Correlation between abnormal urinary organic acid metabolism and retinopathy of prematurity_Chinese Journal of Ocular Fundus Diseases

Authors：

He Lu ,  Sun Huiqing

Department of Neonatology, Children's Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou 450000, China;

Corresponding author：

Sun Huiqing, Email: s_huiqing@sina.com

Keywords：

Urine metabolism of preterm infants; Retinopathy of preterm infants; Urinary amino acids; Urinary metabolites

DOI：

10.3760/cma.j.cn511434-20240116-00029

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Objective To investigate the postnatal changes in urinary metabolic amino acid levels in infants with retinopathy of prematurity (ROP) and their effect on ROP, and to analyze the amino acid metabolic pathways that may be involved in the development of ROP. Methods A retrospective cohort study. From January 2020 to December 2023, 65 premature infants with severe ROP (ROP group) who were hospitalized, born with gestational age ＜32 weeks in Children's Hospital Affiliated to Zhengzhou University were included in the study. Fifty premature infants with matched sex and gestational age and no ROP were selected as the control group. Urine amino acids and their derivatives were detected by gas chromatography-mass spectrometry. The two groups were compared by independent sample t test. The metabonomics of urinary amino acids was analyzed by orthogonal partial least squares discriminant analysis (OPLS-DA) model. The variable projection importance (VIP) score ＞1 suggested that the substance was two groups of differentially expressed amino acids. The predictive value of urinary amino acids for severe ROP was compared by using the receiver's operating characteristic (ROC) curve and the area under the curve. After t test and metabolomics analysis, the two groups of amino acids with large differences were normalized and compared by Pearson correlation analysis. The Kyoto Encyclopedia of Genes and Genomes database was used to analyze the metabolic pathways of differentially expressed amino acids involved in ROP. Results Compared with the control group, the concentrations of oxalic acid -2 and thiodiacetic acid-2 in urine metabolites of children in ROP group were significantly decreased, while the concentrations of 4-hydroxybutyric acid-2, 3-methylpentadienoic acid-2(1), 2-ketoglutarate-ox-2(2) and 3, 6-epoxy-dodecanedioic acid-2 were significantly increased, with statistical differences (t=0.036, 0.005, 0.038, 0.032, 0.022, 0.011; P＜0.05). The results of OPLS-DA analysis showed that amino acids of urinary metabolites in ROP group and control group were distributed in the left and right regions of the scatter plot, and there was a satisfactory separation trend between the two groups (R²Ycum=0.057 4, Q2cum=0.025 7, P＜0.05). As shown in the S-Plot, the amino acids biased towards two stages are glycolic acid-2, phosphoric acid-3, oxalic acid-2, thiodiacetic acid-2, 4-hydroxybutyric acid-2, 3-methylcrotonylglycine-1, 3-methylpentadienoic acid-2(1), 2-ketoglutarate-ox-2(2) and 3, 6-epoxy- dodecanedioic acid-2, respectively. Eleven differentially expressed amino acids with VIP score ＞1 were screened, among which the highest VIP score was oxalate-2, glycerate-3, phosphoric acid-3, 3-methylcrotonylglycine-1, uranoic acid -3 and thiodiacetic acid-2. The difference of amino acid concentration between the two groups was the highest in 4-hydroxybutyric acid-2 and thiodiacetic acid-2. The correlation between oxalic acid-2 and glycerate-3 was the highest (r=0.830, P＜0.001), and most amino acids were positive correlated. ROC curve fitting analysis showed that the combined prediction of 11 differenly-expressed amino groups had the largest area under the curve (0.816), the cutoff value was 0.531, and the sensitivity and specificity were 83.1% and 70.0%, respectively. The enrichment analysis of these 11 amino acids with significant differences suggested that the main pathways involved included butyrate metabolism, glyoxylic acid and dicarboxylic acid metabolism and lipoic acid metabolism. Conclusion Abnormal amino acid metabolism of 4-hydroxybutyrate-2, 3-methylpentadienoic acid-2(1), thiodiacetic acid-2, 2-ketoglutarate-ox-2(2), 3, 6-epoxy-dodecanedioic acid-2 may have a certain effect on the occurrence of ROP.

