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

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.

Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

“…A lthough total parenteral nutrition (TPN) is an essential therapy for patients who cannot tolerate enteral nutrition, there are numerous and significant clinical sequelae associated with TPN treatment (1). These clinical complications, which include altered immunological responses, hepatic dysfunction, metabolic derangements, endotoxemia, bacterial infections, and sepsis, can delay or make it difficult to wean patients back onto enteral nutrition.…”

“…These clinical complications, which include altered immunological responses, hepatic dysfunction, metabolic derangements, endotoxemia, bacterial infections, and sepsis, can delay or make it difficult to wean patients back onto enteral nutrition. Several studies have indicated that early TPN administration in critically ill patients is associated with worsened clinical outcomes and increased rates of septicemia, often from enterically derived organisms (1,2). These issues clearly highlight that a more detailed understanding of the underlying mechanisms of TPN-related intestinal complications is needed both to improve the selection and administration of TPN to patients and for the development of new therapeutic options for patients dependent on TPN.…”

“…The removal of enteral nutrition is associated with decreased crypt proliferation, increased IEC apoptosis, a loss of epithelial barrier function (EBF), and altered enteric microbiota, resulting in a mild proinflammatory state and mucosal atrophy (1). Previous studies have shown that upregulation of tumor necrosis factor alpha (TNF-␣) and its receptor (TNFR1) plays a central role in mediating TPN-induced mucosal atrophy.…”

Microbial Modulation of Host Apoptosis and Pyroptosis

“…The apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis is reviewed in Marriott (2013). The intestinal epithelial cell apoptosis in the setting of altered microbiota with enteral nutrient deprivation is reviewed in Demehri et al (2013).…”

“…The paper (Demehri et al, 2013) in this issue introduces a shift in our understanding of intestinal microbiota such as Gram-negative Proteobacteria after enteral nutrient deprivation. The altered microbiota setting leads to increased intestinal proinflammatory cytokines, decreased epithelial cell proliferation, and increased epithelial cell apoptosis.…”