Loss of enteral nutrition in a mouse model results in intestinal epithelial barrier dysfunction

Abstract

Total parenteral nutrition (TPN) administration in a mouse model leads to a local mucosal inflammatory response, resulting in a loss of epithelial barrier function (EBF). Although, the underlying mechanisms are unknown, a major contributing factor is a loss of growth factors and subsequent critical downstream signaling. An important component of these is the p-Akt pathway. An additional contributing factor to the loss of EBF with TPN is an increase in proinflammatory cytokine abundance within the mucosal epithelium, including TNF-α and IFN-γ. Loss of critical nutrients, including glutamine and glutamate, may affect EBF, contributing to the loss of tight junction proteins. Finding protective modalities for the small intestine during TPN administration may have important clinical applications. Supplemental glutamine and glutamate may be examples of such agents.

Figure 1

(A) Representative image of harvested intestine from control (chow fed) and TPN mice. Note the significantly reduced length of both small and large intestine. (B) Mean length in centimeters of small and large bowel (colon) from control and TPN mice. **P < 0.01.

Figure 2

Summary of potential signaling changes with TPN administration. Note loss of nutrients with TPN administration results in a change in the microbiome (represented by the red dots). This leads to enhanced signaling via toll-like receptors (Tlr) activating lamina propria lymphoid tissue leading to NF-κB nuclear transcription and a proinflammatory state within the mucosa, with increases in TNF-α and IFN-γ, and loss of TNF-β and IL-10. These changes lead to a loss of T_REG cells and an exacerbation in the proinflammatory state. In total this leads to a loss of epithelial barrier function.

Figure 3

Summary of the potential mechanisms which may be involved in sustaining epithelial barrier function via the p-Akt signaling pathway. Note loss of local growth factors, including EGF and GLP2, along with respective receptors results in loss of EBF. Restitution of EBF, along with epithelial cell proliferation and prevention of apoptosis, occurs in TPN mice with supplementation of glutamine or glutamate, as well as with exogenous growth factors.