What is the primary absorption pathway in the gastrointestinal (GI) tract?

Primary Absorption Pathways in the Gastrointestinal Tract

The small intestine is the primary site for nutrient absorption in the GI tract, utilizing both transcellular (carrier-mediated and passive diffusion) and paracellular pathways across polarized epithelial cells. 1

Anatomical Location and Mechanisms

The small intestine serves as the principal absorption site for virtually all nutrients from the diet, with absorption occurring across the highly polarized epithelial cell layer of the intestinal mucosa 1. The upper half of the small intestine is particularly critical for absorption of many compounds, including lipophilic substances like corticosteroids 2.

Transcellular Absorption Pathways

Transcellular transport represents the primary mechanism for most nutrient absorption and occurs through two distinct processes:

• Carrier-mediated transport operates at physiological concentrations, utilizing specific membrane transporters such as SGLT1 for glucose and galactose, and GLUT5 for fructose across the brush border 3
• Passive diffusion becomes the dominant mechanism at high pharmacological doses, particularly for lipophilic compounds 2

The transcellular pathway involves nutrient uptake across the apical brush border membrane, transit through the cytoplasm, and exit across the basolateral membrane into the bloodstream 1, 3.

Paracellular Absorption Pathway

A substantial portion of nutrient absorption occurs via the paracellular route, particularly during active digestion:

• During membrane digestion of nutrients, paracellular transport can account for 60-80% of total absorption when substrate concentrations reach 200-300 mM in the microenvironment 4
• This pathway operates through tight junctions between epithelial cells and is driven by solvent drag and osmotic flow 4
• Paracellular permeability is dynamically regulated by perijunctional actomyosin contraction, which modulates junctional permeability in response to transcellular concentrative transport 4

Specialized Absorption Mechanisms by Nutrient Type

Carbohydrates

• Glucose and galactose utilize sodium-dependent co-transport (SGLT1) at the brush border, then exit via GLUT2 and potentially through exocytosis at the basolateral membrane 3
• Fructose absorption occurs through passive uniporter-mediated transport (GLUT5) 3

Proteins and Peptides

• Amino acids and oligopeptides are absorbed via specific transporters following enzymatic digestion 5, 1
• Recent discoveries have identified new oligopeptide transporters contributing to protein absorption 5

Lipids

• Fatty acids and lipophilic compounds undergo absorption primarily in the upper small intestine through specialized mechanisms 2, 1

Vitamins

• Vitamin B12 requires intrinsic factor for absorption, with separation occurring in the terminal ileum in the presence of calcium 6
• Approximately 1% of vitamin B12 can be absorbed by simple diffusion, but this is only adequate with very large doses 6
• Both water-soluble and lipid-soluble vitamins have distinct absorption pathways 1

Critical Clinical Considerations

Several conditions can significantly impair intestinal absorption:

• Short bowel syndrome, bariatric surgery, Crohn's disease, gastrectomy, or colectomy may impair absorption capacity 2
• Rapid intestinal transit, chronic diarrhea, or celiac disease can lead to unpredictable absorption outcomes 2
• Intrinsic factor deficiency causes pernicious anemia and prevents vitamin B12 absorption, necessitating parenteral administration 6

The paracellular pathway requires minimal oxidative energy beyond that needed to maintain transjunctional concentration gradients and energize cytoskeletal contraction, making it an efficient absorption mechanism during high digestive loads 4. This coupling of membrane digestion with paracellular transport provides nearly perfect matching of absorption to digestive loads because transport by solvent drag is proportional to substrate concentration at cell junctions 4.