An in-line digestive cartridge increases enteral fat and vitamin absorption in a porcine model of short bowel syndrome

ST, Tsikis; SC, Fligor; Secor, Jordan D.; LJ, Yu; Pan, Aihua; Mitchell, Paul D.; Loring, Greta; E, First; AP, Nedder; RM, Grammer; B, Pattison; KM, Gura; Puder, Mark

doi:10.1016/j.clnu.2022.03.026

Cited by 4 publications

(14 citation statements)

References 29 publications

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“…Within these limitations, the risk of infection and deleterious effects on animal welfare increase with longer study durations. The chosen duration and group sample sizes are also consistent with prior translational work in this model 15–17,46 . The sample sizes are further justified by our power calculation and are in accordance with ethical principles in regard to minimizing the use of laboratory animals.…”

Section: Discussionmentioning

confidence: 86%

“…The chosen duration and group sample sizes are also consistent with prior translational work in this model. [15][16][17]46 The sample sizes are further justified by our power calculation and are in accordance with ethical principles in regard to minimizing the use of laboratory animals. Finally, the lack of a normal unresected control group for comparisons is an important additional limitation.…”

Section: Discussionmentioning

confidence: 99%

“…This model has been successfully used to evaluate the effects of various interventions on PN dependence 15,16 . In prior experimentation, we demonstrated improved fat and vitamin absorption with ILC use 17 . Therefore, we hypothesized that the use of this device may reduce PN dependence.…”

mentioning

confidence: 99%

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A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

et al. 2023

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Objective: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). Background: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. Methods: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n = 6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/ EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. Results: ILC animals demonstrated a 19% greater reduction in PN calories (P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P = 0.03) and 1.9-fold higher crypt cell proliferation (P = 0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 (P = 0.02), eicosapentaenoic acid (P < 0.0001), docosahexaenoic acid (P = 0.004), vitamin A (P = 0.02), low-density lipoprotein (P = 0.02), and high-density lipoprotein (P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. Conclusions: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

et al. 2023

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“…12 We have previously performed up to a 90% small bowel resection in Yorkshire piglets with a jejunoileal anastomosis. 13,14 Minipig age was chosen because the minipigs reach sexual maturity at 4-6 months and we sought to have translatable data to the adult human population. Yucatan minipigs were chosen because of their smaller adult size compared with that of Yorkshire pigs, allowing for easier animal care.…”

Section: Animal Models Of Sbsmentioning

confidence: 99%

Absorption of an engineered medium‐chain fatty acid analogue in two short bowel syndrome minipig models

Fligor,

Tsikis,

Hirsch

et al. 2023

J Parenter Enteral Nutr

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BackgroundEnteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS‐IF) because of unpredictable absorption. SEFA‐6179 is an enterally administered medium‐chain fatty acid analogue under development for intestinal failure–associated liver disease. We investigate the pharmacokinetics of two SEFA‐6179 formulations in two large‐animal models of SBS‐IF, including a new pseudojejunostomy model.MethodsTwenty Yucatan minipigs were obtained. Half underwent pre‐resection pharmacokinetic study with single‐dose SEFA‐6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single‐dose pharmacokinetic study was performed.ResultsBoth SBS‐IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs −0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre‐resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA‐6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre‐resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47).ConclusionIn two SBS‐IF minipig models, SEFA‐6179 had substantially decreased absorption compared with pre‐resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS‐IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS‐IF who have enterostomies.

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“…We have recently shown in a large animal model that the use of an immobilized lipase cartridge improved both fat and fat-soluble vitamin absorption [ 14 ]. To evaluate if these findings translate clinically, we propose to conduct a phase 3, open labeled study of RELiZORB in pediatric patients with SBS who are dependent on PN.…”

Section: Introductionmentioning

confidence: 99%

Fat digestion using RELiZORB in children with short bowel syndrome who are dependent on parenteral nutrition: Protocol for a 90-day, phase 3, open labeled study

Tsikis

Fligor²,

Mitchell³

et al. 2023

PLoS ONE

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Background Short bowel syndrome (SBS) is a leading cause of intestinal failure resulting in parenteral nutrition (PN) dependence and nutritional deficiencies. Long-term PN use is associated with the development of sepsis and intestinal failure-associated liver disease. Achieving enteral autonomy is the optimal way to prevent these complications. In SBS, the decreased intestinal length, bile acid deficiency, and rapid transit time contribute to fat malabsorption and continued PN dependence. We propose the use of an immobilized lipase cartridge (ILC; RELiZORB) that connects in-line with enteral feed tubing sets and is designed to breakdown the majority of fats provided in enteral nutrition (EN). Preclinical studies have demonstrated both improved fat and fat-soluble vitamin absorption with ILC use in a porcine model of SBS. To evaluate the clinical applicability of these findings, we designed a phase 3, open labeled, single center, clinical trial to determine the safety, tolerability, and efficacy of the RELiZORB enzyme cartridge when used daily with EN for 90 days. Methods The patient population will include PN dependent children with SBS, aged 2–18 years. The primary outcome is the change in PN calories from baseline, assessed weekly throughout the study. Changes in growth Z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma fatty acids and fat-soluble vitamins will also be evaluated. Assessment of change in continuous outcomes will be made using the area under the curve, expressed as a percent change relative to baseline, calculated over study day 7 to 90 (AUC7-90). The incidence of adverse events will be monitored and summarized by system organ class. Discussion If successful, RELiZORB may offer a safe alternative to reducing PN dependence and achieving enteral autonomy in pediatric intestinal failure. These results would be clinically significant given the clear association between long-term PN use and complications in SBS. Trial registration ClinicalTrials.gov NCT03530852; registered on May 21st, 2018, last update posted on September 14th, 2022.

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An in-line digestive cartridge increases enteral fat and vitamin absorption in a porcine model of short bowel syndrome

Cited by 4 publications

References 29 publications

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model

Absorption of an engineered medium‐chain fatty acid analogue in two short bowel syndrome minipig models

Fat digestion using RELiZORB in children with short bowel syndrome who are dependent on parenteral nutrition: Protocol for a 90-day, phase 3, open labeled study

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