds, breaking down proteins into:
    • Small peptides
    • Individual AAs
  • Enzymes involved are:
    • Secreted by the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach and pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas (see table)
    • Bound to the brush border of enterocytes:
      • Aminopeptidases break down small peptides from their amino end (i.e., N-terminus).
      • Dipeptidases break peptide bonds between 2 AAs → 2 single AAs
Table: Secreted enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in protein digestion
Enzyme Zymogen (precursor) Activated by Notes on activity
Gastric enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes secreted into the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
Pepsin Pepsinogen Hydrochloric acid Most efficient between hydrophobic AAs
Pancreatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes secreted into the duodenum
Trypsin Trypsinogen Enteropeptidase
  • Able to activate:
    • More trypsinogen → trypsin
    • All other pancreatic zymogens
  • Most efficient between lysine and arginine
Chymotrypsin Chymotrypsinogen Trypsin Most efficient between hydrophobic AAs
Carboxypeptidase Procarboxypeptidase Trypsin
  • Attacks the carboxy end of peptide chains
  • Generates individual AAs or very short peptide chains
Elastase Proelastase Trypsin Same as carboxypeptidase
AA: amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids

Absorption

  • Absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine.
  • Only AAs, dipeptides, and tripeptides can be absorbed across the apical membrane into the enterocytes.
  • Only individual AAs can be absorbed across the basolateral membrane into the interstitial space.
  • Individual AAs:
    • Absorbed into the enterocytes across the apical membrane via specialized Na+/AA cotransporters:
      • Uses the Na+ gradient created by the Na+/K+ ATPase pump on the basolateral membrane 
      • [Na+] is high in the lumen but low in the enterocytes → Na+ moves down its concentration gradient into the cell, transporting an AA with it
    • Absorbed across the basolateral membrane by specialized transporters (different types of transporters for different types of AAs)
  • Dipeptides and tripeptides:
    • Absorbed by the enterocytes across the apical membrane via specialized H+/PepT cotransporters
    • Uses the H+ gradient created by the H+/Na+ exchanger on the apical membrane (which pumps 1 H+ ion into the lumen and brings 1 Na+ into the enterocytes)
    • Peptides are broken down into individual AAs by peptidases within the enterocytes.
    • Absorbed across the basolateral membrane in the same manner as AAs
  • Once in the interstitial space, AAs are absorbed into the venous circulation → transported through portal circulation to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
Protein absorption

Transport proteins on enterocyte membranes involved in protein absorption:
The Na+/K+ ATPase on the basolateral membrane generates a Na+ gradient within the cell. A Na+/H+ exchanger (NHE) on the apical membrane also generates the H+ gradient. Individual amino acids (AAs; green balls) are absorbed via a Na+/AA cotransporter, where Na+ flows across the apical membrane into the enterocytes down its concentration gradient, bringing the AA with it (despite moving against the chemical AA gradient). Small peptides are absorbed via the H+/PepT cotransporter with H+ flowing down its concentration gradient into the cell, bringing the small peptides with it. Peptides are broken down into individual AAs by peptidases within the enterocytes. All AAs are then absorbed through specialized transporters on the basolateral membrane.

Image by Lecturio.

Digestion and Absorption of Fats

Digestion

There are 3 primary types of fats that are digested and absorbed: TAGs, phospholipids, and cholesterol esters. All 3 types contain ester bonds (R1‒(C=O)‒O ‒R2) that are broken during digestion.

TAGs:

  • Structure:
    • Glycerol backbone: 3-carbon chain with each carbon attached to an alcohol group
    • Fatty acids: hydrocarbon chain with a carboxyl group at 1 end
    • Each carbon on the glycerol backbone is bound to the carboxy end of a fatty-acid chain by an ester bond.
  • Ester bonds are hydrolyzed by lipases:
    • Lingual lipase (from salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands)
    • Gastric lipase (from chief cells)
    • Pancreatic lipase (from exocrine pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, the most important)
Lipase

Lipase catalyzes the hydrolysis of ester bonds, resulting in 2 free fatty acids and a monoglyceride. Red balls represent oxygen molecules.

Image by Lecturio.

Phospholipids:

  • Similar structure to TAGs, but the glycerol backbone contains a phosphate group
  • Phosphate group confers more polarity.
  • Ester bonds are hydrolyzed by phospholipase A2.
Pla2

Phospholipase A2 (PLA2) hydrolyzes the bond between the 2nd fatty acid of a phospholipid and the glycerol backbone, resulting in a lysophospholipid and free fatty acid.

