Paneth Cell Alterations During Ischemia-reperfusion, Follow-up, and Graft Rejection After Intestinal Transplantation

BACKGROUND Ischemia-reperfusion (IR) injury is inevitable during intestinal transplantation (ITx) and executes a key role in the evolution towards rejection. Paneth cells (PC) are crucial for epithelial immune defense and highly vulnerable to IR injury. We investigated the effect of ITx on PC after reperfusion (T0), during follow-up, and rejection. Moreover, we investigated whether PC loss was associated with impaired graft homeostasis. METHODS Endoscopic biopsies, collected according to center-protocol and at rejection episodes, were retrospectively included (n=28 ITx, n=119 biopsies) Biopsies were immunohistochemically co-stained for PC (lysozyme) and apoptosis, and PC/crypt and lysozyme intensity were scored. RESULTS We observed a decrease in PC/crypt and lysozyme intensity in the first week after ITx (W1) compared to T0. There was a tendency towards a larger decline in PC/crypt (p=0.08) and lysozyme intensity (p=0.08) in W1 in patients who later developed rejection compared to patients without rejection. Follow-up biopsies showed that the PC number recovered, whereas lysozyme intensity remained reduced. This persisting innate immune defect may contribute to the well-known vulnerability of the intestine to infection. There was no clear evidence that PC were affected throughout rejection. CONCLUSION This study revealed a transient fall in PC numbers in the early post-ITx period, but a permanent reduction in lysozyme intensity following ITx. Further research is needed to determine the potential clinical impact of PC impairment after ITx

Current state of adult intestinal transplantation in Europe

PURPOSE OF REVIEW: In Europe, adult intestinal transplantation (ITx) has continuously evolved since the first successful case in 1989. However, despite several recent innovations, no significant improvement in survival has been seen since 2005, illustrating the unique difficulty of transplanting the intestine. In this review, a subanalysis of adult ITx in Europe is discussed and recent publications on adult ITx in Europe are presented. RECENT FINDINGS: Increased medical and surgical arsenal in the treatment of intestinal failure reduce the need for ITx. At the same time, new indications (diffuse ischemia) have emerged. Static cold storage after vascular flush remains the gold standard but promising results are shown with additional luminal preservation. Pretransplant embolization facilitates multivisceral transplantation. Chronic rejection remains a major difficulty to tackle and currently, liver inclusion is the only effective strategy. Treatment of graft-versus-host-disease remains debated. Quality of life substantially improves after successful ITx. ITx becomes cost-effective three years after transplantation. SUMMARY: ITx remains more challenging than other solid organ transplants. However, long term outcome, particularly after combined liver and ITx, is excellent and similar to other solid organ transplants. Further studies are warranted to tackle the fundamental immunobiological challenge that ITx represents.status: publishe

The expanding role of the bile acid receptor farnesoid X in the intestine and its potential clinical implications

Knowledge about the role of farnesoid X receptor (FXR) in the intestine is rapidly expanding. In pre-clinical animal models of inflammatory bowel disease and bile duct ligation, FXR activation has proven to directly target the three pillars of intestinal homeostasis: intestinal permeability, inflammation and bacterial translocation. The protective role of FXR-ligands on this homeostasis has implications for many intestinal pathologies like inflammatory bowel disease, ischemia reperfusion injury, the metabolic syndrome, colon cancer and even diarrhea. In this review, we summarize the mechanisms by which FXR-activation exerts these protective effects and we discuss its potential clinical applications.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=tacb20status: publishe

Tacrolimus-induced optic neuropathy after multivisceral transplantation

Tacrolimus is currently the most commonly prescribed immunosuppressant. Tacrolimus allowed intestinal transplantation (ITx) to become a clinical reality by significantly reducing rejection rates in this highly immunogenic organ. Despite its effectivity, tacrolimus can cause severe neurological complications. Specifically, tacrolimus can lead to neuropathy and posterior reversible encephalopathy syndrome (PRES). The exact mechanism is not fully understood, but both direct neurotoxicity- and vasoconstriction-induced ischemic damage have been proposed. One particular form, tacrolimus-induced optic neuropathy (TION) leading to severe visual loss, has been described after solid-organ transplantation. The clinical course of TION can vary substantially, including the degree of vision loss, ophthalmological findings, and subsequent recovery. As there is no pathognomonic sign, the diagnosis is made after excluding other causes such as inflammatory diseases, stroke, infections, and metabolic problems.The definitive diagnosis is often only made after clinical improvement following withdrawal of tacrolimus. This is possible in most solid-organ transplants but is particularly difficult after ITx where tacrolimus is vital to prevent rejection. We describe a rare case of late-onset, severe, bilateral TION after multivisceral transplantation (MVTx) that was successfully treated while also avoiding rejection.status: Published onlin

