Table 10.
Effect of enteral feeding interventions that decrease intestinal epithelial cell death and increase proliferation in experimental animal models of NEC.
| Enteral Feeding Intervention | Effect on Intestinal Epithelial Cell Death and Proliferation (Compared to NEC Protocol Exposure without Feeding Intervention) |
|---|---|
| Fat-based interventions | |
| Fish oil (rich in n-3 PUFA) | Small intestinal BiP (protein) ↓ [83] Small intestinal caspase 12 (protein) ↓ [83] |
| PUFA | Intestinal apoptosis (TUNEL) = [45] |
| MPL | Small intestinal apoptosis (TUNEL) ↓ [84] Small intestinal Bax (protein) ↓ [84] Small intestinal Bcl-2 (protein) ↑ [84] Small intestinal caspase 9 (protein) ↓ [84] Small intestinal caspase 3 protein) ↓ [84] |
| Pomegranate seed oil | Mean ileal villus length ↑ [47] Ileal epithelial cell proliferation (PCNA) ↑ [47] |
| Carbohydrate/sugar-based interventions | |
| HMO | (Terminal) ileal Ki67-positive cells ↑ [49,86,88] Ileal Sox9-positive cells ↑ [49] Terminal ileal TUNEL (protein) ↓ [86] Ileal cleaved caspase 3 (protein) ↓ [88] Ileal HIF1α (protein) ↓ [88] |
| Mixture of four HMOs | Small intestinal PCNA (mRNA) = [134] |
| 2′-FL | Small intestinal apoptosis (TUNEL) ↓ [92] |
| 6′-SL | Small intestinal apoptosis (TUNEL) ↓ [92] |
| 2′-FL + 6′-SL | Small intestinal apoptosis (TUNEL) ↓ [92] |
| Protein/amino acid-based interventions | |
| Lactoferrin | Proximal intestinal villus length/crypt depth ratio ↓ [36] Middle intestinal Bax-to-Bcl-2 ratio (protein) ↑ [36] Middle intestinal HIF-1α (protein) ↑ [36] Middle intestinal pro-caspase 3 (protein) = [36] Middle intestinal CC3 (protein) = [36] Distal ileal Ki67 (protein) ↑ [101] Distal ileal β-catenin (protein) ↑ [101] Distal ileal LGR5 (mRNA) ↑ [101] |
| L-Glutamine/glutamine | Small intestinal apoptosis (TUNEL) ↓ [84] Small intestinal Bax (protein) ↓ [84] Small intestinal Bcl-2 (protein) ↑ [84] Small intestinal caspase 9 (protein) ↓ [84] Small intestinal caspase 3 (protein) ↓ [84] Jejunum, ileum and colon caspase 3 (protein) ↓ [97] |
| Hormone/growth factor/vitamin-based interventions | |
| EGF | Ileal villus length ↑ [193] Ileal epithelial proliferation (PCNA) = [193] Ileal Bax (mRNA) ↓ [193] Ileal Bax (protein) ↓ [193] Ileal Bcl-2 (mRNA) ↑ [193] Ileal Bcl-2 (protein) ↑ [193] Ileal Bax-to-Bcl-2 ratio (mRNA) ↓ [193] Ileal CC3 villus tips (protein) ↓ [193] Ileal Bax-to-Bcl-2 ratio (protein) ↓ [37,193] Ileal Beclin 1 (protein) ↓ [55] Ileal LC3II (protein) ↓ [55] Ileal LC3II/LCRI ratio (protein) ↓ [55] Ileal p62 (protein) ↑ [55] Ileal autophagy signs (autophagosomes, autophagolysosomes, vacuoles) (transmission electron microscopy) ↓ [55] |