Image by Lecturio.

Cholesterol esters:

  • Cholesterol bound to a fatty acid by an ester bond
  • Ester bonds are hydrolyzed by cholesterol ester hydrolase.
Cholesteryl ester hydrolase

Cholesteryl ester hydrolase catalyzes the hydrolysis of cholesteryl esters into cholesterol and a fatty acid.

Image by Lecturio.
Table: Lipids and their digestive enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
Lipid Enzyme Products
Triacylglycerols Lipases Monoglyceride and 2 fatty acids
Cholesterol esters Cholesterol ester hydrolase Cholesterol and fatty acid
Phospholipids Phospholipase A2 Lysolecithin and a fatty acid

Substances required for lipase activity/digestion of lipids:

  • Bile:
    • Emulsifier produced by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and secreted by the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
    • Contains lecithin (a phospholipid) and bile salts
    • Forms smaller fat droplets, providing the water-soluble lipases more surface area to digest lipids
  • Colipase: helps lipases bind to (and digest) the emulsified fat droplets

Micelles:

As lipids are broken down, they (along with components from the bile) arrange themselves in structures called micelles:

  • Tiny spherical droplets:
    • Interior portion is lipophilic.
    • Exterior portion is hydrophilic.
    • Surrounded by phospholipids from bile
  • Contain all fat-soluble components to be absorbed:
    • Free fatty acids
    • Monoacylglycerides
    • Cholesterol
    • Phospholipids
    • Fat-soluble vitamins: A, D, E, and K
  • Micelles carry the lipid components to the enterocyte walls for absorption.

Absorption

While the majority of absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine, some absorption may begin in the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach.

Long-chain fatty acids (LCFAs):

  • Mixed micelles package LCFAs and bring them to the enterocyte border.
  • pH change near the brush border breaks open the micelles.
  • Lipid components (e.g., fatty acids and monoglycerides) travel across the membrane to enter the cytosol of enterocytes.
  • Lipid components are:
    • Lipid soluble → can cross the phospholipid membrane without specialized transport molecules
    • Resynthesized via esterification in the ER
    • Repackaged as chylomicrons in the golgi apparatus
  • Chylomicrons exit the enterocytes on their basolateral side → enter lymphatic circulation

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs):

  • In the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine:
    • SCFAs and MCFAs travel across the enterocytes without assistance.
    • SCFAs and MCFAs are absorbed into venous circulation → hepatic portal vein → liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • In the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix, SCFAs use the sodium monocarboxylate transporter (SMCT) 1:
    • Na+/SCFA cotransporter
    • Uses the Na+ gradient generated by the basolateral Na+/K+ pump
    • The pump also assists in the absorption of water in the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix.

Digestion and Absorption of Micronutrients

Calcium (Ca2+) absorption

  • Ca2+ is absorbed across the apical membrane via Ca2+ transporters (primarily TRPV6).
  • Calbindin: an intracellular Ca2+-binding protein that immediately binds all absorbed Ca2+ and transports it to the basolateral membrane
    • Purpose:
      • Free Ca2+ could act as an intracellular signaling molecule.
      • High levels of free Ca2+ can be toxic.
    • Calbindin level in the cell determines how much Ca2+ can be absorbed.
  • Ca2+ is absorbed across the basolateral membrane by:
    • Ca2+ ATPase
    • Ca2+/Na+ exchanger
  • Note: A small amount of Ca2+ can also be absorbed paracellularly.
  • Regulation:
    • Production of the apical Ca2+ transporter is induced by:
      • Vitamin D
      • Estrogens
    • Calbindin synthesis is induced by vitamin D.
Calcium absorption

Schematic diagram depicting calcium (Ca2+) absorption:
Calcium is absorbed across the apical membrane by a specialized Ca2+-transport protein and then immediately bound to a Ca2+-binding protein called calbindin.
Calbindin transports Ca2+ to the basolateral membrane where it is absorbed by Ca2+ ATPase and/or a Ca2+/Na+ exchanger.

Image by Lecturio.

