Effect of polyunsaturated fatty acids on postnatal ileum development using the fat-1 transgenic mouse model

Abstract

Background Long-chain polyunsaturated fatty acids (LCPUFAs) play a critical role in neonatal health. We hypothesized that LCPUFAs play an essential role in priming postnatal gut development. We studied the effect of LCPUFAs on postnatal gut development using fat-1 transgenic mice, which are capable of converting n-6 to n-3 LCPUFAs, and wild-type (WT) C57BL/6 mice. Results Fat-1 mice, relative to WT mice, showed increased n-3 LCPUFAs levels (α-linolenic acid, docosahexaenoic acid and eicosapentaenoic acid, p <0.05) and decreased arachidonic acid levels ( p <0.05) in the ileum. Pre-weaning fat-1 mice, compared to WT, showed >50% reduced muc2, Tff3, TLR9 and Camp expression ( p <0.05), markers of the innate immune response. There was a >2-fold increased expression of Fzd5 and EphB2 , markers of cell differentiation ( p <0.05), and Fabp2 and 6 , regulators of fatty acid transport and metabolism ( p <0.05). Despite reduced expression of tight junction genes, intestinal permeability in fat-1 was comparable to WT mice. Conclusions Our data support the hypothesis that fatty acid profiles early in development modulate intestinal gene expression in formative domains such as cell differentiation, tight junctions, other innate host defenses, and lipid metabolism.

Breast Milk Lipids and Fatty Acids in Regulating Neonatal Intestinal Development and Protecting against Intestinal Injury

“…This study confirmed that fatty acid exposure and intestinal levels do impact postnatal intestinal development and that a balance between both n-3 and n-6 may be critical in this early developmental period. In the pre-weaning period, while an n-3 dominant pattern increased gene expression of cell differentiation markers (EphB2, Fzd5) and fatty acid metabolism (fatty acid binding protein 2 and 6), this n-3 dominant pattern also decreased villus height over time and reduced expression of markers that inform innate host defenses, such as a reduced number of acidic mucin filled goblet cells, reduced expression of tight-junction genes (claudin 3 and 7), and reduced gene expression of muc2, trefoil factor 3, toll like receptor 9, and cathelicidin antimicrobial peptide [52]. These data suggest that that LCPUFA changes reflective of those seen in neonatal intensive care units likely influence the trajectory of postnatal intestinal development.…”

“…It is well-documented that in the early postnatal period of preterm infants, whole blood docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (ARA, C20:4n-6) deficits and linoleic acid (LA, C18:2n-6) excesses occur within the first postnatal week [50]. Although these altered fatty acid profiles have been linked to the increased risk of developing bronchopulmonary dysplasia, retinopathy of prematurity, and late onset sepsis, the impact of these altered fatty acid profiles on intestinal development has just recently been described [50][51][52].…”

“…Singh et al took advantage of the fat-1 transgenic mouse model to examine the differences in postnatal gut development in mouse pups in control, wild-type dam fed mice versus dam fed fat-1 transgenic mice [52]. Relative to the wild-type group, fat-1 mice had a greater n-3 shift in their intestinal fatty acid levels with an increase in DHA and eicosapentaenoic acid (EPA, C20:5n-3), and a decrease in ARA in the pre-weaning period.…”

“…The protective effect of LCPUFAs in intestinal inflammatory disease could be partly explained by their effect on gut barrier function [68]. Although in vitro studies have shown mixed results about the impact of LCPUFAs on intestinal permeability [52,69,70], LCPUFA treatment to human intestinal epithelial cells resulted in improved intestinal barrier by decreasing the impairment in intestinal permeability induced by cytokines [71,72].…”

Maltodextrin-induced intestinal injury in a neonatal mouse model

“…Intestinal permeability assay was performed as described previously (Singh et al, 2019). Briefly, mice were gavaged with FITC-dextran 4000 (FD-4) (Sigma-Aldrich) in PBS at a concentration of 600 mg/kg body weight.…”