A cura di Bongiovanni Diego, Federici Francesca e Bugge' Federico.
Description
Studies by Yokohama City University Medicine School (Tatsuo Hashimoto M.D. and his team) discovered that lack of a single amino acid impairs intestinal immunity in mice, altering the guts microbial community and leaving it vulnerable to damage.
Basing on the osbervation that malnutrition enhances the susceptibility to and the severity of gastrointestinal infections and diarreheal diseases, Hashimoto's team dissect the connection between a single amino-acid (Tryptophan) deficiency and intestinal inflammation, uncovering an intricate network involving nutrient transport, microbial ecology, antimicrobial responses and inflammation.
Absorption
Most amino acids can be synthesized in the body from other compounds, but the so-called essential amino acids must be obtained from the diet through the action of specialized amino-acid transport proteins.
The amino acid tryptophan is obtained from the diet and absorbed in the small intestine by a transporter protein B0AT1 that is dependent on the enzyme ACE2. One isoform of the Angiotensin Converting Enzyme
ACE2 is a critical regulator of amino acid transporter function in small intestine. ACE2 regulates the function of the amino acid transporters B0AT1 and B0AT3 in the small intestinal enterocyte brush border. Mutations in a number of residues in the B0AT1 transporter block the association between ACE2 and the transporter and lead to the amino acid uptake defect observed in human Hartnup disorder. The ACE2 homologue, collectrin, carries out this role in the tubular cells of the kidney and is similarly influenced by mutations in B0AT1 (not shown in this diagram)
Both malnutrition and lack of ACE2 reduces levels of intestinal antimicrobial peptides, produced by intestinal epithelial cells, which line the wall of the intestine and travel through the gut, controlling the composition of microbial community: this makes a change in intestinal homeostasis and leads to a more severe susceptibility to inflammation.
Further info:
• Tryptophan Gut Absorption
• Defective Intestinal Amino Acid Absorption
• ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation
Molecular mechanism
It is currently unknown whether the link between gut tryptophan levels and antimicrobial peptides established. A possible explanation is that Tryptophan metabolism by enzymes such as tryptophan-2,3-dioxygenase and indoleamine-2,3-dioxygenase (IDO) , can influence immune function. These enzymes generate tryptophan derivatives such as kynurenines, which can act as ligands for Aryl Hydrocarbon Receptor (AhR), a transcription-factor protein that controls the expression of, among others, cytokine genes in Intraepithelial Lymphocytes (IELs). In this immune cells, AhR activation induces the secretion of the cytokines IL-22 and IL-17 (cytokines are proteins involved in intercellular communication), which are sensed by intestinal epithelial cells (Paneth cells), enhancing their production of antimicrobial peptides.
Antimicrobial peptides (AMPs) are small molecular weight proteins with broad spectrum antimicrobial activity against bacteria, viruses, and fungi.
The principal defense molecules secreted by Paneth cells are alpha-defensins, also known as Cryptdins. These peptides have both hydrophobic and positively-charged domains that can interact with phospholipids in cell membranes. This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell killing. Due to the higher concentration of negatively-charged phospholipids in bacterial membranes than vertebrate membranes, defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect.
In addition to defensins, Paneth cells secrete lysozyme and phospholipase A2, both of which have clear antimicrobial activity.
Indeed, diet-derived AhR ligands are essential for IL-22 production in the intestine: their lack, such as AhR deficiency, compromises the secretion of cytokines and thus the control of the microbial load and composition, resulting in increased vulnerability to epithelial damage and inflammation.
Further info:
• Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides
• Defensins and innate host defence of the gastrointestinal tract
• Immunology: Malnutrition promotes rogue bacteria
• ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation
Conclusion
In summary this study demonstrates the important role of Tryptophan on intestinal homeostasis and how his lack, or interferences with his absorption or his metabolism are involved with gastrointestinal infections and diarrheal diseases.
Prevenction
It is really importatant to have a proper and suitable diet, to avoid lack of Tryptophan and so the predisposition to gut inflammation due to it.
Here is a list of foods and their contribution in Tryptophan: Alimenti che contengono Triptofano
