Changes to the Intestinal Microbiome With Parenteral Nutrition

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142098/1/ncp0798.pd

TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways

Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO‐TPN mice and prevents mucosal atrophy. C57B1/6 and strain‐matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF‐α decreased in TLR4KO‐TPN versus wild‐type (WT)‐TPN mice. Apoptotic positive crypt cells were 15‐fold higher in WT‐TPN versus TLR4KO‐TPN mice. Bcl‐2 was significantly increased in TLR4KOTPN mice, while Bax decreased 10‐fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO‐sTPN mice. TLR4 blockade significantly prevented TPN‐associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF‐α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN‐associated atrophy.—Freeman, J. J., Feng, Y., Demehri, F. R., Dempsey, P. J., Teitelbaum, D. H. TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. FASEB J. 29, 2943‐2958 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154328/1/fsb2fj14269480.pd

TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways

Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO-TPN mice and prevents mucosal atrophy. C57Bl/6 and strain-matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF-α decreased in TLR4KO-TPN versus wild-type (WT)-TPN mice. Apoptotic positive crypt cells were 15-fold higher in WT-TPN versus TLR4KO-TPN mice. Bcl-2 was significantly increased in TLR4KO-TPN mice, while Bax decreased 10-fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO-sTPN mice. TLR4 blockade significantly prevented TPN-associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF-α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN-associated atrophy.—Freeman, J. J., Feng, Y., Demehri, F. R., Dempsey, P. J., Teitelbaum, D. H. TPN-associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways

Giant Gastroschisis with Complete Liver Herniation: A Case Report of Two Patients

Introduction. There are no reported survivors of gastroschisis with complete liver herniation. We describe a case report of two patients, one of whom survived. Case #1. The patient was born with gastroschisis and herniation of the entire liver. Along with silo placement, the abdominal fascia was attached to an external traction system for growth. Complete closure was achieved at 5 months. Due to pulmonary hypoplasia, high-frequency ventilation was required. The patient is doing well, on a home ventilator wean, at 20 months. Case #2. The patient was born prematurely with gastroschisis, total liver herniation, and a defect extending to the pericardium. A silo was attached to the fascia to provide growth of the abdominal cavity. The patient developed respiratory failure, diffuse anasarca, and renal failure. She died at 38 days of life. Discussion. We report the first survivor of gastroschisis with complete liver herniation, contrasting it with a death of a similar case. The associated pulmonary hypoplasia may require long-term ventilation, the inflammatory response can lead to anasarca, and renal injury can occur from acute-on-chronic compartment syndrome. Conclusion. External fascial traction systems can help induce growth of the abdominal wall, allowing closure of the challenging abdomen. While critical care management is complex, survival is possible

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

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