Parenteral nutrition (PN) provides life-saving nutritional support in situations where caloric supply via the enteral route cannot cover the necessary needs of the organism. However, it does have serious adverse effects, including parenteral nutrition-associated liver disease (PNALD). The development of liver injury associated with PN is multifactorial, including non-specific intestine inflammation, compromised intestinal permeability, and barrier function associated with increased bacterial translocation, primary and secondary cholangitis, cholelithiasis, short bowel syndrome, disturbance of hepatobiliary circulation, lack of enteral nutrition, shortage of some nutrients (proteins, essential fatty acids, choline, glycine, taurine, carnitine, etc.), and toxicity of components within the nutrition mixture itself (glucose, phytosterols, manganese, aluminium, etc.). Recently, an increasing number of studies have provided evidence that some of these factors are directly or indirectly associated with microbial dysbiosis in the intestine. In this review, we focus on PN-induced changes in the taxonomic and functional composition of the microbiome. We also discuss immune cell and microbial crosstalk during parenteral nutrition, and the implications for the onset and progression of PNALD. Finally, we provide an overview of recent advances in the therapeutic utilisation of pro- and prebiotics for the mitigation of PN-associated liver complications.

. Activation of ␣2-adrenergic receptors blunts epinephrine-induced lipolysis in subcutaneous adipose tissue during a hyperinsulinemic euglycemic clamp in men. Am J Physiol Endocrinol Metab 285: E599-E607, 2003; 10.1152/ajpendo.00502.2002The aim of this study was to investigate whether hyperinsulinemia modifies adrenergic control of lipolysis, with particular attention paid to the involvement of antilipolytic ␣2-adrenergic receptors (AR). Eight healthy male subjects (age: 23.9 Ϯ 0.9 yr; body mass index: 23.8 Ϯ 1.9) were investigated during a 6-h euglycemichyperinsulinemic clamp and in control conditions. Before and during the clamp, the effect of graded perfusions of isoproterenol (0.1 and 1 M) or epinephrine (1 and 10 M) on the extracellular glycerol concentration in subcutaneous abdominal adipose tissue was evaluated by using the microdialysis method. Both isoproterenol and epinephrine induced a dosedependent increase in extracellular glycerol concentration when infused for 60 min through the microdialysis probes before and during hours 3 and 6 of the clamp. The catecholamine-induced increase was significantly lower during the clamp than before it, with the inhibition being more pronounced in hour 6 of the clamp. Isoproterenol (1 M)-induced lipolysis was reduced by 28 and 44% during hours 3 and 6 of the clamp, respectively, whereas the reduction of epinephrine (100 M)-induced lipolysis was significantly greater (by 63 and 70%, P Ͻ 0.01 and P Ͻ 0.04, respectively) during the same time intervals. When epinephrine was infused in combination with 100 M phentolamine (a nonselective ␣-AR antagonist), the inhibition of epinephrine (10 M)-induced lipolysis was only of 19 and 40% during hours 3 and 6 of the clamp, respectively. The results demonstrate that, in situ, insulin counteracts the epinephrine-induced lipolysis in adipose tissue. The effect involves 1) reduction of lipolysis stimulation mediated by the ␤-adrenergic pathway and 2) the antilipolytic component of epinephrine action mediated by ␣2-ARs. microdialysis; glycerol; isoproterenol; blood flow; ␣ 2-adrenergic receptor antagonist NOREPINEPHRINE AND EPINEPHRINE control human adipocyte lipolysis through different adrenergic receptor (AR) subtypes (1,7,20,30). In vitro studies in isolated human fat cells have shown that the activation of ␣ 2 -ARs by epinephrine and norepinephrine impairs the ␤-adrenergic component of catecholamine-induced lipolysis (19,20). In human fat cells, where ␣ 2 -ARs outnumber ␤-ARs, the preferential recruitment of the ␣ 2 -AR at the lowest catecholamine concentrations inhibits lipolysis (20). It is in subcutaneous adipose tissue from both men and women that the strongest ␣ 2 -adrenergic effect has been observed (20, 30). The antilipolytic action of catecholamines in vitro, particularly that of epinephrine (which exhibits a higher affinity for ␣ 2 -AR), is intense in subcutaneous adipocytes from obese subjects (20, 30). Many physiological and pathological studies have shown that the possible deregulation of adrenergic control in adipos...

Background:The gut microbiome and metabolome may significantly influence clinical outcomes in patients with short bowel syndrome (SBS). The study aimed to describe specific metagenomic/metabolomics profiles of different SBS types and to identify possible therapeutic targets. Methods: Fecal microbiome (FM), volatile organic compounds (VOCs), and bile acid (BA) spectrum were analyzed in parenteral nutrition (PN)-dependent SBS I, SBS II, and PN-independent (non-PN) SBS patients. Results: FM in SBS I, SBS II, and non-PN SBS shared characteristic features (depletion of beneficial anaerobes, high abundance of Lactobacilaceae and Enterobacteriaceae). SBS I patients were characterized by the abundance of oxygen-tolerant microrganisms and depletion of strict anaerobes. Non-PN SBS subjects showed markers of partial FM normalization. FM dysbiosis was translated into VOC and BA profiles characteristic for each SBS cohort. A typical signature of all SBS patients comprised high saturated aldehydes and medium-chain fatty acids and reduced short-chain fatty acid (SCFA) content. Particularly, SBS I and II exhibited low protein metabolism intermediate (indole, p-cresol) content despite the hypothetical presence of relevant metabolism pathways. Distinctive non-PN SBS marker was high phenol content. SBS patients' BA fecal spectrum was enriched by chenodeoxycholic and deoxycholic acids and depleted of lithocholic acid. Conclusions: Environmental conditions in SBS gut significantly affect FM composition and metabolic activity. The common feature of diverse SBS subjects is the altered VOC/BA profile and the lack of important products of microbial metabolism. Strategies oriented on the microbiome/metabolome reconstitution and targeted delivery of key compounds may represent a promising therapeutic strategy in SBS patients. (JPEN J Parenter Enteral Nutr. 2020;44:105-118) Keywords bile acids; gut microbiota; parenteral nutrition; short bowel syndrome, short-chain fatty acids, volatile organic compounds From the

