Review ArticleCompromised nutritional status in patients with end-stage liver disease: Role of gut microbiota
Introduction
Liver is the largest and most important organ for the metabolism control. It participates in lipid and glucose metabolism through lipogenesis, fatty acid oxidation, gluconeogenesis and glycogenolysis [1]. Maintenance of health is largely due to an appropriate diet and nutrients that reach the general blood circulation through the liver. Most clinical problems in patients with liver disease can be correlated with the impaired liver capability to adapt endogenous metabolism to nutrient supply. Metabolic syndrome, chronic alcohol consumption, autoimmune injury, and viral infections by hepatotropic viruses (mainly hepatitis B and C viruses) are the most frequent causes of chronic liver diseases [2].
Non-alcoholic fatty liver disease (NAFLD), considered the most common hepatic manifestation of the metabolic syndrome, is characterized by a detrimental increase of triglycerides within the hepatocytes. NAFLD is also characterized by insulin resistance that is closely related to diabetes and obesity [3], [4]. Changes in cell transcriptional status contribute to the development and progression of NAFLD [1]. The increases of triglycerides, free fatty acids, free cholesterol, and other lipid metabolites induce steatosis [5]. As a result, mitochondrial dysfunction with oxidative stress, production of reactive oxygen species (ROS), increased of pro-inflammatory cytokines, and unregulated hepatocyte apoptosis contribute to the development of non-alcoholic steatohepatitis (NASH), which might degenerate into cirrhosis and/or hepatocellular carcinoma (HCC) [3], [4], [6].
Alcoholic liver disease (ALD) includes injuries such as alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis and development of HCC [7]. Liver failure is characterized by complications such as ascites, variceal hemorrhage, hepatic encephalopathy and HCC, or renal impairment leading to end-stage liver disease (ESLD) (Fig. 1).
Pharmacotherapy to stop or reverse hepatic histological injury in preventing the development of ESLD is specifically offered to NASH patients and those with advanced fibrosis. In this context, the potential of the semi-synthetic bile acid derivative obeticholic acid (OCA), an agonist of the bile acid nuclear receptor farnesoid X receptor, might represent a useful option in NAFLD/NASH patients. This treatment targets a variety of different pathways such as metabolic homeostasis, inflammation, oxidative stress and fibrosis [8], [9]. Indeed, in obese rat model with hepatic steatosis, OCA ameliorated this condition by reducing hepatic expression of genes involved in the synthesis of fatty acid, lipogenesis, and gluconeogenesis [10]. The role of OCA as a promising therapy in NASH, NAFLD as well as thiazolidinedione, and vitamin E in improving histologic endpoints in NAFLD have been confirmed [11], [12]. Other strategies, similarly to regenerative cell therapy for cardiovascular disease, might ameliorate this condition [13], [14], [15].
Unfortunately, the available medical therapies do not reestablish completely the loss of liver function. Up to date, liver transplantation (LT) would seem to be the only eligible therapy for ESLD patients. However, LT presents some drawbacks such as the decreasing number of organs recovered and transplanted, and the frequent ineligibility of these patients for transplant [16], [17]. Awaiting for improving the efficiency of organ donation process, alternative strategies for ESLD patients should be considered [18], [19].
The major part of ESLD patients results in malnutrition: the nutritional deficiencies (macro- or micro-nutrients) contribute significantly to malnutrition [20]. Then, it becomes crucial to identify all malnourished patients to implement the assessment of malnutrition also in liver transplant care [21], [22].
The interaction among nutrients, diet and genes by epigenetics, an inheritable phenomenon that affects gene expression without altering the DNA sequence, has emerged as a potential target to reduce the morbidity and mortality in NAFLD [23], [24]. The regulation of cell-specific transcriptional networks is accomplished by epigenetic mechanisms via chromatin-modifying enzymes whose activity is directly dependent on metabolites such as acetyl-coenzyme A, S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+); consequently, all these nuclear activities are directly influenced by cellular nutritional condition [25], [26].
