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.
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.
Objective To investigate the effect of nutrient withdrawal on human intestinal epithelial barrier function (EBF). We hypothesized that unfed mucosa results in decreased EBF. This was tested in a series of surgical small intestinal resection specimens. Design Small bowel specifically excluding inflamed tissue, was obtained from pediatric patients (aged 2 days to 19 years) undergoing intestinal resection. EBF was assessed in Ussing chambers for transepithelial resistance (TER) and passage of FITC-Dextran (4kD). Tight junction and adherence junction proteins were imaged with immunofluorescence staining. Expression of Toll like receptors (TLR) and inflammatory cytokines were measured in loop ileostomy takedowns in a second group of patients. Results Because TER increased with patient age (p<0.01), results were stratified into infant versus teenage groups. Fed bowel had significantly greater TER versus unfed bowel (p<0.05) in both age populations. Loss of EBF was also observed by an increase in FITC-Dextran permeation in nutrient-deprived segments (p<0.05). Immunofluorescence staining showed marked declines in intensity of ZO-1, occludin, Ecadherin and Claudin-4 in unfed intestinal segments, as well as a loss of structural formation of tight junctions. Analysis of cytokine and TLR expression showed significant increases in TNF-α and TLR4 in unfed segments of bowel compared to fed segments from the same individual. Conclusion EBF declined in unfed segments of human small bowel. This work represents the first direct examination of EBF from small bowel derived from nutrient-deprived humans and may explain the increased infectious complications seen in patients not receiving enteral feeds.
Background and Aims Enteral nutrient deprivation via total parenteral nutrition (TPN) in a mouse model leads to a local mucosal inflammatory response. This pro-inflammatory response leads to a loss of epithelial barrier function and atrophy of the intestine. Although, the underlying mechanisms are unknown, a potential contributing factor is the impact TPN has on the intestinal microbiome. We recently identified a shift in the intestinal microbial community in mice given TPN; however, it is unknown whether such changes occur in humans. We hypothesized that similar microbial changes occur in humans during periods of enteral nutrient deprivation. Methods A series of small bowel specimens were obtained from pediatric and adult patients undergoing small intestinal resection. Mucosally-associated bacteria were harvested, and analyzed using 454 pyrosequencing techniques. Statistical analysis of microbial diversity and differences in microbial characteristics were assessed between enterally-fed and enterally-deprived portions of the intestine. Occurrence of post-operative infectious and anastomotic complications was also examined. Results Pyrosequencing demonstrated a wide variability in microbial diversity within all groups.. Principal coordinate analysis demonstrated only a partial stratification of microbial communities between fed and enterally deprived groups. Interestingly, a tight correlation was identified in patients who had a low level of enteric microbial diversity and those who developed post-operative enteric-derived infections or intestinal anastomotic disruption. Conclusions Loss of enteral nutrients and systemic antibiotic therapy in humans is associated with a significant loss of microbial biodiversity within the small bowel mucosa. These changes were associated with a number of enteric-derived intestinal infections and intestinal anastomotic disruptions.
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