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Objective: The potential insulin-sensitizing function of angiotensin II type 1 receptor blockade (ARB) with regard to selected adipokines is not fully explained so far. Our study aimed to explore the influence of acute hyperinsulinaemia and acutely induced ARB on resistin and adiponectin concentrations and expressions in healthy subjects. Design and methods: Plasma adipokines were measured: 1) at 0, 30 and 240 min of hyperinsulinaemic (1 mU/kg per min) euglycaemic (5 mmol/l) clamp (HEC), and 2) during HEC after acute ARB (losartan 200 mg; AT-HEC) using the same protocol, in eight healthy subjects. Needle biopsy of abdominal s.c. fat was performed at 0, 30 and 240 min of both clamps to assess the adipokines' expressions. Results: Comparing the glucose disposals of HEC and AT-HEC, no difference in insulin sensitivity was found. Plasma resistin increased equally during HEC and AT-HEC (P!0.05). The expression of resistin in s.c. fat increased during HEC (P!0.05), while no significant changes in expression were observed during AT-HEC. Plasma levels of adiponectin did not change during both clamps. Adiponectin expression increased during HEC (P!0.05), while it did not change during AT-HEC. Conclusions: In healthy subjects, acute hyperinsulinaemia is associated with an increase in plasma resistin independently of ARB, while plasma adiponectin is not influenced by insulin or ARB. The expressions of both resistin and adiponectin in s.c. adipose tissue are stimulated by acute hyperinsulinaemia, whereas losartan attenuates their insulin-stimulated expressions. This suggests a potential effect of losartanon adipokines' expression.

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Background: The objective of the present study was to determine concentrations of zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in blood plasma and manganese (Mn) in the whole blood in patients with long-term home parenteral nutrition (HPN) in comparison to the control group. Patients and Methods: We examined 68 patients (16 men and 52 women) aged from 28 to 68 years on a long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily doses of Zn, Cu, Fe, Se and Mn in the last 3 months were determined. Results: No significant differences in blood plasma were found for Zn, Cu and Fe in patients with HPN and in the control group (p > 0.05). The concentration of Mn in whole blood was significantly increased in HPN patients (p < 0.0001), while Se concentration in these patients was significantly decreased (p < 0.005). The concentration of Mn in the whole blood of 16 patients with cholestasis was significantly increased compared to the patients without cholestasis (p < 0.001). The Cu concentration was increased with no statistical significance. Conclusion: In long-term HPN, the status of trace elements in the patients has to be continually monitored and the daily substitution doses of these elements have to be flexibly adjusted. Dosing schedule needs to be adjusted especially in cases of cholestatic hepatopathy. A discussion about the optimal daily dose of Mn in patients on HPN is appropriate. For clinical practice, the availability of a substitution mixture of trace elements lacking Mn would be advantageous.

Objective: Telmisartan improves glucose and lipid metabolism in rodents. This study evaluated the effect of telmisartan on insulin sensitivity, substrate utilization, selected plasma adipokines and their expressions in subcutaneous adipose tissue (SAT) in metabolic syndrome. Design and methods: Twelve patients with impaired fasting glucose completed the double-blind, randomized, crossover trial. Patients received telmisartan (160 mg/day) or placebo for 3 weeks and vice versa with a 2-week washout period. At the end of each period, a hyperinsulinemic euglycemic clamp (HEC) combined with indirect calorimetry was performed. During HEC (0, 30, and 120 min), plasma levels of adipokines were measured and a needle biopsy (0 and 30 min) of SAT was performed. Results: Fasting plasma glucose was lower after telmisartan compared with placebo (P!0.05). There were no differences in insulin sensitivity and substrate utilization. We found no differences in basal plasma adiponectin, resistin and tumour necrosis factor a (TNFa), but an increase was found in basal leptin, after telmisartan treatment. Insulin-stimulated plasma adiponectin (P!0.05), leptin and resistin (P!0.001) were increased, whereas TNFa was decreased (P!0.05) after telmisartan treatment. Expression of resistin, but not adiponectin, TNFa and leptin was increased after telmisartan treatment. Conclusions: Despite the decrease in fasting plasma glucose, telmisartan does not improve insulin sensitivity and substrate utilization. Telmisartan increases plasma leptin as well as insulin-stimulated plasma adiponectin, leptin and resistin, and decreases plasma TNFa during HEC. Changes in plasma adipokines cannot be explained by their expressions in SAT. The changes in plasma adipokines might be involved in the metabolic effects of telmisartan in metabolic syndrome.