Protective Effect of Oxygen and Isoflurane in Rodent Model of Intestinal Ischemia-Reperfusion Injury

Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague–Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O2) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O2), supplying 100% O2 improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O2, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research

Cost analysis of chronic intestinal failure

BACKGROUND & AIMS: Chronic intestinal failure is a complex medical condition which is associated with high costs. These patients require long-term home parenteral nutrition (HPN) and costs are compounded by frequent admissions for the underlying disease and HPN. However, it is unknown what the specific costs subdivisions are and how they evolve over time. The aim of the study was to evaluate the cost dynamics of HPN care in a cohort of stable, long-term intestinal failure patients. METHODS: A retrospective analysis of our single-center long-term (>2 years), benign HPN population was performed. All relevant clinical and financial data were collected: costs of hospital admissions, diagnostics, treatments, out-patient clinics, home care, medication, materials and HPN education. The costs were tabulated and assigned by cause (HPN related, underlying disease-related or -unrelated). Patients with complicated intestinal failure (defined as impending loss of vascular access, liver failure or recurrent fluid/electrolyte disorders) were excluded. Data are presented as median (range). RESULTS: Thirty-seven patients (24 female; age 58.6 ± 13.3 years) were included in the study. HPN duration was 5.3 years (2.1-15.1) at 4.3 infusion days per week (1.5-7). Total cost of the first HPN year was €83,503 (35,364-256,780). HPN-related costs accounted for 69% (€57,593) vs 27% for underlying disease-related costs (€22,505) and 4% for disease-unrelated costs (€3065). HPN complications cost €16,077 in the first year and accounted for 31% of HPN costs. The total cost dropped by 15% in the second year to €71,311. This reduction was due to fewer hospital admissions and fewer HPN complications. This trend continued and by year 5 the annual cost was 40% cheaper compared to year 1 (€58,187 vs €83,503). CONCLUSIONS: HPN related costs accounted for the majority of the total expenses in IF patients. The costs declined after the first year due to a reduction in complications and hospital admissions.status: publishe

Protective Effect of Oxygen and Isoflurane in Rodent Model of Intestinal Ischemia-Reperfusion Injury

Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague–Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O2) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O2), supplying 100% O2 improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O2, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research

Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut

Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin-induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium-dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region-selective targeting of gut taste receptors in obesity is indicated.-Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.status: publishe

Intravenous Polyethylene Glycol Alleviates Intestinal Ischemia-Reperfusion Injury in a Rodent Model

Intestinal ischemia-reperfusion injury (IRI) is a common clinical entity, and its outcome is unpredictable due to the triad of inflammation, increased permeability and bacterial translocation. Polyethylene glycol (PEG) is a polyether compound that is extensively used in pharmacology as an excipient in various products. More recently, this class of products have shown to have potent anti-inflammatory, anti-apoptotic, immunosuppressive and cell-membrane-stabilizing properties. However, its effects on the outcome after intestinal IRI have not yet been investigated. We hypothesized that PEG administration would reduce the effects of intestinal IRI in rodents. In a previously described rat model of severe IRI (45 min of ischemia followed by 60 min of reperfusion), we evaluated the effect of IV PEG administration at different doses (50 and 100 mg/kg) before and after the onset of ischemia. In comparison to control animals, PEG administration stabilized the endothelial glycocalyx, leading to reduced reperfusion edema, bacterial translocation and inflammatory reaction as well as improved 7-day survival. These effects were seen both in a pretreatment and in a treatment setting. The fact that this product is readily available and safe should encourage further clinical investigations in settings of intestinal IRI, organ preservation and transplantation