No Gut No Gain! Enteral Bile Acid Treatment Preserves Gut Growth but Not Parenteral Nutrition–Associated Liver Injury in a Novel Extensive Short Bowel Animal Model

Villalona, Gustavo A.; Price, Amber; Blomenkamp, Keith; Manithody, Chandrashekhara; Saxena, Sanjeev; Ratchford, Thomas L; Westrich, Matthew; Kakarla, Vindhya; Pochampally, Shruthika; Phillips, William; Heafner, Nicole; Korremla, Niraja; Greenspon, José; Guzmán, Miguel A.; Jain, Ajay K.

doi:10.1002/jpen.1167

Cited by 15 publications

(21 citation statements)

References 78 publications

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“…In consultation with our university statistician, for our calculations, we used historical data of 5-10-fold changes in serum bilirubin [1,18,30,31], as well as a 2-3 fold reduction in the V/C ratio [1,22,29] with TPN to model the sample size calculation. From our previous work [1,7,8,20,21,32], we predicted that the actual effects across variables would be larger, thus reasonably obtainable with eight animals per group.…”

Section: Sample Sizementioning

confidence: 95%

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Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

et al. 2020

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Background: Total parenteral nutrition (TPN) provides all nutritional needs intravenously. Although lifesaving, enthusiasm is significantly tempered due to side effects of liver and gut injury, as well as lack of mechanistic understanding into drivers of TPN injury. We hypothesized that the state of luminal nutritional deprivation with TPN drives alterations in gut–systemic signaling, contributing to injury, and tested this hypothesis using our ambulatory TPN model. Methods: A total of 16 one-week-old piglets were allocated randomly to TPN (n = 8) or enteral nutrition (EN, n = 8) for 3 weeks. Liver, gut, and serum were analyzed. All tests were two-sided, with a significance level of 0.05. Results: TPN resulted in significant hyperbilirubinemia and cholestatic liver injury, p = 0.034. Hepatic inflammation (cluster of differentiation 3 (CD3) immunohistochemistry) was higher with TPN (p = 0.021). No significant differences in alanine aminotransferase (ALT) or bile ductular proliferation were noted. TPN resulted in reduction of muscularis mucosa thickness and marked gut atrophy. Median and interquartile range for gut mass was 0.46 (0.30–0.58) g/cm in EN, and 0.19 (0.11–0.29) g/cm in TPN (p = 0.024). Key gut–systemic signaling regulators, liver farnesoid X receptor (FXR; p = 0.021), liver constitutive androstane receptor (CAR; p = 0.014), gut FXR (p = 0.028), G-coupled bile acid receptor (TGR5) (p = 0.003), epidermal growth factor (EGF; p = 0.016), organic anion transporter (OAT; p = 0.028), Mitogen-activated protein kinases-1 (MAPK1) (p = 0.037), and sodium uptake transporter sodium glucose-linked transporter (SGLT-1; p = 0.010) were significantly downregulated in TPN animals, whereas liver cholesterol 7 alpha-hydroxylase (CyP7A1) was substantially higher with TPN (p = 0.011). Conclusion: We report significant alterations in key hepatobiliary receptors driving gut–systemic signaling in a TPN piglet model. This presents a major advancement to our understanding of TPN-associated injury and suggests opportunities for strategic targeting of the gut–systemic axis, specifically, FXR, TGR5, and EGF in developing ameliorative strategies.

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Section: Sample Sizementioning

confidence: 95%

“…For the EN group, a swine replacement formula was provided enterally, as previously described. For the TPN group, a commercially available parenteral nutrition preparation and lipid was delivered via the jugular catheter, as previously described [1,20,21]. The nutritional constituents are included in Table 1.…”

Section: Nutritionmentioning

confidence: 99%

Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

et al. 2020

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“…PNAC is now more commonly referred to as PN‐associated liver disease (PNALD) or intestinal failure–associated liver disease . Such is supported by the idea that because PN is typically utilized in the absence of enteral feeding, the lack of activation of enterocyte receptors by luminal agonists may decrease downstream signaling to the liver through the portal circulation, interrupting the normal gut‐liver cross talk . Liver disease associated with PN includes steatosis, altered glucose and fat metabolism, and hepatic fibrosis or cirrhosis possibly via the downregulation of bile acid transporters …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Parenteral Nutrition–Associated Liver and Gut Injury

