High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age

Abstract

Background Vitamin A (VA) stores are low in early infancy and may impair development of the immune system. Objective This study determined if neonatal VA supplementation (VAS) affects the following: 1) development of regulatory T (Treg) cells; 2) chemokine receptor 9 (CCR9) expression, which directs mucosal targeting of immune cells; and 3) systemic endotoxin exposure as indicated by changed plasma concentrations of soluble CD14 (sCD14). Secondarily, VA status, growth, and systemic inflammation were investigated. Methods In total, 306 Bangladeshi infants were randomly assigned to receive 50,000 IU VA or placebo (PL) within 48 h of birth, and immune function was assessed at 6 wk, 15 wk, and 2 y. Primary outcomes included the following: 1) peripheral blood Treg cells; 2) percentage of Treg, T, and B cells expressing CCR9; and 3) plasma sCD14. Secondary outcomes included the following: 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 percentage 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. The decreased systemic exposure to endotoxin and improved VA status at 2 y may have been due to VA-mediated improvements in gut development resulting in improved barrier function and nutrient absorption. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.

The Influence of Nutritional Factors on Immunological Outcomes

“…In low birth weight infants receiving vitamin A supplementation, the expression of CCR9 on Tregs was increased, indicating an increase in their numbers in the intestinal mucosa with a consequent decrease in intestinal inflammation. The decrease in sCD14 concentration after vitamin A supplementation at 2 years of age showed an important role of vitamin A in improving intestinal integrity, also considering the better vitamin A status at the same age ( 92 ). Considering the possible positive role of vitamin A in intestinal immunity and homeostasis, it could be proposed as a therapeutic factor in patients with inflammatory bowel disease.…”

Evidence to Underpin Vitamin A Requirements and Upper Limits in Children Aged 0 to 48 Months: A Scoping Review

“…Studies assessing the relationship between vitamin A intake and a marker of vitamin A status (Excel sheet 2B Intake Status) and between status and health, growth, or development outcomes (Excel sheet 2C Status Outcome) may in combination support the data directly assessing intake and outcomes. For Intake Status studies, we included three systematic reviews published since early 2013 [ 24 , 25 , 26 ], which were data-extracted and assessed for risk of bias (plus two older systematic reviews), 31 recent trials, of which 12 appeared particularly recent and relevant [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] (and 80 older trials). Alongside these we noted 12 recent cohort or case–control studies, 15 earlier studies, nine recent cross-sectional studies, 25 older studies, and nine non-systematic reviews.…”

“…Only one of the 18 recent systematic reviews assessed effects of vitamin A sources other than high-dose preformed vitamin A supplements, assessing fortification of staple foods [ 25 ] (as did one of the 26 older systematic reviews, assessing agricultural interventions [ 53 ]). Recent trials report effects of increasing vitamin A intake in infants and children on mortality and a variety of types of morbidity such as immune response [ 28 , 29 , 54 , 55 , 56 ], atopy [ 57 , 58 ], respiratory infection [ 59 ], cognition [ 60 , 61 ], eye health [ 33 , 38 , 62 ] and growth [ 38 , 63 ]. Most of the 43 recent trials assessed effects of supplementation (though two assessed effects of complementary foods, one alongside home fortification [ 64 , 65 ], two biofortified maize [ 33 , 62 ], one biofortified cassava [ 66 ], one carotenoid enriched juice [ 67 ], and one fortified milk [ 68 ]).…”

Biological evidence to define a vitamin A deficiency cutoff using total liver vitamin A reserves

“…At the current time, it is unknown what TLR supports optimal immune function, but VA supplementation enhanced T-regulatory cells in low birth weight Bangladeshi infants. 67 Furthermore, maternal VA status affects fetal immunity structure; 57 however, it is unknown if this is associated with maternal TLR storage or immediate VA supplementation effects.…”