Macrophages are key cells in the occurrence and development of inflammatory diseases (16). They maintain the internal environment by polarization into pro-inflammatory macrophages M1 and anti-inflammatory macrophages M2 and regulating the balance of pro-inflammatory/anti-inflammatory cytokines. At the site of inflammation, amino acids as vital substances contribute greatly to the nodes involved in the elimination of inflammation. Relevant studies and literature over the years indicate that the participation of amino acids in eliminating the inflammatory process can be achieved through mutual regulation with macrophages ( Figure 1 ). Several major amino acids and their metabolites directly or indirectly inhibit the levels of inflammatory factors such as TNF- α, IFN- γ, and IL-6 by promoting M2 polarization, inhibiting NF- κ B, STST 1, and STAT 5, and simultaneously reducing the levels of ROS, iNOS, and COX 2 in macrophages ( Figure 1 ). As shown in the figure, Trp acts on 5-hydroxytryptamine receptor (5-HTR) expressed in macrophages through catabolism leading to serotonin (5-HT), inhibiting the release of pro-inflammatory factors by macrophages (17, 18); Under inflammatory conditions, pro-inflammatory factors such as TNF-α can up-regulate indoleamine 2, 3-dioxygenase 1(IDO1) and then increase the activity of Trp catabolism leading to kynurenine (KYN) (19). Histidine inhibits NF-κB activity in a concentration-dependent manner and then reduces the release levels of TNF- α, and IL-6 in macrophages (20). Glutamine inhibits the production of ROS, NOS, iNOS, COX-2, and other pro-inflammatory mediators to protect tissue (21). Reducing the level of NF-κB activation in inflammation while simultaneously inhibiting STAT1, STAT5, and Akt phosphorylation, inhibiting the increase of TNF-α and IFN-γ (22). Glu also promotes the conversion of M1 to M2 in muscle, down-regulating IL-1β et al. (23). Glycine (Gly) blunted calcium influx in macrophages to inhibit the production of toxic free radicals by macrophages (24). Additionally, Macrophage M1 polarization promotes iNOS expression and stimulates arginine to generate NO while inhibiting ROS activity (25). Thus, amino acids can function by interacting with macrophages.

T lymphocytes are also important players and balancers at the sites of inflammation. Among them, CD8 + T cells receive antigen signals submitted by major histocompatibility complex I (MHCI) to directly eliminate pathogens or tumor cells through cytotoxic effects. Therefore, it is considered the key to the anti-tumor immune response (26). CD4 + T cells mainly receive the presenting signal of major histocompatibility complexII (MHCII) to eliminate the antigen by releasing various cytokines. There are many subsets of CD4 + T cells, among which the Th subset is important in the pathogenic process of inflammatory diseases, capable of mediating a variety of chronic inflammation and autoimmune diseases. For example, the Th 17, which has been discovered for more than a decade, is indispensable for the onset of IBD and is also found to be actively involved in experimental autoimmune encephalomyelitis (EAE) by releasing IL-17 (27). However, CD4+ T cells can differentiate into regulatory T cells (Tregs). As immunosuppressive T cells, Tregs can inhibit the activation of other T cells and become a mainstay in controlling the proper immunity of the body under normal physiological conditions (28). Tregs have been proven to be dysfunctional when the body experiences chronic inflammation or autoimmune diseases, so Tregs have become an important regulatory target to deal with excessive immune responses (29, 30). In recent years, studies on treating inflammatory diseases by regulating Th 17/Treg levels have emerged. Researchers use many methods to restore the balance of the Th 17/Treg axis to regulate the inflammatory response (31–33).

Amino acids and their metabolites play an important role in the growth and function of T cells. First, amino acids and their metabolites can participate in T cell internal nutrient metabolism through the intracellular entry of various amino acid transport proteins widely expressed on the T cell membrane to maintain T cell survival and proliferation. For example, glutamine (Gln) enters T cells through Recombinant Solute Carrier Family 1, Member 5 (SLC1A5)/Recombinant Solute Carrier Family 38, Member 1(SLC38A1) and is metabolized to α-ketoglutarate, and then participates in the intra-cellular TCA cycle to generate ATP to provide energy for T cell proliferation (34). Arginine (Arg) enters the cell through SLC7A1 and can generate polyamines to maintain the needs of T cell growth (35). Secondly, the mammalian target of rapamycin (mTOR) and general control nonderepressible 2 (GCN2) are important amino acid sensors. Various amino acids and their metabolites, such as leucine (Leu), arginine (Arg), and glutathione (GSH), regulate the proliferation and differentiation of T cells by activating the amino acid sensor mTORC1 (36). Trp and its metabolite kynurenine (Kyn) can enter T cells through Solute Carrier Family7, Member5 (SLC7A5) and activate intra-cellular GCN2 to inhibit Th 17 differentiation (37), and T cell proliferation is partly dependent on the activity of GCN2 (38). In addition, amino acid post-translational modifications, such as methylation, acetylation, etc., are important players in directly regulating T cell typing from the genetic level. The methionine (Met) metabolite S-adenosine methionine (SAM) is the main methyl donor (39), while Gln and branched-chain amino acids can be metabolically metabolized to CoA to provide acetyl groups (40) ( Figure 2 ).