Citation： He Lu, Sun Huiqing. Correlation between abnormal urinary organic acid metabolism and retinopathy of prematurity. Chinese Journal of Ocular Fundus Diseases, 2024, 40(6): 434-442. doi: 10.3760/cma.j.cn511434-20240116-00029 Copy

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3.	Li X, Kumar A, Carmeliet P. Metabolic pathways fueling the endothelial cell drive[J]. Annu Rev Physiol, 2019, 81: 483-503. DOI: 10.1146/annurev-physiol-020518-114731.
4.	Oberkersch RE, Santoro MM. Role of amino acid metabolism in angiogenesis[J]. Vasc Pharm, 2019, 112: 17-23. DOI: 10.1016/j.vph.2018.11.001.
5.	Bloomfield FH, Jiang Y, Harding JE, et al. Early amino acids in extremely preterm infants and neurodisability at 2 years[J]. N Engl J Med, 2022, 387(18): 1661-1672. DOI: 10.1056/NEJMoa2204886.
6.	International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited[J]. Arch Ophthalmol, 2005, 123(7): 991-999. DOI: 10.1001/archopht.123.7.991.
7.	Palmer EA. Results of U. S. randomized clinical trial of cryotherapy for ROP (CRYO-ROP)[J]. Doc Ophthalmol, 1990, 74(3): 245-251. DOI: 10.1007/bf02482615.
8.	Dwivedi A, Dwivedi D, Lakhtakia S, et al. Prevalence, risk factors and pattern of severe retinopathy of prematurity in eastern madhya pradesh[J]. Indian J Ophthalmol, 2019, 67(6): 819-923. DOI: 10.4103/ijo.IJO_1789_18.
9.	Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group. Final results of the early treatment for retinopathy of prematurity (ETROP) randomized trial[J]. Trans Am Ophthalmol Soc, 2004, 102: 233-248.
10.	中华医学会儿科学分会眼科学组. 早产儿视网膜病变治疗规范专家共识[J]. 中华眼底病杂志, 2022, 38(1): 10-13. DOI: 10.3760/cma.j.cn511434-20211119-00647.Ophthalmology Group of Pediatrics Society of Chinese Medical Association. Expert consensus on the treatment of retinopathy of prematurity[J]. Chin J Ocul Fundus Dis, 2022, 38(1): 10-13. DOI: 10.3760/cma.j.cn511434-20211119-00647.
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12.	Sinclair TJ, Ye C, Chen Y, et al. Progressive metabolic dysfunction and nutritional variability precedes necrotizing enterocolitis[J]. Nutrients, 2020, 12(5): 1275. DOI: 10.3390/nu12051275.
13.	Teoh ST, Leimanis-Laurens ML, Comstock SS, et al. Combined plasma and urinary metabolomics uncover metabolic perturbations associated with severe respiratory syncytial viral infection and future development of asthma in infant patients[J]. Metabolites, 2022, 12(2): 178. DOI: 10.3390/metabo12020178.
14.	李思涛, 郝虎, 刘梦娴, 等. 基于液相色谱-串联质谱联用技术的支气管肺发育不良患儿血代谢产物分析[J]. 中华围产医学杂志, 2019, 22(3): 173-179. DOI: 10.3760/cma.j.issn.1007-9408.2019.03.005.Li ST, Hao H, Liu MX, et al. Analysis of blood metabolites in children with bronchopulmonary dysplasia based on liquid chromatography-tandem mass spectrometry[J]. Chin J Perinat Med, 2019, 22(3): 173-179. DOI: 10.3760/cma.j.issn.1007-9408.2019.03.005.
15.	Harman JC, Pivodic A, Nilsson AK, et al. Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)[J/OL]. iScience, 2023, 26(10): 108021[2023-09-22]. https://pubmed.ncbi.nlm.nih.gov/37841591/. DOI: 10.1016/j.isci.2023.108021.
