Longitudinal changes in serum intestinal fatty acid-binding protein and claudin-2 levels in children during the first 24 months of life: a prospective observational cohort study

Background. Maturation of the intestinal epithelial barrier in early life is accompanied by variability in biomarkers of enterocyte injury and permeability. However, longitudinal serum profiles of I-FABP and claudin-2 in seemingly healthy children, including those born preterm, remain insufficiently studied.

Aim. To assess the dynamics of serum I-FABP and claudin-2 concentrations in children born at 34–41 weeks’ gestation during the first 24 months of life, with consideration of gestational age.

Methods. This prospective observational cohort study included three time points: up to 7 days; 1–1.5 months/postmenstrual age (PMA) 40–41 weeks; and 18–24 months. At time points 1–2, 98 newborns were enrolled; by time point 3, follow-up was completed in 88 children: preterm (34–36 weeks, n = 30) and term (37–41 weeks, n = 58). Loss to follow-up was 10.2 % (n = 10). I-FABP and claudin-2 were measured by ELISA.

Results. I-FABP remained stable during the first 1–1.5 months and increased by the second year of life: in preterm children 1.12 [1.07; 1.30] – 1.30 [0.97; 1.87] – 6.09 [3.18; 6.65] ng/mL (p < 0.001), and in term children 1.10 [0.80; 1.95] – 1.21 [0.92; 1.73] – 3.89 [2.33; 6.10] ng/mL (p < 0.001); no between-group differences were observed at the respective time points (p = 0.738; 0.610; 0.131). In preterm children, claudin-2 did not change significantly: 6.76 [3.00; 9.14] – 7.59 [5.20; 10.96] – 7.77 [6.33; 9.20] ng/mL (p = 0.497).

In term children, claudin-2 increased: 1.85 [1.02; 5.22] – 5.10 [3.47; 8.31] – 7.95 [6.32; 11.28] ng/mL (p < 0.001). At time points 1–2, claudin-2 values were higher in preterm than in term children (p = 0.006; p = 0.009), whereas at time point 3 they were comparable (p = 0.326).

Conclusions. Within the 34–41-week gestational range, gestational age does not determine I-FABP levels, whereas claudin-2 is gestational age-dependent. Interpretation of these biomarkers requires consideration of both chronological age and gestational age.

1. Hasan MM, Gazi MA, Das S, Fahim SM, Hossaini F, Khan AR, et al. Gut biomolecules (I-FABP, TFF3 and lipocalin-2) are associated with linear growth and biomarkers of environmental enteric dysfunction (EED) in Bangladeshi children. Sci Rep. 2022; 12(1): 13905. doi: 10.1038/s41598-022-18141-8

2. Lee GO, McCormick BJ, Seidman JC, et al. Infant nutritional status, feeding practices, enteropathogen exposure, socioeconomic status, and illness are associated with gut barrier function as assessed by the lactulose mannitol test in the MAL-ED birth cohort. Am J Trop Med Hyg. 2017; 97(1): 281–290. doi: 10.4269/ajtmh.16-0830

3. Kosek M, Lee GO, Guerrant RL, et al. Age and sex normalization of intestinal permeability measures for the improved assessment of enteropathy in infancy and early childhood: results from the MAL-ED study. J Pediatr Gastroenterol Nutr. 2017; 65(1): 31–39. doi: 10.1097/MPG.0000000000001610

4. McCormick BJ, Lee GO, Seidman JC, et al. Dynamics and trends in fecal biomarkers of gut function in children from 1–24 months in the MAL-ED study. Am J Trop Med Hyg. 2017; 96(2): 465–472. doi: 10.4269/ajtmh.16-0496

5. Loshkova EV, Prudnikova VK, Rafikova YuS, Kim LV, Lyulka TS, Zhelev VA, et al. Necrotizing enterocolitis in preterm infants: state of the intestinal barrier, features of vitamin D metabolism and their regulation. Experimental and Clinical Gastroenterology. 2022; (6): 61–75. (In Russ.). doi: 10.31146/1682-8658-ecg-202-6-61-75

6. Zvyagin AA, Bavykina IA, Nastausheva TL, Bavykin DV. Intestinal Fatty Acid Binding Protein as the Promising Marker of Small Intestine Permeability. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2020; 65(6): 29–33. (In Russ.). doi: 10.21508/1027-4065-2020-65-6-29-33

