Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

Abstract

Intestine is always exposed to external environment and intestinal microorganism; thus it is more sensitive to dysfunction and dysbiosis, leading to intestinal inflammation, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and diarrhea. An increasing number of studies indicate that dietary amino acids play significant roles in preventing and treating intestinal inflammation. The review aims to summarize the functions and signaling mechanisms of amino acids in intestinal inflammation. Amino acids, including essential amino acids (EAAs), conditionally essential amino acids (CEAAs), and nonessential amino acids (NEAAs), improve the functions of intestinal barrier and expressions of anti-inflammatory cytokines and tight junction proteins but decrease oxidative stress and the apoptosis of enterocytes as well as the expressions of proinflammatory cytokines in the intestinal inflammation. The functions of amino acids are associated with various signaling pathways, including mechanistic target of rapamycin (mTOR), inducible nitric oxide synthase (iNOS), calcium-sensing receptor (CaSR), nuclear factor-kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), nuclear erythroid-related factor 2 (Nrf2), general controlled nonrepressed kinase 2 (GCN2), and angiotensin-converting enzyme 2 (ACE2).

Figure 1

Possible signaling mechanisms of amino acids in intestinal inflammation in the ECs are illustrated. Amino acids ameliorate intestinal inflammation by impressing NF-κB and MAPK pathway. Amino acids activate Nrf2 pathway to regulate intestinal inflammation via inhibiting oxidative stress and the expressions of proinflammatory cytokines. Amino acids activate iNOS to inhibit NF-κB pathway by the production of NO. ACE2 combines B0AT1 to regulate uptake of Trp in IECs, which activates expressions of antimicrobial peptides to regulate intestinal microbiota. ACE2 illuminate intestinal inflammation by regulating innate immune responses and intestinal microbiota is not shown in the figure. GCN2 regulates intestinal inflammation by inhibiting inflammasome activation, triggering autophagy, and preventing oxidative stress. CaSR activated by Trp exerts anti-inflammation roles via activating the complex of Β-arrestin 2 (β-arr2) to inhibit NF-κB and MAPK pathway in IECs. After being activated by amino acids, mTOR signaling could inhibit autophagy.

Figure 2

Specific signaling pathways of different amino acids in intestinal inflammation are showed. Thr, His, Arg, Leu, Asn, Cys, Gln, Met, and Gly inhibit NF-κB signaling pathway to ameliorate intestinal inflammation. Thr, Arg, Leu, Asn, Trp, Gln, and Ile inhibit MAPK signaling pathway to relieve intestinal inflammation; Leu, Ile, and Val activate GCN2 pathway to improve intestinal inflammation. Tyr, Lys, Trp, Val, and Phe activate CaSR pathway to attenuate intestinal inflammation. NEAAs, Thr, Gln, Leu, Cys, and Trp may promote intestinal inflammation through activating mTOR. Trp reduces intestinal inflammation via activating ACE2 pathway; Cys decreases intestinal inflammation through activating Nrf2 signaling pathway. Arg decreases intestinal inflammation by iNOS signaling pathway.