Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

Total parenteral nutrition (TPN), a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD). PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR) in the gut and enhance fibroblast growth factor 19 (FGF19) level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA). Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs). GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.

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

Nutrients ◽

10.3390/nu12051493 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1493

Author(s):

Miguel Guzman ◽

Chandrashekhara Manithody ◽

Joseph Krebs ◽

Christine Denton ◽

Sherri Besmer ◽

...

Keyword(s):

Parenteral Nutrition ◽

Total Parenteral Nutrition ◽

Organic Anion ◽

Farnesoid X Receptor ◽

Organic Anion Transporter ◽

Liver Cholesterol ◽

Muscularis Mucosa ◽

Associated Injury ◽

Systemic Signaling ◽

Anion Transporter

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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O.37 Effect of continuous infusion of catecholamine on fat and glucose metabolism and on amount of liver triglyceride during total parenteral nutrition in rats

Clinical Nutrition ◽

10.1016/s0261-5614(83)80039-9 ◽

1983 ◽

Vol 2 ◽

pp. 21

Author(s):

K. Iriyama ◽

T. Teranishi ◽

H. Nishiwaki

Keyword(s):

Glucose Metabolism ◽

Parenteral Nutrition ◽

Continuous Infusion ◽

Total Parenteral Nutrition ◽

Liver Triglyceride

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Total parenteral nutrition drives glucose metabolism disorders by modulating gut microbiota and its metabolites

10.1101/2021.10.26.466009 ◽

2021 ◽

Author(s):

Haifeng Sun ◽

Peng Wang ◽

Gulisudumu Maitiabula ◽

Li Zhang ◽

Jianbo Yang ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Gut Microbiota ◽

Parenteral Nutrition ◽

Total Parenteral Nutrition ◽

Gut Microbiome ◽

Resistance Index ◽

Glucose Metabolism Disorders ◽

Model Assessment ◽

Mice Model

Glucose metabolism disorders are serious complications of total parenteral nutrition (TPN). However, the mechanisms of TPN-associated glucose metabolism disorders remain unclarified. Given that the glucose metabolism was related to gut microbiome and TPN could induce the gut microbiome disturbance, we hypothesized that gut dysbiosis might contribute to glucose metabolism disorders in TPN. By performing a cohort study of 256 type 2 IF (Intestinal failure) patients given PN，we found that H-PN (PN>80%) patients exhibited insulin resistance and a higher risk of complications. Then, TPN and microbiome transfer mice model showed that TPN promotes glucose metabolism disorders by inducing gut microbiome disturbance; 16S rRNA sequencing showed that the abundance of Lactobacillaceae was decreased in mice model and was negatively correlated with HOMA-IR (Homeostasis model assessment insulin resistance index) and lipopolysaccharide level in TPN patients. Untargeted metabolomics found that indole-3-acetic acid (IAA) and kynurenic acid were decreased in TPN mice, and their serum levels were also decreased in H-PN patients. Furthermore, GLP-1(Glucagon-like peptide-1) secretione regulated by IAA through aryl hydrocarbon receptor was also decreased in TPN mice and patients; IAA or liraglutide completely prevented glucose metabolism disorders in TPN mice. In conclusion, TPN drives glucose metabolism disorders by inducing alteration of gut microbiota and its metabolites.

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Hepatic and muscle glucose metabolism during total parenteral nutrition: impact of infection

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.275.5.e763 ◽

1998 ◽

Vol 275 (5) ◽

pp. E763-E769 ◽

Cited By ~ 10

Author(s):

Owen P. McGuinness ◽

Christine Donmoyer ◽

Joseph Ejiofor ◽

Suzanne McElligott ◽

D. Brooks Lacy

Keyword(s):

Glucose Metabolism ◽

Parenteral Nutrition ◽

Glucose Uptake ◽

Total Parenteral Nutrition ◽

Vena Cava ◽

Glucose Disposal ◽

Peripheral Tissues ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake ◽

The Impact

We examined the impact of infection on hepatic and muscle glucose metabolism in dogs adapted to chronic total parenteral nutrition (TPN). Studies were done in five conscious chronically catheterized dogs, in which sampling (artery, portal and hepatic vein, and iliac vein), infusion catheters (inferior vena cava), and Transonic flow probes (hepatic artery, portal vein, and iliac artery) were implanted. Fourteen days after surgery, dogs were placed on TPN. After 5 days of TPN, an infection was induced, and the TPN was continued. The balance of substrates across the liver and limb was assessed on the day before infection ( day 0) and 18 ( day 1) and 42 h ( day 2) after infection. On day 0, the liver was a marked net consumer of glucose (4.3 ± 0.6 mg ⋅ kg−1⋅ min−1) despite near normoglycemia (117 ± 5 mg/dl) and only mild hyperinsulinemia (16 ± 2 μU/ml). In addition, the majority (79 ± 13%) of the glucose taken up by the liver was released as lactate (34 ± 6 μmol ⋅ kg−1⋅ min−1). After infection, net hepatic glucose uptake decreased markedly on day 1(1.6 ± 0.9 mg ⋅ kg−1⋅ min−1) and remained suppressed on day 2 (2.4 ± 0.5 mg ⋅ kg−1⋅ min−1). Net hepatic lactate output also decreased on days 1 and 2 (15 ± 5 and 12 ± 3 μmol ⋅ kg−1⋅ min−1, respectively). This occurred despite increases in arterial plasma glucose on days 1 and 2 (135 ± 9 and 144 ± 9 mg/dl, respectively) and insulin levels on days 1 and 2 (57 ± 14 and 34 ± 9 μU/ml, respectively). In summary, the liver undergoes a profound adaptation to TPN, making it a major site of glucose disposal and conversion to lactate. Infection impairs hepatic glucose uptake, forcing TPN-derived glucose to be removed by peripheral tissues.

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