Iron absorption

  • Primarily absorbed in the duodenum
  • Fe3+ (the primary form of iron found in food) must be reduced to Fe2+ for absorption via duodenal cytochrome B (DcytB) located on the brush border of enterocytes.
  • Absorption across the apical membrane:
    • DMT (divalent metal transporter) 1: a specialized Fe2+/H+ cotransporter absorbing most nonheme iron
    • Within heme molecules (e.g., from meat)
  • Within the cell:
    • Mobilferrin: an iron-binding protein that binds Fe2+ and transports it across the enterocyte to the basolateral membrane
    • Heme oxygenase: releases Fe2+ from heme → Fe2+ is bound and transported by mobilferrin
  • Release across the basolateral membrane:
    • Ferroportin 1: a membrane-bound transport protein that releases Fe2+ into the interstitial space
    • Hephaestin:
      • A copper-dependent membrane-bound ferroxidase
      • Oxidizes Fe2+ to Fe3+, which is necessary for iron to move into capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries and bind transferrin (plasma iron transport protein)
  • Regulation:
    • Hepcidin:
      • Inactivates ferroportin 1 (the primary negative regulatory outcome of intestinal iron absorption)
      • Clinical relevance: Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations/deficiency of hepcidin results in hereditary hemochromatosis.
    • Hypoxia-inducible factor (HIF)-2α induces synthesis of DMT1 and DcytB → ↑ absorption
    • Hypoxia and anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview → ↑ iron absorption via:
      • ↓ Hepcidin → ↑ activity of ferroportin 1
      • ↑ HIF-2α
    • Ascorbic acid (vitamin C) enhances absorption.
    • Phosphates (present in teas, bran) inhibit absorption.
Schematic diagram depicting iron absorption

Schematic diagram depicting iron absorption

Image by Lecturio.

Digestion and absorption of other micronutrients

Fat-soluble vitamins:

  • A, D, E, and K
  • Absorbed with lipids → packaged in micelles
  • Absorbed across the apical membrane → repackaged into chylomicrons
  • Chylomicrons → released into the interstitial fluid → absorbed into lymphatic circulation

Water-soluble vitamins:

  • Includes all B vitamins and vitamin C
  • Primarily absorbed in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine:
    • Via active transport:
      • Vitamin C
      • Thiamine (B1)
      • Pantothenic acid (B5)
      • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 (B9)
      • Cobalamine (B12)
    • Via passive transport and/or facilitated diffusion:
      • Riboflavin (B2)
      • Niacin (B3)
      • Pyridoxine (B6)
  • Absorption of B12:
    • Vitamin B12 Vitamin B12 Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 is bound to proteins in food.
    • In the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach:
      • Acid and pepsin release vitamin B12 from dietary proteins.
      • Vitamin B12 Vitamin B12 Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 binds haptocorrin.
      • Parietal cells release intrinsic factor (IF).
    • In the duodenum:
      • Pancreatic proteases remove haptocorrin from B12.
      • B12 binds IF.
    • The B12-IF complex is absorbed by receptor-mediated endocytosis in the terminal ileum.
    • Vitamin B12 Vitamin B12 Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 is secreted into the blood by active transport, where it binds to transcobalamin.
  • Clinical relevance:
    • ↓ Vitamin C → scurvy
    • ↓ Vitamin B1 → beriberi; Wernicke- Korsakoff syndrome Korsakoff syndrome Korsakoff syndrome is a severe and late neuropsychiatric manifestation of Wernicke encephalopathy. Korsakoff syndrome presents with personality changes, anterograde and retrograde amnesia, and confabulation. Some of these changes are irreversible. Wernicke Encephalopathy and Korsakoff Syndrome
    • ↓ Vitamin B3 → pellagra
    • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 and/or vitamin B12 → megaloblastic anemia Megaloblastic anemia Megaloblastic anemia is a subset of macrocytic anemias that arises because of impaired nucleic acid synthesis in erythroid precursors. This impairment leads to ineffective RBC production and intramedullary hemolysis that is characterized by large cells with arrested nuclear maturation. The most common causes are vitamin B12 and folic acid deficiencies. Megaloblastic Anemia
    • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 in early pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care → neural-tube defects in infants
    • Gastric bypass → may remove a majority of parietal cells → ↓ IF → ↓ vitamin B12 absorption
    • Surgical removal of the terminal ileum → ↓ vitamin B12 absorption

Clinical Relevance of Malabsorption and Maldigestion

Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion involves many disorders wherein the gut cannot absorb nutrients including water and/or electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes from the diet. Maldigestion is a closely related term, which is the inability of the gut to break down large food molecules into their smaller constituents. Maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins, minerals), or both. Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion and maldigestion Maldigestion Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion present with weight loss, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, weakness, and fatigue.