The body’s metabolism is disturbed by a pathological state, and amino acid metabolism is no exception. In recent years, there has been constant new evidence that amino acid metabolism is closely related to inflammation ( Table 1 ). A randomized controlled trial of the relationship between branched-chain amino acids and inflammation directly revealed this (52). A large number of studies have shown that compared with the normal state, in the course of inflammatory diseases, the serum levels of 20 amino acids are reduced to varying degrees (5, 53), with glutamic acid, arginine, glycine, etc. being the most significant. Metagenomic analysis showed major perturbations in amino acid metabolism in IBD: the abundance of metabolic and biosynthetic genes decreased for almost all amino acids (especially histidine and lysine), while the abundance of arginine, histidine, and lysine transporter genes increased (54). These findings indicate that amino acid metabolism is affected by IBD pathological status. Table 2 summarizes some amino acid changes during the IBD process ( Table 2 ). Mingyan Jing et al. reviewed the real location of amino acids in the body under inflammation or disease, especially mentioning that threonine is closely related to intestinal metabolism and plays an important role in maintaining the non-specific immune barrier of intestinal mucosa (6).

A typical example is 5-HT. 5-HT is an important regulator in the human body, derived from the catabolism of tryptophan. More than 90% of 5-HT in the human body is produced in the gut, specifically in intestinal chromaffin cells (ECs), a specific subtype of intestinal epithelial cells (63). This process occurs through the action of the Trp hydroxylase 1 enzyme (TpH1), which produces 5-hydroxytryptophan (5-HTP), and is further metabolized into 5-HT (64). Under physiological conditions, peripheral 5-HT does not cross the blood-brain barrier. Peripheral 5-HT triggers many functions in the gastrointestinal tract and is associated with a wide range of human physiological functions through the activation of specific 5-HT receptors. Specifically, 5-HT is an important gastrointestinal signaling molecule that transmits signals from the gut to internal or external neurons and influences intestinal peristalsis and movement, secretion, vasodilation, and nutrient absorption (58).The intestinal microbiota is a major player in intestinal 5-HT production (65). Its effect has been demonstrated in germ-free mice that exhibit impaired 5-HT production in the colon (but not in the small intestine) and low 5-HT concentration in the blood. The mechanism by which intestinal microbiota regulates 5-HT production 3 is not fully understood, but the role of SCFAs in stimulating TpH1 expression has been proposed (66). In addition, some secondary bile acids, such as deoxycholate produced by microbial bioconversion of cholate, can also stimulate 5-HT biosynthesis. Most studies (67–70) report a decrease in intestinal microbiome diversity in patients with IBD, and this change is considered to be an important factor in the development of IBD (54, 71, 72). IBD patients have obvious intestinal flora imbalance, which is mainly manifested as a decreased abundance of intestinal flora, decreased stability of intestinal dominant flora, decreased protective flora, and increased pathogenic bacteria. Intestinal inflammation is usually associated with a significant decrease in Bacteroides (gram-negative microorganisms) and Firmicutes (gram-positive) populations (67, 68), and an increase in the ratio of gram-negative to gram-positive microbes in the gut leads to an increase in the release of inflammatory LPS (73).

It has been reported that glutamine can reduce the damage caused by oxidative stress in DSS-induced colitis mice (74). Mechanistically, glutamine can up-regulate the expression of tight junction proteins and maintain intestinal barrier integrity (75); Meanwhile, glutamine can also inhibit the activity of NF-κB and STAT and increase the stability of IκB, and this may be related to the increased expression of HSP 70 and HSP 25 (76). There is also a conjecture that glutamine may influence the production of IL-8, thereby targeting intestinal inflammation (77). Arginine can stimulate the synthesis of collagen, reduce the expression of iNOS, and reduce the level of pro-inflammatory cytokine IL-17 (74) so that the improvement of the colitis mouse model can be observed. There have been several articles on dietary treatments for IBD that have demonstrated the involvement of exogenous amino acids in improving the intestinal environment. Amino acid-balanced diet-fed mice can effectively alleviate inflammation and this effect is associated with amino acid interaction with gut microbes (78). Thus, amino acids and their metabolites have strong links with intestinal health.