16.	Zhang X, Xia M, Wu Y, et al. Branched-chain amino acids metabolism and their roles in retinopathy: from relevance to mechanism [J]. Nutrients, 2023, 15(9). DOI:10.3390/nu15092161.
17.	Ozcan Y, Huseyin G, Sonmez K. Evaluation of plasma amino acid levels in preterm infants and their potential correlation with retinopathy of prematurity[J/OL]. J Ophthalmol, 2020, 2020: 8026547[2020-11-10]. https://europepmc.org/article/MED/33489343. DOI:10.1155/2020/8026547.
18.	Sedel F, Challe G, Mayer JM, et al. Thiamine responsive pyruvate dehydrogenase deficiency in an adult with peripheral neuropathy and optic neuropathy[J]. J Neurol Neurosurg Psychiatry, 2008, 79(7): 846-847. DOI: 10.1136/jnnp.2007.136630.
19.	Li G, Lin J, Zhang C, et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease[J/OL]. Gut Microbes, 2021, 13(1): 1968257[2021-01-01]. https://pubmed.ncbi.nlm.nih.gov/34494943/. DOI: 10.1080/19490976.2021.1968257.
20.	Zhang L, Liu C, Jiang Q, et al. Butyrate in energy metabolism: there is still more to learn[J]. Trends Endocrinol Metab, 2021, 32(3): 159-169. DOI: 10.1016/j.tem.2020.12.003.
21.	Islinger M, Voelkl A, Fahimi HD, et al. The peroxisome: an update on mysteries 2.0[J]. Histochem Cell Biol, 2018, 150(5): 443-471. DOI: 10.1007/s00418-018-1722-5.
22.	Ding L, Sun W, Balaz M, et al. Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis[J]. Nat Metab, 2021, 3(12): 1648-1661. DOI: 10.1038/s42255-021-00489-2.
23.	Cohen LH, Noell WK. Glucose catabolism of rabbit retina before and after development of visual function[J]. J Neurochem, 1960, 5: 253-276. DOI: 10.1111/j.1471-4159.1960.tb13363.x.
24.	Chinchore Y, Begaj T, Wu D, et al. Glycolytic reliance promotes anabolism in photoreceptors[J/OL]. Elife, 2017, 6: e25946. https://pubmed.ncbi.nlm.nih.gov/28598329/. DOI: 10.7554/eLife.25946.
25.	Wong BW, Marsch E, Treps L, et al. Endothelial cell metabolism in health and disease: impact of hypoxia[J]. Embo J, 2017, 36(15): 2187-2203. DOI: 10.15252/embj.201696150.
26.	Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation[J]. J Biol Chem, 2018, 293(20): 7522-7530. DOI: 10.1074/jbc.TM117.000259.
27.	Habarou F, Hamel Y, Haack TB, et al. Biallelic mutations in LIPT2 cause a mitochondrial lipoylation defect associated with severe neonatal encephalopathy[J]. Am J Hum Genet, 2017, 101(2): 283-290. DOI: 10.1016/j.ajhg.2017.07.001.
28.	Zhou Y, Xu Y, Zhang X, et al. Plasma levels of amino acids and derivatives in retinopathy of prematurity[J]. Int J Med Sci, 2021, 18(15): 3581-3587. DOI: 10.7150/ijms.63603.
29.	Paris LP, Johnson CH, Aguilar E, et al. Global metabolomics reveals metabolic dysregulation in ischemic retinopathy[J]. Metabolomics, 2016, 12: 15. DOI: 10.1007/s11306-015-0877-5.
30.	Low SWY, Connor TB, Kassem IS, et al. Small leucine-rich proteoglycans (SLRPs) in the retina[J/OL]. Int J Mol Sci, 2021, 22(14): 7293[2021-07-07]. https://pubmed.ncbi.nlm.nih.gov/34298915/. DOI: 10.3390/ijms22147293.
31.	Skondra D, Rodriguez SH, Sharma A, et al. The early gut microbiome could protect against severe retinopathy of prematurity[J]. J Aapos, 2020, 24(4): 236-238. DOI: 10.1016/j.jaapos.2020.03.010.

