This is the first prospective cohort study, to our knowledge, to examine the relationship between serum DAO activity and the response to chemotherapy in patients with EC. In this study, we determined the cut-off value of serum DAO activity according to the antitumor effect and found that adverse events were significantly suppressed in the DAO high group. It is reported that about 70% of all lymphocytes in the human body are concentrated in the intestinal intra-epithelial and subepithelial layers, and the largest pool of tissue macrophages is located in the intestinal wall . Given these findings, serum DAO activity at the first visit would appear to be related to the immunity and absorptive capacity of small intestinal villi, which may affect the efficacy and adverse events of chemotherapy, so we measured markers of inflammation and blood amino acid levels related to absorption capacity. The present study showed that the DAO high group had significantly lower IL-6 associated with C reactive protein (CRP) than the low group. Additionally, myelosuppression was significantly reduced in the DAO high group. Cytotoxic chemotherapy damages the villi of the small intestine, where lymphocytes are concentrated throughout the body, and raises the levels of inflammatory cytokines . Besides, chemotherapy causes mucosal barrier damage, and its disruption of highly controlled host-microbial interactions can result in resident microorganisms causing bloodstream infections that lead to a strong inflammatory response due to cytokine release. In this paradigm, chemotherapy-induced “neutropenia” and “villi disorder” are complementary . In the present study, it is possible that inflammatory cytokines derived from villous disorders were suppressed in the DAO high group by maintaining relatively high activity even after chemotherapy-induced damage to the villi.
According to Tanaka et al., an elemental diet is easily absorbed even in diminished small intestinal villi, and an elemental diet plus normal meal resulted in a low CRP level during chemotherapy and significantly reduced the frequency of myelosuppression [21, 22]. In the present study, we eliminated the effects of oral nutritional supplements and observed clinical outcomes purely due to serum DAO activity. The clinical findings of the suppression of inflammation and myelosuppression in patients receiving chemotherapy by taking an elemental diet were supported by the fact that the same condition occurred in the population with higher villus activity in this study. We further investigated the difference in amino acid absorption capacity due to high DAO activity. Looking at the types of amino acids that could be maintained with a significant difference 4 weeks after the end of the second course of chemotherapy, glutamine, threonine, alpha aminobutyric acid, valine, leucine, tryptophan, lysine, and arginine showed significantly higher values in the DAO high group. Macrophages and lymphocytes consume more glutamine when the human body is in an inflamed state. Glutamine utilization is said to be 10-fold greater in proliferating lymphocytes than in resting cells . Moreover, for malignant disease, mitochondrial glutaminase was reported to be more active in tumor than in normal cells . Glutamine is used for immunity throughout the body, including the intestinal tract, and for in vivo synthesis and degradation in the liver and kidneys. It is a major fuel for rapidly dividing cells in the intestinal mucosa, and in mammals it plays an important role in carbon metabolism and the proliferation of lymphocytes, fibroblasts, and intestinal cells [25, 26]. This point also suggests that glutamine absorption capacity was maintained in the group with relatively high small intestinal villi, which may have contributed to the anti-inflammatory effect. Considering that the EAA showed significantly higher values in the DAO high group, it is thought that the absorption capacity was also maintained. Very interesting findings have been reported for valine. Mouse and human hematopoietic stem cells are particularly vulnerable compared to other amino acids, and feeding mice a valine-restricted diet causes a decrease in bone marrow hematopoietic stem cells . Thus, several EAA including glutamine, may be involved in neutropenia.
In regard to QoL, fatigue was significantly less in the DAO high group. Decreased blood lysine and arginine levels have been implicated in mental fatigue , and supplementation with valine and arginine has been reported to improve physical fatigue . In the present study, the blood concentration of these amino acids was significantly higher in the DAO high group. Further, a low incidence of diarrhea has also been reported in patients with high serum DAO activity , and this was also the case in the present study.
Currently, many anti-cancer drugs are calculated based on the body surface area of the patient ; however, there are also some skeptical reports. In fact, we frequently experience clinical differences in the appearance of adverse events with anticancer drugs and may feel that some patients may be given higher dose intensities. Th cut-off value of 6.5 units/L for DAO could be used to adjust the dose and intensity of anticancer drugs and to predict side effects.
This study has several limitations. First, this study was conducted in single institution, and the number of enrolled patients was low. Second, we did not evaluate the histological response in surgical specimens or in progression-free survival and overall survival. In the future, it will be desirable to investigate whether the dose of an anticancer drug can be adjusted based on the serum DAO activity at the first visit, and as a result, whether the response rate of preoperative chemotherapy, the histopathological response rate, and the prognosis of the patient can be improved. It will be necessary to investigate these effects in a large-scale prospective study.