Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation

Farokh R Demehri, Meredith Barrett, Matthew W Ralls, Eiichi A Miyasaka, Yongjia Feng, Daniel H Teitelbaum, Farokh R Demehri, Meredith Barrett, Matthew W Ralls, Eiichi A Miyasaka, Yongjia Feng, Daniel H Teitelbaum

Abstract

Total parenteral nutrition (TPN), a commonly used treatment for patients who cannot receive enteral nutrition, is associated with significant septic complications due in part to a loss of epithelial barrier function (EBF). While the underlying mechanisms of TPN-related epithelial changes are poorly understood, a mouse model of TPN-dependence has helped identify several contributing factors. Enteral deprivation leads to a shift in intestinal microbiota to predominantly Gram-negative Proteobacteria. This is associated with an increase in expression of proinflammatory cytokines within the mucosa, including interferon-γ and tumor necrosis factor-α. A concomitant loss of epithelial growth factors leads to a decrease in epithelial cell proliferation and increased apoptosis. The resulting loss of epithelial tight junction proteins contributes to EBF dysfunction. These mechanisms identify potential strategies of protecting against TPN-related complications, such as modification of luminal bacteria, blockade of proinflammatory cytokines, or growth factor replacement.

Keywords: epithelial barrier function; epithelial call proliferation; epithelial cell apoptosis; microbiome; parenteral nutrition; small intestine.

Figures

Figure 1
Figure 1
Loss of epithelial barrier function with TPN leads to bacterial translocation and sepsis. Lymph node (LN) and spleen isolates from TPN-dependent mice were incubated on Columbia-CNA agar (A) to isolate Gram-positive bacteria. Similarly, culture on MacConkey agar demonstrates Gram-negative bacteria from TPN-dependent LN isolates (B). Rates of bacteremia are significantly greater in TPN-dependent vs. fed mice (C) (Sun et al., 2006).
Figure 2
Figure 2
Epithelial and whole-bowel changes with TPN. Unfed bowel demonstrates decreased epithelial cell proliferation (green = PCNA, proliferating cells; red = DAPI, all nucleated cells) compared to fed intestine (A). Representative images of harvested mouse intestine demonstrate decreased length with TPN-dependence (B).
Figure 3
Figure 3
Phylum-level changes in intestinal microbiota with TPN. Enteric bacteria from TPN-dependent mice (A) demonstrate a relative increase in Proteobacteria and Bacteroidetes vs. fed mice (B), where Firmicutes dominates. MyD88−/− mice, with defective TLR signaling, demonstrate an additional expansion of Verrucomicrobia with TPN-dependence (C) vs. fed controls (D). Akkermansia species predominate among the Verrucomicrobia. Adapted from Miyasaka et al. (2013).
Figure 4
Figure 4
Summary of TPN-induced epithelial signaling changes. Lack of enteral nutrition leads to a change in luminal microbiota where Gram-negative Proteobacteria dominate. Lipopolysaccharide (LPS) derived from these bacteria signal lamina propria (LP) cells via Toll-like receptors (TLR), leading to increased NF-κ B transcription. This creates a pro-inflammatory state with increased TNF-α and IFN-γ, loss of Treg cells, and decreased intraepithelial lymphocyte (IEL)-derived IL-10 and EGF. These changes lead to break down of tight junctions, loss of epithelial barrier function, bacterial translocation, and sepsis.

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