1. Sabri K, Ells AL, Lee EY, et al. Retinopathy of prematurity: a global perspective and recent developments[J/OL]. Pediatrics, 2022, 150(3): e2021053924[2022-09-01]. https://pubmed.ncbi.nlm.nih.gov/35948728/. DOI: 10.1542/peds.2021-053924.
2. Longchamp A, Mirabella T, Arduini A, et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H(2)S production[J]. Cell, 2018, 173(1): 117-129. DOI: 10.1016/j.cell.2018.03.001.
3. Li X, Kumar A, Carmeliet P. Metabolic pathways fueling the endothelial cell drive[J]. Annu Rev Physiol, 2019, 81: 483-503. DOI: 10.1146/annurev-physiol-020518-114731.
4. Oberkersch RE, Santoro MM. Role of amino acid metabolism in angiogenesis[J]. Vasc Pharm, 2019, 112: 17-23. DOI: 10.1016/j.vph.2018.11.001.
5. Bloomfield FH, Jiang Y, Harding JE, et al. Early amino acids in extremely preterm infants and neurodisability at 2 years[J]. N Engl J Med, 2022, 387(18): 1661-1672. DOI: 10.1056/NEJMoa2204886.
6. International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited[J]. Arch Ophthalmol, 2005, 123(7): 991-999. DOI: 10.1001/archopht.123.7.991.
7. Palmer EA. Results of U. S. randomized clinical trial of cryotherapy for ROP (CRYO-ROP)[J]. Doc Ophthalmol, 1990, 74(3): 245-251. DOI: 10.1007/bf02482615.
8. Dwivedi A, Dwivedi D, Lakhtakia S, et al. Prevalence, risk factors and pattern of severe retinopathy of prematurity in eastern madhya pradesh[J]. Indian J Ophthalmol, 2019, 67(6): 819-923. DOI: 10.4103/ijo.IJO_1789_18.
9. Good WV, Early Treatment for Retinopathy of Prematurity Cooperative Group. Final results of the early treatment for retinopathy of prematurity (ETROP) randomized trial[J]. Trans Am Ophthalmol Soc, 2004, 102: 233-248.
10. 中华医学会儿科学分会眼科学组. 早产儿视网膜病变治疗规范专家共识[J]. 中华眼底病杂志, 2022, 38(1): 10-13. DOI: 10.3760/cma.j.cn511434-20211119-00647.Ophthalmology Group of Pediatrics Society of Chinese Medical Association. Expert consensus on the treatment of retinopathy of prematurity[J]. Chin J Ocul Fundus Dis, 2022, 38(1): 10-13. DOI: 10.3760/cma.j.cn511434-20211119-00647.
11. Ye C, Wu J, Reiss JD, et al. Progressive metabolic abnormalities associated with the development of neonatal bronchopulmonary dysplasia[J]. Nutrients, 2022, 14(17): 3547. DOI: 10.3390/nu14173547.
12. Sinclair TJ, Ye C, Chen Y, et al. Progressive metabolic dysfunction and nutritional variability precedes necrotizing enterocolitis[J]. Nutrients, 2020, 12(5): 1275. DOI: 10.3390/nu12051275.
13. Teoh ST, Leimanis-Laurens ML, Comstock SS, et al. Combined plasma and urinary metabolomics uncover metabolic perturbations associated with severe respiratory syncytial viral infection and future development of asthma in infant patients[J]. Metabolites, 2022, 12(2): 178. DOI: 10.3390/metabo12020178.
14. 李思涛, 郝虎, 刘梦娴, 等. 基于液相色谱-串联质谱联用技术的支气管肺发育不良患儿血代谢产物分析[J]. 中华围产医学杂志, 2019, 22(3): 173-179. DOI: 10.3760/cma.j.issn.1007-9408.2019.03.005.Li ST, Hao H, Liu MX, et al. Analysis of blood metabolites in children with bronchopulmonary dysplasia based on liquid chromatography-tandem mass spectrometry[J]. Chin J Perinat Med, 2019, 22(3): 173-179. DOI: 10.3760/cma.j.issn.1007-9408.2019.03.005.
15. Harman JC, Pivodic A, Nilsson AK, et al. Postnatal hyperglycemia alters amino acid profile in retinas (model of Phase I ROP)[J/OL]. iScience, 2023, 26(10): 108021[2023-09-22]. https://pubmed.ncbi.nlm.nih.gov/37841591/. DOI: 10.1016/j.isci.2023.108021.