The gastrointestinal tract hosts a huge amount of symbiotic bacteria as a whole called “gut microbiota” that can be altered intentionally or unintentionally through dietary changes [27]. The intimate proximity and circulatory loop of liver and gut have focused the attention of scientific community on the crucial role of microbiota in the development and progression of liver diseases [28]. The alteration of gut microbiota, also known as dysbiosis, influences the development of NAFLD by endogenous alcohol production [29]. The translocation of microbiota into the portal blood appears to play a crucial role in ALD [30]. Dynamic changes in gut microbiota provided important insights into host-microbe interactions during liver disease evolution and HCC development [31], [32], [33]. The bile acids and the intestinal microbiota influenced each other and together regulated the various signaling pathways to maintain the health of digestive tract. One study highlighted a strong association between gut microbiota, bile acids, and liver cancer, in a sex-dependent manner [31]. Intestinal overgrowth of Escherichia coli might contribute to the process of HCC, in patients with liver cirrhosis [32]. Besides, dietary or genetic obesity induced alterations of gut microbiota increasing the levels of deoxycholic acid (DCA), a gut bacterial metabolite that causes DNA damage. In obese mice, it was demonstrated that HCC development is prevented by blocking DCA production or by reducing gut bacteria efficiently [33]. Consequently, the administration of probiotics to modulate the gut microbiota both in chronic liver diseases and during pre-, peri- and early post-liver transplantation in ESLD patients could be a promising strategy to reduce alcohol-induced liver injury [30], [31], [32], [33].
A systematic review of literature based on extensive articles in PubMed Database was performed by searching keywords such as liver disease, non-alcoholic liver disease, alcoholic liver disease, malnutrition, epigenetics, gut microbiota, and probiotics. All pertinent English-language articles, published from 2001 to 2017 and screened for their relevance, were considered. Articles and studies looking for these associations between the key words and chronic liver diseases represented the main source of data and were reviewed.
This review provides an update on the association between malnutrition and gut-liver axis in ESLD patients highlighting the potential epigenetic effect of the nutrient intake. The evidence of the preventive and therapeutic benefit of probiotics on the management of ESLD patients has been underlined too. Besides, we report some clinical trials to demonstrate the constant and growing clinical interest on these potential therapeutic approaches.
Section snippets
Malnutrition and management of ESLD patients: potential epigenetic link
All advanced liver disease patients and screened positive for malnutrition, present a nutrient imbalance determined by a deficit/excess of nutrient intake. They are characterized by a reduced hepatic expression of the antioxidant enzyme glutathione S-transferase with a consequent increase of free radicals and oxidative stress in the liver (Fig. 1) [34]. Besides, these patients show protein deficiency, anorexia, and hyporexia, one of the most important factors related to a poor calorie intake
Gut microbiota and probiotics in ESLD patients
The relationships between diet and microbiota induce changes in the intestinal microbial balance and/or bacterial translocation (Fig. 1) [60], [61], [62].
Given the close anatomical and functional relationship between gut and liver (known as gut-liver axis) and the intestinal blood supply to the liver through the portal vein, bacteria and/or pathogen-derived factors might shift from the intestine to the liver in case of dysbiosis. Dysbiosis plays an essential role in the pathogenesis of chronic
Conclusions
Malabsorption, poor dietary intake, low protein synthesis, higher intestinal protein deficiency, and disturbances in substrate utilization are known for nutritional imbalance in ESLD patients. Regrettably, the nutritional status is often disregarded and inadequately managed in the clinical setting before LT. In addition, ESLD patients go through a significantly longer hospital stay, higher rates of infections, poor quality of life with a decreased life span. Nutritional support for malnourished
Contributors
VM and PR proposed the study. VM, PR, SC, SL and CO searched the literature and wrote the first draft. NC reviewed and edited the manuscript. All authors approved the final version of the manuscript. VM and PR contributed equally to this study. SL is the guarantor. CO is Chief Emeritus of Surgery of Department of Liver Transplant, AORN A. Cardarelli, Naples, Italy.
Funding
This work was supported by a grant from “Ricerca Corrente 2013–15” from Italian Ministry of Health (RRC-2015-2360454).
Ethical approval
Not needed.
Competing interest
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
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