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. 2020 Jan 30:10:3062.
doi: 10.3389/fimmu.2019.03062. eCollection 2019.

Bovine Colostrum Before or After Formula Feeding Improves Systemic Immune Protection and Gut Function in Newborn Preterm Pigs

Yanqi Li  1 , Xiaoyu Pan  1 , Duc Ninh Nguyen  1 , Shuqiang Ren  1 , Arshnee Moodley  2 , Per Torp Sangild  1   3   4
Affiliations

Bovine Colostrum Before or After Formula Feeding Improves Systemic Immune Protection and Gut Function in Newborn Preterm Pigs

Yanqi Li et al. Front Immunol. .

Abstract

Objectives: Maternal milk is often absent or in limited supply just after preterm birth. Many preterm infants are therefore fed infant formula as their first enteral feed despite an increased risk of feeding intolerance, necrotizing enterocolitis (NEC), and infection. Using preterm pigs as a model for preterm infants, we hypothesized that bovine colostrum given before or after formula feeding would alleviate formula-induced detrimental effects during the first days after preterm birth. Methods: A total of 74 preterm pigs received gradually increasing volumes of formula (F) or bovine colostrum (C) until day 5, when they were euthanized or transitioned to either C or F for another 4 days, resulting in six groups: C or F until day 5 (C5, F5, n = 11 each), C or F until day 9 (CC, FF n = 12-13 each), C followed by F (CF, n = 14), and F followed by C (FC, n = 13). Results: Systemically, colostrum feeding stimulated circulating neutrophil recruitment on day 5 (C5 vs. F5, P < 0.05). Relative to initial formula feeding, initial colostrum feeding promoted the development of systemic immune protection as indicated by a decreased T-helper cell population and an increased regulatory T-cell population (CC + CF vs. FC + FF, P < 0.01). In the gut, colostrum feeding improved intestinal parameters such as villus heights, enzymes, hexose absorption, colonic goblet cell density, and decreased the incidence of severe NEC (27 vs. 64%), diarrhea (16 vs. 49%), and gut permeability on day 5, coupled with lowered expression of LBP, MYD88, IL8, HIF1A, and CASP3 (C5 vs. F5, all P < 0.05). On day 9, the incidence of severe NEC was similarly low across groups (15-21%), but diarrhea resistance and intestinal parameters were further improved by colostrum feeding, relative to exclusive formula feeding (CC, CF, or FC vs. FF, respectively, all P < 0.05). The expression of MYD88 and CASP3 remained downregulated by exclusive colostrum feeding (CC vs. FF, P < 0.01) and colostrum before or after formula feeding down regulated HIF1A and CASP3 expression marginally. Conclusion: Colostrum feeding ameliorated detrimental effects of formula feeding on systemic immunity and gut health in preterm newborns, especially when given immediately after birth.

Keywords: bovine colostrum; formula feeding; gut health; necrotizing enterocolitis; preterm infants; systemic immunity.

