The difference in serum metabolomics between patients with colorectal cancer (CRC) who are not in a state of obstruction and healthy people is mostly reflected in the differences in glycolysis represented by pyruvate and lactic acid, and differences in glycerol and fatty acid metabolism represented by hydroxybutyric acid. [4,6,7,13,15−17] This study used 1H-NMR to analyze the serum metabolites of patients with colon cancerous bowel obstruction(CBO) and patients with adhesive bowel obstruction(ABO) for the first time, and found that the metabolic differences mainly reflect in the metabolism of aromatic amino acids between the two group. In particular, the up-regulation of tryptophan catabolism, which is based on the kynurenine pathway, may further decrease the cellular immune function and bowel smooth muscle’s neurotransmitter conduction in CBO.
The pathological processes of bowel obstruction includes increasing secretions in the digestive tract and insufficient peripheral perfusion caused by the fluid accumulation of the third space, which leads to the decline of intestinal peristalsis, intestinal epithelial injury and inflammatory reactions. Intestinal secretions accumulate in the intestinal lumen, and when the reabsorption process fails, the intestine continues to lose fluid and electrolytes, leading to a vicious cycle of "expansion-secretion-expansion" , which directly leads to tissue glycolysis increasing and ischemia of Intestinal mucosa. Then there is a surge in lactic acid and fatty acids in the circulation . Such metabolic changes also partially appears in the serum of non-obstructed CRC patients, which should be an important reason why the serum did not show significant differences in glycolysis and glycerol fatty acid metabolism pathways beyween CBO and ABO in this study. It’s found that the difference in serum metabolism between the two group is mainly reflected in the tryptophan, tyrosine and phenylalanine metabolism pathways (all P < 0.05), especially the difference in the tryptophan metabolism pathway has the greatest impact (impact = 0.19). Tan et al.  observed differential metabolites of tryptophan, phenylalanine and tyrosine metabolism in the non-obstructed CRC serum. These metabolites are related to the co-metabolism of gut microbes and hosts. It is speculated that abnormal metabolism of intestinal flora may be an obvious metabolic feature of CRC. Continuous intestinal obstruction causes the necrosis of intestinal mucosal cells and the decline of intestinal smooth muscle function, which in turn causes a sharp decline in intestinal barrier function. The bacterial load in the intestine may exceed the host's defense capabilities, such as the obvious proliferation of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus epidermidis, Candida and Enterococcus . When obstruction occurs, CRC patients’ fragile intestinal ecological balance is further destroyed, which may be the reason why the aromatic amino acid metabolism of CBO is more active than ABO.
In mammals, tryptophan (Try) catabolism is a physiological regulation to maintain immune homeostasis and immune tolerance, which avoids acute and chronic excessive inflammation and autoimmunity . Colon cancer cells (such as HT-29, Caco-2 and LC-180 cells) have a complete Try catabolism mechanism, and its decomposition rate is several times higher than that of normal colonic epithelium . Try is excessively consumed due to the high expression of indoleamine 2,3-dioxygenase (IDO-1/-2) In CRC patient. According to the tryptophan depletion theory : Try starvation may affect this the local utilization of amino acids which inhibits the proliferation of T cells and create an immunosuppressive environment that results in the body's tolerance to potentially immunogenic tumor antigens. When bowel obstructs, the intestinal barrier function is lost, and the enteric infection eventually causes systemic inflammatory syndrome, a large number of inflammatory mediators (such as IFN-G and IL-6) stimulate IDO1 excessive expression  makes Try catabolism more active in CBO patients. More than 95% of L-Try degradation produces L-kynurenine and a variety of downstream metabolites through the kynurenine pathway (KP), which are collectively referred to kynurenines (Kyns), including 3-Hydroxyanthranilic acid ( 3-HAA), Quinolinic acid, Xanthine acid (XA) and Kynuric acid (KA), etc. . In this study, the serum Try level of the CBO group was found significantly lower than that of the ABO group (t=-2.65, P = 0.011), while the CBO’s levels of XA (t = 10.43, P = 3.87E-14), 3-HAA ( t = 9.1236, P = 3.21E-12) and KA (t = 4.5773, P = 3.14E-05) were significantly higher than ABO’s. Malignant tumors are prone to cause malnutrition due to their strong metabolism in the process of growth. When patients are suffering from bowel obstruction, the degree of malnutrition and cachexia increases significantly. When CRC patient suffers from inflammatory reaction caused by obstruction, the higher ratio of Kyns/Try that caused by rapid consumption of Try and the excessive production of Kyns is a possible disease identification index. Kyns/Try ratio increasing may indicate tumorigenesis  and ischemic necrosis of muscle cells . It’s found that CBO’s serum L-Try level is negatively correlated with XA level (P = 0.0282, PACF = -0.227).