et al. 2019

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Parenteral nutrition (PN) has revolutionized the care of patients with intestinal failure by providing nutrition intravenously. Worldwide, PN remains a standard tool of nutrition delivery in neonatal, pediatric, and adult patients. Though the benefits are evident, patients receiving PN can suffer serious cholestasis due to lack of enteral feeding and sometimes have fatal complications from liver injury and gut atrophy, including PN-associated liver disease or intestinal failure-associated liver disease. Recent studies into gut-systemic cross talk via the bile acid-regulated farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) axis, gut microbial control of the TGR5-glucagon-like peptide (GLP) axis, sepsis, and role of prematurity of hepatobiliary receptors are greatly broadening our understanding of PN-associated injury. It has also been shown that the composition of ω-6/ω-3 polyunsaturated fatty acids given parenterally as lipid emulsions can variably drive damage to hepatocytes and cell integrity. This manuscript reviews the mechanisms for the multifactorial pathogenesis of liver disease and gut injury with PN and discusses novel ameliorative strategies. (Nutr Clin Pract. 2020;35:63-71)

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“…2657, US Department of Agriculture registration 43-R-011) and in accordance with the Guide for the Care and Use of Laboratory Animals. 21,22 Neonatal piglets 7 to 10 days old were used for this study, procured from a University approved class A vendor. Ear tags were used to identify animals.…”

Section: Methodsmentioning

confidence: 99%

Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis

Manithody

Denton

Price

et al. 2020

Exp Biol Med (Maywood)

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Extensive bowel resection results in short bowel syndrome. Absence of the ileocecal valve and length of remaining bowel are important prognostic factors. Such patients require total parenteral nutrition for survival, which has significant side effects, thus understanding mechanisms driving total parenteral nutrition-associated complications in short bowel syndrome is a major research focus. We hypothesized that we could develop an ambulatory total parenteral nutrition-short bowel syndrome piglet model recapitulating human short bowel syndrome for advanced research. Fourteen neonatal pigs received duodenal, jugular catheters, and a jacket with a miniaturized pump. Animals were randomly allocated to enteral nutrition ( n = 5), total parenteral nutrition only ( n = 5) or total parenteral nutrition with 75% small bowel, ileocecal valve resection, and ileo-colonic anastomosis ( n = 4). Blood, liver, and gut were analyzed. Animals underwent successful bowel resection and anastomosis. Increased bilirubin was noted in short bowel syndrome and total parenteral nutrition. Mean conjugated bilirubin (mg/dL)±SE was 0.036 ± 0.004 for enteral nutrition ( P = 0.03), 1.29 ± 0.613 for total parenteral nutrition ( P = 0.01), and 3.89 ± 0.51 for short bowel syndrome ( P = 0.000064). Linear gut density was reduced in short bowel syndrome and total parenteral nutrition vs. enteral nutrition. The mean linear gut density (g/cm)±SE for distal gut was 0.30 ± 0.02 for enteral nutrition ( P = 0.0005); 0.16 ± 0.01 for total parenteral nutrition ( P = 0.01), and 0.11 ± 0.008 for short bowel syndrome ( P = 0.0001). We noted gut adaptation in short bowel syndrome ( P = 0.015) with significant reduction in gut FXR, gut FGF19, and enhanced hepatic CyP7A1 expression in short bowel syndrome and total parenteral nutrition ( P < 0.05). We successfully created an ambulatory total parenteral nutrition-short bowel syndrome model with distal small bowel and ileocecal valve resection recapitulating human short bowel syndrome. Our model validated total parenteral nutrition-related hyperbilirubinemia and gut changes, as noted in human short bowel syndrome. This model holds great potential for future innovative research and clinical applications. Impact statement Short bowel syndrome is associated with significant comorbidities and mortality. This study is important as unlike current systems, it provides a validated piglet model which mirrors anatomical, histological, and serological characteristics observed in human SBS. This model can be used to advance knowledge into mechanistic pathways and therapeutic modalities to improve outcomes for SBS patients. This study is novel in that in addition to significant reduction in the remnant bowel and noted liver disease, we also developed a method to emulate ileocecal valve resection and described gut adaptive responses which has important clinical implications in humans.

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No Gut No Gain! Enteral Bile Acid Treatment Preserves Gut Growth but Not Parenteral Nutrition–Associated Liver Injury in a Novel Extensive Short Bowel Animal Model

Cited by 15 publications

References 78 publications

Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

Mechanisms of Parenteral Nutrition–Associated Liver and Gut Injury

Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis

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