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Protein digestion begins with pepsin in the acidic stomach, which cleaves internal peptide bonds; the resulting peptides pass to the small intestine where pancreatic proteases (trypsin, chymotrypsin, elastase) and intestinal peptidases complete hydrolysis to dipeptides, tripeptides, and amino acids. Free amino acids are absorbed via active transport (different carriers for acidic, basic, neutral, and imino amino acids); small peptides (di- and tri-peptides) are absorbed intact via PepT1 transporter. Digestibility varies by food source and amino acid profile.
Compare amino acid absorption from free amino acid mixtures, whole protein, and peptide supplements using post-absorption amino acid profiles. Examine digestibility tables for different protein sources (egg, meat, plant-based).
When you eat a piece of chicken, the protein in it is not absorbed as protein — it is dismantled piece by piece along the GI tract and then its components are taken up across the intestinal wall. You already know from your study of dietary protein and amino acids that proteins are polymers of amino acids linked by peptide bonds, and from your study of primary structure that the sequence of a polypeptide determines its three-dimensional shape. Digestion is the controlled reversal of that architecture: breaking peptide bonds to liberate amino acids and short peptides that the intestinal lining can actually transport into the bloodstream.
The process begins in the stomach with pepsin, a protease secreted as the inactive zymogen pepsinogen and activated by gastric acid (pH 1.5–3.5). Pepsin cleaves preferentially at aromatic residues (phenylalanine, tryptophan, tyrosine), producing large peptide fragments — but the stomach is not the main site of protein digestion, more a preliminary chopper. The acidic chyme entering the small intestine triggers secretin and cholecystokinin (CCK) release, stimulating the pancreas to secrete a battery of proteases: trypsin (cleaves after basic residues Lys, Arg), chymotrypsin (cleaves after aromatic residues), elastase (cleaves after small nonpolar residues), and carboxypeptidases that trim from the C-terminus. Trypsinogen is first activated by enteropeptidase on the brush border; active trypsin then autocatalytically activates the rest — a cascade analogous to the coagulation amplification system.
The result of pancreatic digestion is a mixture of single amino acids, dipeptides, and tripeptides. Here is where absorption diverges from what many students expect: PepT1, a proton-coupled transporter on the intestinal brush border, absorbs di- and tripeptides intact and does so faster than free amino acid transporters can handle individual amino acids. Inside the enterocyte, cytosolic peptidases complete hydrolysis before export into the portal blood. Free amino acids meanwhile are absorbed via distinct sodium-coupled transporters segregated by amino acid class: neutral amino acids use one system, basic amino acids (lysine, arginine, histidine) use another, acidic amino acids (aspartate, glutamate) use a third, and imino acids (proline) use yet another. This multiplicity matters clinically — genetic defects in a single transporter cause diseases like Hartnup disorder (neutral amino acid malabsorption) without disrupting absorption of the other classes, because PepT1 can partially compensate by absorbing the affected amino acids as di-/tripeptides.
Digestibility — the fraction of dietary protein that actually reaches the portal blood — varies widely by food source and processing. Egg and meat proteins are roughly 95-97% digestible; legumes and whole grains range from 75-85%, because plant cell walls limit enzyme access and many plants contain antinutritional factors (trypsin inhibitors, phytates) that impair proteolysis. Cooking dramatically improves plant protein digestibility: heat denatures the protein (unfolding polypeptide chains for easier enzymatic attack), destroys antinutritional factors, and disrupts cell walls. This is why the digestibility-corrected amino acid score (DIAAS) — which accounts for both amino acid content and digestibility — is a more meaningful measure of protein quality than crude protein content alone. What the nutrition label reports and what actually reaches your portal circulation are often quite different numbers.