7. Coufal S, Kokesova A, Tlaskalova-Hogenova H, et al. Urinary I-FABP, L-FABP, TFF-3, and SAA can diagnose and predict the disease course in necrotizing enterocolitis at the early stage of disease. J Immunol Res. 2020; 2020: 3074313. doi: 10.1155/2020/3074313

8. Berdnikov AA, Bavykina IA. The importance of Claudin-2 in the diagnosis of necrotizing enterocolitis in children (brief review). Journal of New Medical Technologies. 2022; 29(4): 65–68. (In Russ.). doi: 10.24412/1609-2163-2022-4-65-68

9. Venugopal S, Anwer S, Szászi K. Claudin-2: roles beyond permeability functions. Int J Mol Sci. 2019; 20(22): 5655. doi: 10.3390/ijms20225655

10. Shores DR, Fundora J, Go M, et al. Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages. BMC Pediatr. 2020; 20(1): 250. doi: 10.1186/s12887-020-02142-5

11. Prikhodchenko NG, Shumatova TA, Ni AN, Zernova ES. Clinical and diagnostic significance of the intestinal fraction of fatty acid binding protein in children with protein-induced enteropathy. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2021; 66(4): 58–63. (In Russ.). doi: 10.21508/1027-4065-2021-66-4-58-63

12. Prikhodchenko NG, Shumatova TA, Ni AN, Zernova ES. Pathogenetic and diagnostic significance of monitoring intestinal fatty acid-binding protein fraction in children with gastrointestinal forms of food allergy. Doktor. Ru. 2021; (11): 66–71. (In Russ.). doi: 10.21518/2079-701X-2021-11-66-71

13. Ren L, Hei M, Wu H, et al. The value of intestinal fatty acid binding protein as a biomarker for the diagnosis of necrotizing enterocolitis in preterm infants: a meta-analysis. BMC Pediatr. 2025; 25(1): 338. doi: 10.1186/s12887-025-05687-5

14. Aktas ON, Mateja A, Li MJ, Chatman L, Grieco MC, Baloh CH, et al. Evaluation of intestinal permeability using serum biomarkers in Learning Early About Peanut Allergy Trial. Allergy. 2025; 80(8): 2286–2296. doi: 10.1111/all.16464

15. Koumangoye R, Penny P, Delpire E. Loss of NKCC1 function increases epithelial tight junction permeability by upregulating Claudin-2 expression. Am J Physiol Cell Physiol. 2022; 323(4): C1251–C1263. doi: 10.1152/ajpcell.00334.2022

16. Raju P, Shashikanth N, Tsai P-Y, Pongkorpsakol P, Chanez-Paredes SD, Steinhagen PR, et al. Inactivation of paracellular cation-selective Claudin-2 channels attenuates immune-mediated experimental colitis in mice. J Clin Invest. 2020; 130(10): 5197–5208. doi: 10.1172/JCI138697

17. Hamilton I, Hill A, Bose B, Bouchier IAD, Forsyth JS. Small intestinal permeability in pediatric clinical practice. J Pediatr Gastroenterol Nutr. 1987; 6(5): 697–701. doi: 10.1097/00005176-198709000-00006

18. Costa PN, Soares AM, Filho JQ, Junior FS, Ambikapathi R, Rogawski McQuade ET, et al. Dietary intake from complementary feeding is associated with intestinal barrier function and environmental enteropathy in Brazilian children from the MAL-ED cohort study. Br J Nutr. 2020; 123(9): 1003–1012. doi: 10.1017/S0007114520000215

19. Koivusaari K, Niinistö S, Nevalainen J, et al. Infant feeding, gut permeability, and gut inflammation markers. J Pediatr Gastroenterol Nutr. 2023; 76(6): 822–829. doi: 10.1097/MPG.0000000000003756

20. Dubrovskaya MI, Gryaznova EI, Khavkin AI. Interrelation between the maternal emotional state during pregnancy and childhood functional gastrointestinal disorders. Voprosy detskoy dietologii. 2020; 18(4): 54-61. (In Russ.). doi: 10.20953/1727-5784-2020-4-54-61

21. Dubrovskaya MI, Gryaznova EI, Turchinskaya AI, Chak AA, Kovtun TA. Comparative analysis of the results of an online survey of mothers and outpatient observation of children in the first year of life with functional gastrointestinal disorders. Voprosy detskoy dietologii. 2023; 21(3): 17-21. (In Russ.). doi: 10.20953/1727-5784-2023-3-17-21