Some special amino acids play a key role in inflammation and immune response (6). Nikolaus et al. found that changes in Trp metabolism are closely related to the progression of IBD (79). Allison et al. also found that Trp metabolism is associated with host intestinal inflammation, epithelial barrier, and energy homeostasis in IBD (80), and is closely related to the intestinal flora. Intestinal microbes such as Bacteroides and Fusobacterium have been shown to act as modulators of intestinal tryptophan metabolism (81). Examples include Clostridium, which is involved in Trp decarboxylation and leads to the production of the neurotransmitter tryptamine (64). Escherichia coli and Lactobacillus, which directly convert Trp to indole and its derivatives, are key to enhancing intestinal AHR activity. AHR signaling is considered to be a key component of the barrier site immune response and is essential for intestinal homeostasis (82, 83).. The AHR also plays an extremely important role in controlling the inflammatory function of macrophages. AHR can be expressed in microglia. A study showed that loss of microglial AHR aggravates inflammation in the central nerve system in mice (84) and dietary amino acid deficiency further aggravates the symptoms of autoimmune encephalomyelitis. Previous studies have also demonstrated that damage to AHR ligand, equally tryptophan metabolite, is detected in patients with IBD (82, 85), resulting in decreased activation of AHR in intestinal epithelial cells and immune cells, thus affecting intestinal homeostasis. Studies have shown that CARD 9, a susceptibility gene for IBD, promotes the recovery of colitis by promoting the production of interleukin (IL) -22, and that CARD 9-/-mice are more likely to develop colitis. The microbiota from Card9-/-mice cannot metabolize tryptophan as a metabolite acting as a ligand for the aryl hydrocarbon receptor (AHR) (85). This may directly indicate that the Trp-AHR pathway is a key therapeutic target in colitis. In addition, other tryptophan metabolites also play an important role in the process of anti-inflammatory. For example, under the catalysis of tryptophan decarboxylase (TrpD), tryptophan oxygenase - 2 - sheet (TMO), and bacteria tryptophan gradually turns into indole - 3 - acetic acid (IAA) and indole - 3 - propionic acid (IPA) which even have direct anti-inflammatory effects (86).

It has been found that in the large intestine, Escherichia coli participates in the process of amino acid fermentation, mainly using lysine, arginine, glycine, and branched amino acids as substrates to produce a large number of complex metabolites including ammonia, acetic acid, butyric acid, and branched fatty acids. These products have been shown to affect the physiological function of intestinal epithelial cells by affecting their signaling pathways and regulating the mucosal immune system. Butyric acid (87), in particular, plays such major roles and is a major source of energy for intestinal lining cells. Butyric acid provides 90 percent of its total energy requirements. These cells need this SCFA to perform their important functions, especially maintaining the integrity of the intestinal wall (88). The intestinal wall is very important because it acts as a barrier between the intestinal environment and the rest of the body.

All the above examples illustrate that intestinal flora plays an important role in the metabolism of amino acids in the process of IBD. Intestinal bacteria can decompose proteins into their constituent amino acids, which are then absorbed by the human body and used in various metabolic processes. Under the condition of inflammation, intestinal flora may affect the bioavailability of amino acids (67). Therefore, it is necessary to attach importance to the regulation of the intestinal microbial environment in future research concerning the treatment of IBD.

Several studies (89, 90) report that there is a link between amino acid metabolisms and IBD process, which may be realized through various signaling pathways. There are many examples, such as glutamine and glutamate, which promote the proliferation of intestinal epithelial cells by regulating the activity of the mTOR pathway, activate the MAPK pathway to promote the proliferation and differentiation of intestinal epithelial cells, increase the expression of tight junction protein, and maintain the stability of intestinal mucosa to ensure its barrier function. Glutamine can regulate NF-κB signal transduction and STAT signaling pathway activation, to inhibit the release of IFN-γ, TNF-α, and other pro-inflammatory cytokines and reduce intestinal inflammatory response. Hsp70 has been reported to inhibit the production of LPs-stimulated inflammatory mediators such as TNF-α, IL-1, and inducible nitric oxide synthase (iNOS) (91). However, another study on the signal transduction pathway of extracellular heat shock protein HSP70 found that an exogenous (e.g., Exosome-derived) HSP70-induced signaling cascade uses TLR2 and TLR4 to activate NF-κB activity (92). However, no adverse effects caused by HSP70 have been found in the treatment of IBD. Although there are no reports, we may assume that exosomes HSP70 can be antagonized by amino acids such as glutamine in the gut to avoid the activation of NF-κB and the up-regulation of the release of TNF-α, IL-1β, IL-6, and other pro-inflammatory factors.

