Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model

Abstract

Feeding strategies to care for patients who transition from enteral nutrient deprivation while on total parenteral nutrition (TPN) to enteral feedings generally proceed to full enteral nutrition once the gastrointestinal tract recovers; however, an increasing body of literature suggests that a subgroup of patients may actually develop an increased incidence of adverse events, including death. To examine this further, we studied the effects of acute refeeding in a mouse model of TPN. Interestingly, refeeding led to some beneficial effects, including prevention in the decline in intestinal epithelial cell (IEC) proliferation. However, refeeding led to a significant increase in mucosal expression of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), as well as an upregulation in Toll-like receptor 4 (TLR-4). Refeeding also failed to prevent TPN-associated increases in IEC apoptosis, loss of epithelial barrier function, and failure of the leucine-rich repeat-containing G protein-coupled receptor 5-positive stem cell expression. Transitioning from TPN to enteral feedings led to a partial restoration of the small bowel microbial population. In conclusion, while acute refeeding led to some restoration of normal gastrointestinal physiology, enteral refeeding led to a significant increase in mucosal inflammatory markers and may suggest alternative strategies to enteral refeeding should be considered.

Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model

“…As in this zebrafish model, tgfβ has been noted to rise with refeeding in the mouse model noted above [34]. …”

“…Interestingly, dkk3 (2.3 log 2 FC), a secreted Wnt antagonist, was also increased. In a study of enteral atrophy followed by refeeding and therefore epithelial expansion in the mouse, wnt5A , cyclin D1 and c-Myc all decline without enteral nutrition and then are restored with the reintroduction of enteral nutrition and the subsequent adaptive response [34]. …”

Interdependency of EGF and GLP-2 Signaling in Attenuating Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

“…Loss of enteral nutrition through long-term caloric depletion, fasting, or parenteral nutrition can alter the function of ISC/progenitor populations as well as that of other accessory cells in the intestinal stem cell niche such as Paneth cells 66, 67, 68. Previous studies have shown that phosphatase and tensin homolog, a negative regulator of the PI3K/AKT/mammalian target of rapamycin complex 1 (mTORC1)-signaling pathway, is an important regulator of reserve facultative ISCs 67 .…”

Early downregulation of P‐glycoprotein facilitates bacterial attachment to intestinal epithelial cells and thereby triggers barrier dysfunction in a rodent model of total parenteral nutrition

“…However, despite its advantages, evidence is accumulating that TPN, especially long‐term TPN, may lead to increasing associated complications like gut‐derived infections due in part to disruption of intestinal barrier function. To date, although the underlying mechanisms of intestinal barrier dysfunction have not been fully elucidated, a number of possible contributing factors have been reported in a rodent model of TPN, including aberrant signaling pathways in enterocyte proliferation/apoptosis, decline in mucosal immunity, dysbiosis, and cascade of inflammatory cytokines leading to disassembly of tight junctions . However, the question is, in addition to all those contributing factors that appear with the development of intestinal barrier dysfunction, whether there exists something else that occurs much earlier and triggers the disruption of barrier function.…”

“…To date, although the underlying mechanisms of intestinal barrier dysfunction have not been fully elucidated, a number of possible contributing factors have been reported in a rodent model of TPN, including aberrant signaling pathways in enterocyte proliferation/ apoptosis, [25][26][27] decline in mucosal immunity, 28,29 dysbiosis, and cascade of inflammatory cytokines leading to disassembly of tight junctions. 30,31 However, the question is, in addition to all those contributing factors that appear with the development of intestinal barrier dysfunction, whether there exists something else that occurs much earlier and triggers the disruption of barrier function. Recently, intestinal P-gp has been considered as a natural defense mechanism that antagonizes the translocation of harmful substances from the gut to circulation via transcellular route.…”