Hepatic Cholesterol Metabolism Drives Enteric Immunity and Development of Necrotizing Enterocolitis
Abstract
Necrotizing Enterocolitis (NEC) is a disease of the neonatal gastrointestinal tract
related to prematurity, low birth weight and formula feeding that has been linked to
imbalances in tolerizing versus inflammatory lymphocytes. Lipid metabolism is crucial
to T cell phenotype. We hypothesized that derangements in hepatic lipid processing
predispose to inflammatory T cell types, including gamma delta T cells (GDTCs), and
diminish tolerizing regulatory T cells (Tregs) in the genetically susceptible host.
First, we conducted an epidemiological study of babies predisposed to NEC.
Flow cytometric analysis was conducted on cord blood Tregs from susceptible babies.
Next, we analyzed microarray data to determine genetic differences in lipid metabolism
of babies who developed NEC. We studied strain-specific differences in T cell
activation in murine models in response to manipulations of lipid substrates. Finally, we
explored the direct effect of low density lipoproteins (LDL) and high density lipoproteins
(HDL) on lymphocyte profiles in vitro and in vivo.
We found that babies who had intrauterine growth restriction (IUGR) and were
born to pre-eclamptic mothers had a nine-fold higher risk of developing NEC compared
to controls. Prematurity led to higher numbers of poorly suppressing Tregs while IUGR
led to low frequencies of normally-functioning Tregs in cord blood. Microarray data
showed significant differences in cholesterol metabolism genes in babies with NEC. In
vitro, LDL supplementation decreased Treg numbers and increased IL-17-producing
cells (a pro-inflammatory cytokine). Liver was found to have higher ratios of GDTCs to
Tregs. Finally, a neonatal mouse model of formula feeding combined with epithelial
destruction of the intestine showed that formula-feeding primed the immune system with
high GDTCs and low Tregs for response to enteric pathogens, as seen in NEC.
The implications of cholesterol metabolism in the development of NEC are novel.
Our data suggest that lipid derangements favoring high LDL and low HDL prime the
system towards an IL-17-producing GDTC phenotype as mediated in the liver. These
findings may be important for both diagnostic and therapeutic purposes, though further
studies are needed.
Citation
Mukhopadhyay, Dhriti (2018). Hepatic Cholesterol Metabolism Drives Enteric Immunity and Development of Necrotizing Enterocolitis. Doctoral dissertation, Texas A & M University. Available electronically from https : / /hdl .handle .net /1969 .1 /173378.