  • Etiologies of maldigestion Maldigestion Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion:
  • Abnormal milieu due to:
    • Small intestinal bacterial overgrowth
    • Zollinger-Ellison syndrome (hypersecretion of gastric acid resulting in low pH)
  • Abnormal motility due to:
    • Diabetic gastroparesis
    • Systemic sclerosis Systemic sclerosis Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma
    • Thyroid dysfunction
  • Biliary obstruction and/or cholestasis
  • Bile salt deficiency due to:
    • Hepatic cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
    • Primary biliary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Pancreatic diseases:
    • Exocrine pancreatic insufficiency
    • Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis
    • Chronic pancreatitis Chronic pancreatitis Chronic pancreatitis is due to persistent inflammation, fibrosis, and irreversible cell damage to the pancreas, resulting in a loss of endocrine and exocrine gland function. The most common etiologies are alcohol abuse and pancreatic duct obstruction. Patients often present with recurrent epigastric abdominal pain, nausea, and features of malabsorption syndrome (diarrhea, steatorrhea, and weight loss). Chronic Pancreatitis
    • Pancreatic cancer
  • Disaccharidase deficiencies:
    • Lactase deficiency (resulting in lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance)
    • Sucrase deficiency
  • Etiologies of malabsorption:
    • Acutely abnormal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium:
      • Acute intestinal infections such as giardiasis Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis
      • Alcohol ingestion
    • Chronically abnormal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium:
      • Celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease
      • Inflammatory bowel disease (IBD): Crohn disease and ulcerative colitis Ulcerative colitis Ulcerative colitis (UC) is an idiopathic inflammatory condition that involves the mucosal surface of the colon. It is a type of inflammatory bowel disease (IBD), along with Crohn's disease (CD). The rectum is always involved, and inflammation may extend proximally through the colon. Ulcerative Colitis
      • Intestinal ischemia Intestinal ischemia Intestinal ischemia occurs when perfusion fails to meet the demands of the intestines, resulting in ischemic tissue injury that can be life-threatening if bowel necrosis and/or perforation occurs. Symptoms can range from mild indigestion or diarrhea to severe abdominal pain. Intestinal Ischemia
      • Radiation enteritis
      • Whipple disease
    • Infiltrative disease: can affect both motility and absorptive ability
      • Lymphoma
      • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
      • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis
      • Systemic sclerosis Systemic sclerosis Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion of carbohydrates:
    • Most commonly due to deficiency of disaccharidases (e.g., lactase)
    • Colonic bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview ferment unabsorbed carbohydrates into gases and fatty acids.
    • Results in flatulence, bloating, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion of proteins: Deficiency can result in muscle atrophy and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema.
  • Malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion of lipids:
    • Deficiency in lipases prevent the effective breakdown of fats.
    • Most commonly due to pancreatic insufficiency
    • Results in:
      • Steatorrhea
      • Deficiencies of fat-soluble vitamins
      • Diarrhea (stimulation of water secretion in the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix by unabsorbed bile salts)

References

  1. Boland, M. (2016). Human digestion–a processing perspective. J Sci Food Agric. 96(7), 2275-2283. doi: 10.1002/jsfa.7601. Epub 2016 Feb 5. PMID: 26711173.
  2. Cheng, L.K., O’Grady, G., Du, P., Egbuji, J.U., Windsor, J.A., Pullan, A.J. (2010). Gastrointestinal system. Wiley Interdiscip Rev Syst Biol Med. 2(1), 65-79. doi:10.1002/wsbm.19
  3. Konturek, P.C., Brzozowski, T., Konturek, S.J. (2011). Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 62(6), 591-599. PMID: 22314561.
  4. Kusano, M., Hosaka, H., Kawada, A., Kuribayashi, S., Shimoyama, Y., Zai, H., Kawamura, O., Yamada, M. (2014). Gastrointestinal motility and functional gastrointestinal diseases. Curr Pharm Des. 20(16), 2775-2782. doi: 10.2174/13816128113199990572. PMID: 23886379.
  5. Auerbach, M. (2021). Causes and diagnosis of iron deficiency and iron deficiency anemia in adults. UpToDate. Retrieved Dec 6, 2021 from https://www.uptodate.com/contents/causes-and-diagnosis-of-iron-deficiency-and-iron-deficiency-anemia-in-adults 
  6. Camaschella, C. (2021). Regulation of iron balance. UpToDate. Retrieved Dec 6, 2021 from https://www.uptodate.com/contents/regulation-of-iron-balance

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