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Figures

Figure 1
Figure 1
Schematic overview of the animal experimental design. Seventy-four preterm pigs from four sows were delivered at 106 days gestation. The pigs were stratified according to birth weight and gender and allocated randomly into two groups: one group receiving colostrum (C, n = 37) and the other group receiving formula (F, n = 37) for 4 days until day 5 of the experiment. On day 4, pigs in each group were further stratified into three groups to be euthanized on day 5, fed the same feeding for another 4 days, and fed the other diet for another 4 days resulting in six groups: colostrum feeding until day 5 (C5, n = 11), formula feeding until day 5 (F5, n = 11), colostrum feeding for 4 days followed by formula until day 9 (CF, n = 14), colostrum feeding until day 9 (CC, n = 12), formula feeding for 4 days followed by colostrum until day 9 (FC, n = 13), and formula feeding until day 9 (FF, n = 13). Pigs received gradually increasing volumes of enteral nutrition 16–64 ml kg−1 day−1 on days 1–4 and 64–112 ml kg−1 day−1 on days 5–8. Parenteral nutrition was given at decreasing rates of 96–84 ml kg−1 day−1. C, colostrum; EN, enteral nutrition; F, formula; PN, parenteral nutrition.
Figure 2
Figure 2
Time to acquisition of basic motor skills and home cage activity. Kaplan–Meier plots of time to first eyelid opening (A,B), first stand (C,D), and first walk (E,F) expressed as percentage of pigs. Home cage activity percentage over postnatal hours 24–48 (G) and 120–192 (H) expressed as means ± SEM. Means marked with different letters on the same day are significantly different, P < 0.05. n = 11 for C5 and F5 groups, n = 37 each for C and F groups, and n = 12–14 for CC, CF, FC, and FF groups. C, colostrum feeding for the first 4 days; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; F, formula feeding for the first 4 days; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
Figure 3
Figure 3
Systemic immunity, including neutrophil function and blood T-cell subsets. Neutrophil phagocytic rate (A), Th frequency (B), DN frequency (C), and Treg frequency (D). n = 21–27 for C and F groups and n = 4–8 for CC, CF, FC, and FF groups. Values (means ± SEM) designated with asterisks are significantly different, *P < 0.05; Th, helper T cells. DN, double-negative T cells; Treg, regulatory T cells; C, colostrum feeding for the first 4 days; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; F, formula feeding for the first 4 days; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
Figure 4
Figure 4
Mucosal morphology. Villus heights in the proximal, middle, and distal small intestine (A–C), crypt depth in the proximal, middle, and distal small intestine (D–F), villus/crypt ratio in the proximal, middle, and distal small intestine (G–I). Values (means ± SEM) designated with asterisks are significantly different, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n = 11 for C5 and F5 groups and n = 12–14 for CC, CF, FC, and FF groups. C5, colostrum feeding until day 5; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; F5, formula feeding until day 5; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
Figure 5
Figure 5
Goblet cell density and in vivo intestinal functions. Goblet cell density in the colon (A), intestinal hexose absorptive capacity on days 4 and 8 (B), and intestinal permeability measure before euthanasia (C). Values (means ± SEM) designated with asterisks are significantly different, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n = 8–11 for C5 and F5 groups, n = 33 each for C and F groups, and n = 7–14 for CC, CF, FC, and FF groups. C, colostrum feeding for the first 4 days; C5, colostrum feeding until day 5; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; F, formula feeding for the first 4 days; F5, formula feeding until day 5; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
Figure 6
Figure 6
Brush border enzyme activities. Sucrase (A,B), maltase (C,D), lactase (E,F), ApN (G,H), ApA (I,J), and DPPIV (K,L) in the proximal, middle, and distal small intestine. Values (means ± SEM) designated with asterisks are significantly different, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. n = 11 each for C5 and F5 groups, and n = 12–14 for CC, CF, FC, and FF groups. ApA, aminopeptidase A; ApN, aminopeptidase N; C5, colostrum feeding until day 5; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; DPPIV, dipeptidylpeptidase IV; F5, formula feeding until day 5; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
Figure 7
Figure 7
Fold change of intestinal gene expression levels relative to the C5 group. LBP (A), MYD88 (B), IL8 (C), C3 (D), MPO (E), TLR4 (F), HIF1A (G), OCLN (H), CASP3 (I), VEGF (J), OLFM4 (K) in the distal small intestine. Values (means ± SEM) designated with asterisks are significantly different, *P < 0.05, **P < 0.01. n = 8 each for C5 and F5 groups, and n = 9–13 for CC, CF, FC, and FF groups. C5, colostrum feeding until day 5; CC, colostrum feeding until day 9; CF, 4 days colostrum feeding followed by formula feeding until day 9; F5, formula feeding until day 5; FC, 4 days formula feeding followed by colostrum feeding until day 9; FF, formula feeding until day 9.
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