High-dose vitamin A supplementation at birth increases the percentage of CCR9+ treg cells in infants with lower birthweight in early infancy and decreases plasma sCD14 and prevalence of vitamin A deficiency at two years

Authors: AHMAD, SHAIKH - International Centre For Diarrhoeal Disease Research; HUDAA, NAZMUL - University Of California, Davis; RAQIB, RUBHANA - International Centre For Diarrhoeal Disease Research; QADRI, FIRDAUSI - International Centre For Diarrhoeal Disease Research; PEERSON, JAN - University Of California, Davis; TANUMIHARDJO, SHERRY - University Of Wisconsin; Stephensen, Charles

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/3/2020
Publication Date: 9/16/2020
Citation: Ahmad, S.M., Hudaa, N.M., Raqib, R., Qadri, F., Peerson, J., Tanumihardjo, S., Stephensen, C.B. 2020. High-dose vitamin A supplementation at birth increases the percentage of CCR9+ treg cells in infants with lower birthweight in early infancy and decreases plasma sCD14 and prevalence of vitamin A deficiency at two years. Journal of Nutrition. 150(11):3005-3012. https://doi.org/10.1093/jn/nxaa260.
DOI: https://doi.org/10.1093/jn/nxaa260

Interpretive Summary: Early infancy is a period of high risk for vitamin A deficiency and for development of the infant’s immune system. Since vitamin A is a critical nutrient for proper functioning of the immune system, this study was conducted to determine if providing vitamin A supplements to newborn infants at risk of deficiency would improve specific aspects of immune function that are sensitive to vitamin A. In particular, the mucosal immune system associated with the infant’s intestinal tract is sensitive to vitamin A and plays an important role in maintaining a barrier to invasive infections and in maintaining a “tolerant” response to antigens found in food or on beneficial commensal bacteria. In this study we examined three aspects of this intestinal immune system: (1) development of T regulatory (Treg) cells, which promote tolerance to food antigens and commensal bacteria; (2) expression of the molecule chemokine receptor 9 (CCR9) on the surface of Treg cells, as CCR9 helps immune cells move from the bloodstream into intestinal immune tissue; and (3) concentration of the soluble CD 14 (sCD14) protein in plasma, as CD14 increases upon systemic exposure to bacterial endotoxin leaking from the intestine into the blood; thus higher levels are suggestive of a disruption of the intestinal barrier. This study was conducted among 306 infants born in a hospital in Dhaka, Bangladesh who were randomized to receive either a single high-dose of vitamin A or a placebo within 48 h of birth. The study found that vitamin A did not affect the level of Treg cells in peripheral blood, but it did decrease sCD14 levels in plasma suggesting improved intestinal integrity. In addition, infants with low birthweight (who are at greater risk of malnutrition) who received vitamin A had a higher percentage of Treg cells that expressed CCR9, suggesting improved targeting of these cells to intestinal immune tissue. However, the opposite was seen in infants with higher birthweight, which might be explained by more of the Treg cells in that group actually leaving the blood and being retained in intestinal immune tissue. In summary, vitamin A supplementation to newborns improved some aspects of mucosal immune function, suggesting health benefits for these infants related to improved immune function.

Technical Abstract: Background: Vitamin A (VA) stores are low in early infancy, a critical period for development of the immune system, and VA deficiency may impair this development. Objective: Determine if neonatal VA supplementation (VAS) affects (1) development of regulatory T (Treg) cells; (2) mucosal targeting of Treg cells, T cells and B cells; and (3) systemic endotoxin exposure. Secondarily, determine if VAS affects (4) VA status; (5) growth; and (6) systemic inflammation. Methods: 306 infants were randomized to 50,000 IU VA or placebo (PL) at birth and immune function was assessed at 6 wk, 15 wk and 2 y. Primary outcomes included (1) peripheral blood Treg cells; (2) percentage of Treg, T and B cells expressing chemokine receptor 9 (CCR9); and (3) plasma soluble CD14 (sCD14). Secondary outcomes included (4) VA status measured using the modified relative dose-response (MRDR) test and plasma retinol; (5) infant growth; and (6) plasma C-reactive protein (CRP). Statistical analysis identified group differences and interactions with sex and birthweight. Results: VAS increased (p = 0.004) the percent of CCR9+ Treg cells (13.2 ± 1.37%) relative to PL (9.17 ± 1.15%) in children below the median birthweight but had the opposite effect (p = 0.04) in those with higher birthweight (VA, 9.13 ± 0.89; PL, 12.1 ± 1.31%) at 6 and 15 wk (values are combined mean ± SE). VAS decreased (p = 0.003) plasma sCD14 (1.56 ± 0.025 mg/L) relative to PL (1.67 ± 0.032 mg/L) and decreased (p = 0.034) the prevalence of VA deficiency (2.3%) relative to PL (9.2%) at 2 y. Conclusions: Neonatal VAS enhanced mucosal targeting of Treg cells in low-birthweight infants during early infancy. VAS also decreased endotoxin exposure and improved VA status at 2 y, perhaps due to VA-mediated improvements in gut development that enhanced both intestinal integrity and nutrient absorption.