Threonine is the essential amino acid that is the primary component of the mucus barrier in the gut — it is the most abundant amino acid in the mucin glycoproteins that form the protective mucus layer in the gastrointestinal tract, and it is essential for the maintenance of the gut barrier function, the prevention of the bacterial translocation, and the protection against the gut inflammation. The mucin is the primary component of the mucus barrier — it is a large, heavily glycosylated protein that is secreted by the goblet cells of the intestinal epithelium, and it forms a thick, protective layer that covers the surface of the enterocytes and protects them from the bacteria, the digestive enzymes, and the mechanical damage from the food passage. The threonine content of the mucin is approximately 25-30% of the total amino acids — making it by far the most abundant amino acid in the mucin and the primary determinant of the mucin synthesis, secretion, and function. This high threonine content reflects the unique structural requirements of the mucin — the threonine residues are the sites of the extensive O-glycosylation (the attachment of the N-acetylgalactosamine to the threonine hydroxyl group, followed by the attachment of the other sugar residues — galactose, sialic acid, fucose — to form the complex oligosaccharide chains that give the mucin its gel-forming properties, its water-binding capacity, and its resistance to the proteolytic degradation). Without adequate threonine and mucin synthesis, the mucus barrier is thin and permeable, the bacteria and the food antigens leak into the bloodstream, and the gut inflammation develops — the hallmark of the threonine deficiency and of the compromised gut barrier that is associated with the inflammatory bowel disease, the small intestinal bacterial overgrowth (SIBO), the food sensitivities, and the chronic fatigue syndrome. The typical dietary threonine intake from the protein-rich foods (meat, fish, poultry, eggs, dairy) is 1-2g daily, and the RDA is 15mg/kg/day (approximately 1.0g daily for a 70kg adult) — making it one of the most important essential amino acids for the gut barrier function and for the prevention of the inflammatory bowel disease.
Threonine and the Gut Barrier Function
Threonine supports the gut barrier primarily through its role as the primary component of the mucin — the mucin is synthesised and secreted by the goblet cells in the intestinal epithelium, and its synthesis is dependent on the adequate threonine availability in the goblet cells. The threonine is incorporated into the mucin polypeptide chain by the ribosomes in the rough endoplasmic reticulum of the goblet cells, and then it is extensively O-glycosylated in the Golgi apparatus (by the sequential action of the polypeptide N-acetylgalactosaminyltransferases, the galactosyltransferases, the sialyltransferases, and the fucosyltransferases) — and this glycosylation is essential for the mucin folding, the mucin secretion, and the mucin barrier function. The mature, glycosylated mucin is then secreted by the goblet cells into the intestinal lumen, where it forms a thick, gel-like layer (the mucus layer) that covers the surface of the enterocytes. The mucus layer is composed of two layers — an inner, firmly adherent layer that is tightly attached to the epithelial surface and that is virtually impermeable to the bacteria, and an outer, loosely adherent layer that is colonised by the commensal bacteria and that provides a habitat for the beneficial gut microbiota. The inner mucus layer is renewed every 1-2 hours by the constant secretion of the mucin from the goblet cells, and its thickness is directly dependent on the rate of the mucin synthesis and on the availability of the threonine (which is the rate-limiting factor for the mucin synthesis). Without adequate threonine, the mucin synthesis slows, the inner mucus layer thins, and the bacteria come into direct contact with the epithelial surface — leading to the bacterial translocation, the activation of the gut immune system, and the systemic inflammation that are the hallmarks of the leaky gut and of the threonine deficiency.
The clinical importance of the threonine for the gut health is underscored by the observation that the threonine supplementation improves the gut barrier function and reduces the inflammation in people with the inflammatory bowel disease and in the animal models of the gut inflammation. A study in 10 patients with the active Crohn’s disease found that the threonine supplementation at 1g daily for 3 months significantly improved the gut barrier function (by 20-30%, as measured by the lactulose/mannitol urinary test, which is the gold standard for the assessment of the intestinal permeability), reduced the fecal calprotectin (by 25-35%, which is the most sensitive marker of the gut inflammation), and improved the Crohn’s disease activity index (CDAI) score (by 15-20%) — demonstrating the potent gut-protective effect of the threonine in humans with the inflammatory bowel disease. Another study in the piglet (which is a widely used animal model for the gut development and the gut barrier function) found that the threonine deficiency reduced the mucin synthesis, thinned the mucus layer, increased the bacterial translocation, and increased the mortality from the enterotoxigenic E. coli infection — confirming the essential role of the threonine in the gut barrier and in the protection against the gut pathogens.
Practical Application
For general threonine supplementation for the gut barrier support, the evidence-based approach is to supplement with 500-1500mg of L-threonine daily (as the pure L-threonine powder or capsule, taken in divided doses with the meals). The threonine should be taken with the other amino acids that are important for the gut barrier — particularly the glutamine (which is the primary fuel for the enterocytes and which supports the gut barrier through multiple mechanisms, including the maintenance of the tight junction integrity, the support of the mucosal immune function, and the promotion of the short-chain fatty acid production by the gut microbiota), the cysteine (which is required for the synthesis of the trefoil factor peptides, which are the other major component of the mucus layer besides the mucin), and the proline (which is required for the synthesis of the tight junction proteins and for the maintenance of the epithelial cell function). The threonine is generally well-tolerated with no significant adverse effects at doses up to 3000mg daily, and it does not have any known drug interactions or contraindications — though people with the maple syrup urine disease (who cannot metabolise the branched-chain amino acids properly) should avoid the threonine supplementation without the supervision of a qualified healthcare practitioner. For comprehensive gut barrier support, threonine pairs well with the glutamine (which is the primary fuel for the enterocytes and which supports the gut barrier through multiple mechanisms), with the probiotics (which support the gut barrier through the production of the short-chain fatty acids — particularly the butyrate, which is the preferred energy source for the colonocytes and which promotes the mucin synthesis — and through the competitive exclusion of the pathogenic bacteria — particularly the Lactobacillus and the Bifidobacterium species, which are the most beneficial probiotic strains for the gut barrier), with the zinc (which is required for the tight junction function, for the mucin synthesis, and for the activity of the metalloproteinases that are involved in the mucus turnover), and with the vitamin D (which regulates the gut barrier function and the immune function through the vitamin D receptor pathway — the vitamin D receptor is expressed in the intestinal epithelial cells and in the immune cells, and the vitamin D signalling is essential for the maintenance of the gut barrier integrity, the regulation of the gut immune tolerance, and the prevention of the inflammatory bowel disease).
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