XA has a competitive inhibitory effect on the transport of L-glutamate (L-Glu) . By blocking the transport of L-Glu to synaptic vesicles, it ultimately reduces the release of L-Glu from synapses, thereby glutamatergic transmission is inhibit. KA is an antagonist of the Glu receptor (GluR). The overexpression of KA in the nerve injury model can block the conduction of Glu . Glu is the main excitatory neurotransmitter in the central nervous system, and it may also act as an excitatory neurotransmitter in the enteric nervous system. The excitatory transmission of intestinal smooth muscle is mainly cholinergic in nature. Glu activates N-methyl-D-aspartic acid receptors (NRs) and promotes the release of acetylcholine of neurons in the ileum and colon . Therefore, the peristalsis may be affect by the Kyns’ inhibition to the Glu transport and GluR of enteric neurons. When CRC patients suffer from obstruction, the level of Kyns increases significantly, which means that peristalsis is further weakened.
KA has also been identified as an endogenous aryl hydrocarbon receptor (AhR) agonist . In addition to impairing immune T cell function through tryptophan starvation, high levels of KA produced by DCs and tumors under inflammatory conditions caused by bowel obstruction can activate IL-10 in DCs and NK cells though AhR activating  and IL6 transcription in cancer cells and macrophages  in the absence of Trp, which causes immunosuppression and immune tolerance. 3-Hydroxyanthranilic acid (3-HAA) is an intermediate metabolite and precursor of the excitotoxin Quinolinic acid with high redox activity. It inhibits T cells’ expression and increases the percentage of Tregs by inducing the expression of heme oxygenase-1 (HMOX-1) , consuming intracellular glutathione, inhibiting cytokine release , inducing T cells that produce antigen-specific IL-10  and inhibiting PDK1 expression , therefor the immune response is directly damaged. Compared with ABO patients, the high level of Kyns in the serum of CBO patients means more severe immunosuppression and immune escape occuring.
Gentisic acid (GA) is usually considered to be a salicylic acid’s metabolite catalyzed by CYP450 enzyme in the liver, but endogenous GA is produced by oxidation of Homogentisic acid, a common metabolite of phenylalanine and tyrosine. Then GA produces Maleylpyruvic acid which enters the pyruvate metabolism. Vanillylmandelic acid(VMA) is also a downstream metabolite of tyrosine. In this study, it ‘s found that the levels of GA and VMA have a higher correlation (P = 7.7e-05, PACF = 0.501), which proves that the tyrosine metabolism of CBO is more active than that of ABO. GA inhibits the activity of cdK1 enzyme in vitro and has a highly inhibitory effect on the cell proliferation of three different colon cancer cell lines (HcT-116, HT-29 and Mda-MB-231) . Salicyluric acid (SUA) is formed by the conjugation of salicylic acid (SA) and glycine , and SUA is the main metabolite of SA. Endogenous SA is formed by oxidation of benzoic acid, a downstream product of phenylalanine metabolism, mediated by NADPH. SUA has a DNA repairing function, because it has a phenolic hydroxyl structure that similar to tannic acid, which has an inhibitory effect on the genotoxicity induced by mitomycin C (MMC)  .Endogenous Ferulic acid (FA) is produced by caffeic acid, the downstream product of phenylalanine metabolism, under the action of methyltransferase. It’s an antioxidant that can reduce the strength of various inflammatory mediators. At the same time, its phenolic core and expanded side chain conjugationt structure make it have anti-cancer properties. It interferes the signal pathways that control cell growth in cells, and activates programmed cell death and oxidative stress-related responses . Resveratrol combined with Ferulic acid can inhibit 3D proliferation in vitro by increasing the expression of p15 in colon cancer HCT116 cells. It’s found that the serum levels of GA (t = 6.8674, P = 9.68E-09), SUA (t = 6.2593, P = 8.64E-08) and FA (t = 4.9326, P = 9.38E-06) of CBO patients are significantly higher than those of ABO patients. These three metabolites that belong to phenylalanine and tyrosine metabolism pathways can exert anti-cancer effects through different mechanisms in different cell types. Therefore, whether up-regulating the phenylalanine and tyrosine metabolism pathways can inhibit the growth of colon cancer cells requires further research.