16. Zhang X, Xia M, Wu Y, et al. Branched-chain amino acids metabolism and their roles in retinopathy: from relevance to mechanism [J]. Nutrients, 2023, 15(9). DOI:10.3390/nu15092161.
17. Ozcan Y, Huseyin G, Sonmez K. Evaluation of plasma amino acid levels in preterm infants and their potential correlation with retinopathy of prematurity[J/OL]. J Ophthalmol, 2020, 2020: 8026547[2020-11-10]. https://europepmc.org/article/MED/33489343. DOI:10.1155/2020/8026547.
18. Sedel F, Challe G, Mayer JM, et al. Thiamine responsive pyruvate dehydrogenase deficiency in an adult with peripheral neuropathy and optic neuropathy[J]. J Neurol Neurosurg Psychiatry, 2008, 79(7): 846-847. DOI: 10.1136/jnnp.2007.136630.
19. Li G, Lin J, Zhang C, et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease[J/OL]. Gut Microbes, 2021, 13(1): 1968257[2021-01-01]. https://pubmed.ncbi.nlm.nih.gov/34494943/. DOI: 10.1080/19490976.2021.1968257.
20. Zhang L, Liu C, Jiang Q, et al. Butyrate in energy metabolism: there is still more to learn[J]. Trends Endocrinol Metab, 2021, 32(3): 159-169. DOI: 10.1016/j.tem.2020.12.003.
21. Islinger M, Voelkl A, Fahimi HD, et al. The peroxisome: an update on mysteries 2.0[J]. Histochem Cell Biol, 2018, 150(5): 443-471. DOI: 10.1007/s00418-018-1722-5.
22. Ding L, Sun W, Balaz M, et al. Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis[J]. Nat Metab, 2021, 3(12): 1648-1661. DOI: 10.1038/s42255-021-00489-2.
23. Cohen LH, Noell WK. Glucose catabolism of rabbit retina before and after development of visual function[J]. J Neurochem, 1960, 5: 253-276. DOI: 10.1111/j.1471-4159.1960.tb13363.x.
24. Chinchore Y, Begaj T, Wu D, et al. Glycolytic reliance promotes anabolism in photoreceptors[J/OL]. Elife, 2017, 6: e25946. https://pubmed.ncbi.nlm.nih.gov/28598329/. DOI: 10.7554/eLife.25946.
25. Wong BW, Marsch E, Treps L, et al. Endothelial cell metabolism in health and disease: impact of hypoxia[J]. Embo J, 2017, 36(15): 2187-2203. DOI: 10.15252/embj.201696150.
26. Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation[J]. J Biol Chem, 2018, 293(20): 7522-7530. DOI: 10.1074/jbc.TM117.000259.
27. Habarou F, Hamel Y, Haack TB, et al. Biallelic mutations in LIPT2 cause a mitochondrial lipoylation defect associated with severe neonatal encephalopathy[J]. Am J Hum Genet, 2017, 101(2): 283-290. DOI: 10.1016/j.ajhg.2017.07.001.
28. Zhou Y, Xu Y, Zhang X, et al. Plasma levels of amino acids and derivatives in retinopathy of prematurity[J]. Int J Med Sci, 2021, 18(15): 3581-3587. DOI: 10.7150/ijms.63603.
29. Paris LP, Johnson CH, Aguilar E, et al. Global metabolomics reveals metabolic dysregulation in ischemic retinopathy[J]. Metabolomics, 2016, 12: 15. DOI: 10.1007/s11306-015-0877-5.
30. Low SWY, Connor TB, Kassem IS, et al. Small leucine-rich proteoglycans (SLRPs) in the retina[J/OL]. Int J Mol Sci, 2021, 22(14): 7293[2021-07-07]. https://pubmed.ncbi.nlm.nih.gov/34298915/. DOI: 10.3390/ijms22147293.
31. Skondra D, Rodriguez SH, Sharma A, et al. The early gut microbiome could protect against severe retinopathy of prematurity[J]. J Aapos, 2020, 24(4): 236-238. DOI: 10.1016/j.jaapos.2020.03.010.

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