| HB-EGF | Intestinal TUNEL score (protein) ↓ [60] Intestinal CC3 score (protein) ↓ [60] Ileal cell migration (BrdU-positive cells) ↑ [59,61] Small intestinal integrin subunit α5 (mRNA) ↑ [61] Small intestinal integrin subunit β1 (mRNA) ↑ [61] Small intestinal integrin subunit α1 (mRNA) = [61] Small intestinal integrin subunit α2 (mRNA) = [61] Small intestinal integrin subunit α3 (mRNA) = [61] Small intestinal integrin subunit α6 (mRNA) = [61] Small intestinal integrin subunit α5 (protein) ↑ [61] Small intestinal integrin subunit β1 (protein) ↑ [61] Ileal epithelial cell proliferation (number of BrdU-positive cells) ↑ [59] Ileal Bax-to-Bcl-2 ratio (protein) = [37] Jejunal crypt epithelial cell proliferation (PCNA) ↑ [176] Jejunal number of enterocytes per villus ↑ [176] Jejunal number of LGR5+/prominin-1+ stem cells ↑ [176] |
| EPO | Ileal Beclin 1 immunoreactivity ↓ [194] Ileal LC3 immunoreactivity ↓ [194] Small intestinal Beclin 1 (protein) ↓ [194] Small intestinal LC3II (protein) ↓ [194] Ileal p62 immunoreactivity ↑ [194] Small intestinal p62 (protein) ↑ [194] Ileal CC3 immunoreactivity ↓ [194] Small intestinal Bcl-2 (protein) ↑ [194] |
| ATRA | Terminal ileal apoptosis intestinal crypts (TUNEL) ↓ [109] Terminal ileal proliferation crypt intestinal epithelial cells (Ki67, BrdU) ↑ [109] |
| Vitamin D | Intestinal cleaved caspase 3 (protein) ↓ [112] Intestinal Bcl-2 (protein) ↑ [112] Intestinal Ki67 (protein) ↑ [112] |
| Probiotic interventions | |
| Bacteroides fragilis strain ZY-312 | Intestinal CC3 (protein) ↓ [113] Intestinal Bax (protein) ↓ [113] Intestinal Bcl-2 (protein) ↓ [113] Intestinal caspase 1 (protein) ↓ [113] Intestinal ASC (protein) ↓ [113] Intestinal NLRP3 (protein) ↓ [113] Intestinal IL1β (protein) ↓ [113] Intestinal gasdermin-D (protein) ↓ [113] |
| Lactobacillus rhamnosus GG | Ileal CC3 (protein) ↓ [161] Ileal apoptotic index (TUNEL) ↓ [161] |
| Bifidobacterium bifidum OLB6378 | Ileal Bax (protein) ↓ [74] Ileal Bcl-w (protein) ↑ [74] Ileal Bax/Bcl-w ratio ↓ [74] Ileal CC3-positive cell number ↓ [74] |
| Bifidobacterium breve M-16V | Ileal caspase 3 (mRNA) ↓ [117] |
| Other interventions | |
| Amniotic fluid | Terminal ileal PCNA immunoreactivity ↑ [40] |
| Ginger | Intestinal TUNEL-positive cell number ↓ [121] Intestinal C3-positive cell number ↓ [121] Intestinal C8-positive cell number ↓ [121] Intestinal caspase 3 (protein) ↓ [121] |
| Fennel seed extracts | Terminal ileal C3-positive cells number ↓ [122] Terminal ileal C8-positive cells number ↓ [122] Terminal ileal C9-positive cells number ↓ [122] Intestinal C3 concentration (protein) ↓ [122] |
| Preterm human breast milk exosomes | Intestinal enterocyte proliferation (BrdU) ↑ [120] |
| Sesamol | Intestinal Bcl-2-positive cell number ↓ [125] Intestinal caspase-3 positive cell number ↓ [125] |
| Curcumin | Intestinal caspase 1 (protein) ↓ [124] Intestinal NLRP3 (protein) ↓ [124] Intestinal caspase 1 (mRNA) ↓ [124] Intestinal NLRP3 (mRNA) ↓ [124] |
↑ depicts an increase, ↓ depicts a decrease; PUFA, polyunsaturated fatty acids; MPL, milk polar lipids; HMO, human milk oligosaccharides; EGF, epidermal growth factor; HB-EGF, hemoglobin-binding EGF-like growth factor; EPO, erythropoietin; ATRA, all-trans retinoic acid.