Amino acid transporters are essential in amino acid absorption in the gut. As early as 2006, some scholars discovered that the L-Arg transporter CAT-2 (SLC7A2) could regulate macrophage function by controlling the activities of NOS2 and arginase, thus regulating gastrointestinal inflammation (93). Recovery of the inflammatory-injured colonic epithelium also depends on the ability of CAT2 to transport L-Arg into the cells (94). Previously reported mutations in the neutral amino acid transporter B⁰AT1(SLC6A19) in Hartnup disease may result in an almost complete lack of tryptophan absorption in the gut (95). In addition to being regulated by the B⁰AT1 transporter, tryptophan absorption is also mainly regulated by the neutral amino acid transporter B^0,+AT(SLC6A14) and the aromatic amino acid transporter TAT1(SLC16A10) (96), but the extent to which this is impaired remains to be determined. It has been reported that mRNA of neutral amino acid transporter SLC6A19/B⁰AT1 is significantly down-regulated in biopsies of patients with active CD and UC (79). It is easy to speculate that when inflammation occurs, the intestinal mucosa is damaged, permeability is damaged, and amino acid transporter expression is decreased, in particular the tryptophan transporters, which further increases the degree of intestinal inflammation. Tryptophan is also an upstream regulator of the recovery process of intestinal inflammation (97, 98). Voluntary ingestion of exogenous tryptophan can control the expression of antimicrobial peptides in the mouse small intestine and affect the regeneration and repair of the damaged intestinal epithelium.

There are many key enzymes and rate-limiting enzymes in amino acid metabolism, which may also be therapeutic targets for diseases. For instance, biopsies of the diseased colon in patients with IBD significantly express IDO1mRNA (99). Pro-inflammatory cytokines, including IFN-γ, TNF-α, IL1β, IL2, IL6, IL18, and IFN-α induce IDO1 expression in chronic inflammatory conditions. IDO1 plays an important role in immune regulation under pathophysiological conditions, and is one of the most overexpressed genes in CD, mediating potent anti-inflammatory effects through tryptophan metabolism along the Canine uric acid pathway (100).

Amino acid metabolism demonstrates an integral role in disease progression, and the importance of the gut microbiome in gut metabolism cannot be overemphasized. There are still some mechanisms that have not been clarified in the progression and treatment of IBD. For example, the microbial community involved in intestinal amino acid metabolism is regulated by the IBD susceptibility gene NOD2, which may indicate that intestinal amino acid metabolism is more regulated at the genetic level. However, due to fewer studies, this remain s to be fully understood.

An article on patients with rheumatoid arthritis, spinal joint disease, and osteoarthritis reported that glycine in dog urine (endogenous metabolites of tryptophan) in inflammatory state local defects (101). Sun etc. summarized the immunomodulatory effects of several specific amino acids, such as glutamine and glycine (102). These examples indicate that amino acids have great potential in the treatment of these inflammatory diseases.

Rheumatoid arthritis characterized by synovial inflammation is a kind of autoimmune disease. Although the etiology of RA is not fully evident, it is clear that amino acid metabolism disorders definitely engage in the chronic inflammation of later RA (103). Several amino acids and amines including citrulline, succinate, and glutamine were reported to be potential biomarkers for RA (103). According to a study, compared with healthy people, RA patients’ serum analysis shows the kynurenine pathway is active (104). Trp content decreased at the same time the dog urine glycine content increased significantly. One of the most obvious factors is the IDO1 increased significantly in RA (105). IDO1 plays a protective role in RA. Research has shown that IDO1 deficiency can exacerbate tissue damage (106), and the kynurenine pathway mediated by IDO1 can inhibit T cell immune response (107). However, the process of IDO1 in RA is not static from beginning to end. In the inflammatory synovial region, hypoxia conditions actually lead to a decrease in IDO1 levels (108), while IFN-γ expressed by extensive immune cells in the inflammatory environment can induce IDO activation. Therefore, the detection of IDO1 activation in RA patients may be a forward regulation of inflammation development.

Multiple sclerosis(MS) is a chronic inflammatory disease of the central nervous system. Similar to RA, the two most representative regulatory amino acids are Trp and Arg (109). Amino acids have long been found to be necessary in the activation of the mTOR pathway (110). In multiple sclerosis (MS), IDO1 and ARG1 defects cause a decline in the catabolism of Trp and Arg, increase mTOR activity, and decrease Treg and proinflammatory factor increases (44). Although amino acids have been recognized as key inputs in this pathway, the mechanism of action of the mTORC1 amino acid sensor is still not clear (111).

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal responses to self-antigens (112). In the SLE process, the most significant immunol regulatory amino acid metabolism is Glutamine catabolism. Glu catabolism is essential to T cell immune response in SLE (113). A research pointed out that glutaminolysis enzymes are significantly elevated in CD4+T cells from lupus-prone TC mice (114). Therefore, inhibiting overwhelming glutaminolysis may be an important target for treating SLE (115).