What is the role of vitamin B12 in the intestine?

Vitamin B12 Function in the Intestine

Vitamin B12 (cobalamin) is selectively absorbed in the distal ileum through a highly specialized receptor-mediated mechanism that requires binding to intrinsic factor, a gastric-derived protein. 1

Anatomical Site of Absorption

• The terminal ileum is the exclusive site of physiological vitamin B12 absorption in humans. 1, 2
• IF-B12 receptors are distributed throughout the distal three-fifths of the small intestine, with the highest concentration in the terminal ileum. 3
• The ileal mucosa contains specialized receptors (cubilin and amnionless) that mediate the uptake of the intrinsic factor-B12 complex through receptor-mediated endocytosis. 4

Mechanism of Intestinal Absorption

Step 1: Gastric Phase

• Vitamin B12 is released from dietary proteins by gastric acid and pepsin in the stomach. 1, 2
• Free B12 initially binds to R-protein (haptocorrin) produced by salivary glands. 1, 4
• B12 then binds to intrinsic factor, a glycoprotein secreted by gastric parietal cells. 1, 2

Step 2: Small Intestinal Phase

• Pancreatic proteases degrade R-protein in the duodenum, allowing transfer of B12 to intrinsic factor. 4
• The pH change in the duodenum triggers this transfer of B12 from haptocorrin to intrinsic factor. 4

Step 3: Ileal Absorption

• The intrinsic factor-B12 complex travels to the terminal ileum where it binds to specific receptors (cubilin and amnionless) on the ileal enterocyte surface. 1, 4
• This binding requires calcium ions for the separation of B12 from intrinsic factor and subsequent absorption. 2
• The complex is internalized through receptor-mediated endocytosis in the terminal ileum. 5, 4

Step 4: Cellular Transport

• Once inside the ileal cell, B12 is released from intrinsic factor and binds to transcobalamin II for transport into the bloodstream. 2, 5
• A small amount (approximately 1% of ingested B12) can be absorbed by passive diffusion, but this mechanism is only adequate with very large doses. 2

Enterohepatic Circulation

• Part of hepatic B12 stores is excreted in bile and undergoes enterohepatic circulation, being reabsorbed in the distal ileum. 4
• This recycling mechanism helps maintain B12 stores but is disrupted in ileal disease or resection. 4

Clinical Implications of Ileal Dysfunction

Resection Thresholds

• Resection of more than 20 cm of distal ileum mandates prophylactic vitamin B12 supplementation (1000 mcg intramuscularly monthly for life). 1
• Resection of more than 30 cm of distal ileum significantly increases the risk of B12 deficiency. 1
• Resection of less than 20 cm typically does not cause deficiency. 1

Disease-Related Malabsorption

• Ileal Crohn's disease involving more than 30-60 cm of ileum puts patients at risk for B12 deficiency even without resection. 1
• Patients with ileal involvement should be screened yearly for B12 deficiency. 1
• Other causes of ileal malabsorption include tropical sprue, celiac disease, bacterial overgrowth, and inflammatory bowel diseases. 4

Bacterial Production in the Intestine

• While bacteria in the human small intestine (particularly Pseudomonas and Klebsiella species) can synthesize vitamin B12, this source does not contribute significantly to human B12 status. 6
• Colonic bacteria produce appreciable quantities of B12, but this is unavailable for absorption since the colon is distal to the site of B12 absorption. 6, 7
• Bacterial overgrowth in the small intestine can actually compete for available B12, potentially causing deficiency rather than supplementation. 4

Common Pitfalls

• Oral B12 supplementation is unreliable in patients with ileal disease, resection, or intrinsic factor deficiency because it depends on intact ileal absorption mechanisms. 2
• Patients with pernicious anemia (intrinsic factor deficiency) cannot absorb B12 through the normal ileal pathway and require parenteral supplementation. 2, 5
• The absence of intrinsic factor or defects in the ileal receptor system (Imerslund-Gräsbeck syndrome) result in megaloblastic anemia despite adequate dietary intake. 5, 4