Gut Microbiota and NAFLD Development: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Annalisa Barbieri.

NAFLD, the most common liver disorder in the Western world, is characterized by intrahepatic lipid accumulation; is highly prevalent in the aging population; and is closely associated with obesity, insulin resistance, hypertension, and dyslipidemia.

  • liver
  • age-related disease
  • NAFLD
  • gut microbiota

1. Introduction

The so-called gut microbiota (GM) is constituted by numerous different populations of microorganisms (bacteria, archaea, fungi, and viruses) that reside in the gastrointestinal tract of mammals. In recent years, a significant interest in the intestinal microbiota has spread, as it is considered one of the key factors contributing to the maintenance of physiological intestinal homeostasis, the protection against pathogens, and the modulation of the immune system. All these important functions make the GM a fundamental system able to regulate the host’s health [1,2][1][2]. Many researches on GM composition, conducted both in animals and humans, have highlighted its involvement in the onset and progression of several disorders, including neurodegenerative; cardiovascular; gastrointestinal; and metabolic diseases, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) [3].
The progressive degeneration of the tissues, with consequent alteration of organs’ structure and function, and the loss of homeostasis, make the elderly people more prone to develop diseases [4,5,6][4][5][6]. During aging, it is widely reported that the increased imbalance between reactive oxygen species (ROS) production and antioxidant enzymes expression leads to the onset of oxidative stress (OS), with consequent damage to proteins, DNA, and cellular organelles [7]. Specifically, in the gut, OS, together with a sedentary lifestyle, changes in diet, and administration of drugs, causes GM dysbiosis, which contributes to the increase in intestinal permeability, resulting in the release of bacteria, endotoxins, and pro-oxidants into the systemic circulation. Ultimately, all these factors contribute to the development of hepatic diseases, such as NAFLD [8]. Currently, NAFLD is considered the most common chronic liver disease in the Western world and it is characterized by an excessive intrahepatic fat accumulation, and strongly associated with obesity, hypertension, and insulin resistance [9]. The pathogenesis of NAFLD is not completely understood, but the most accredited hypothesis is the interaction among environmental factors (such as a hypercaloric diet), GM changes, sedentary lifestyle, and genetic predisposition [10]. Over time, NAFLD can become non-alcoholic steatohepatitis (NASH), and eventually progress into fibrosis, cirrhosis, and hepatocellular carcinoma [11]. In order to block the progression of NAFLD, thus improving the elderly’s health, the prevention of the disease is important. The use of probiotics, which are alive microorganisms with numerous health benefits, could be a valid strategy, thanks to their ability to restore the GM and relieve oxidative stress [12].

2. Changes in Gut Microbiota in Animal Models of NAFLD

Many preclinical studies have tried to associate specific alterations in GM composition, often referred to as a microbial signature, with NAFLD and NASH development. Prolonged (80 weeks) high-fat diet feeding in mice was associated with an increase in the relative abundance of the Firmicutes phylum with respect to the Bacterioidetes; at the genus level, an increase in the abundance of Adercreutzia (Actinobacteria), Coprococcus (Firmicutes), Dorea (Firmicutes), and Ruminococcus (Firmicutes) was observed in mice fed with a high-fat diet in comparison with the low-fat diet group [91][13]. In germ-free mice colonized with the microbiota from responder and non-responder mice to high-fat diet, NAFLD was positively associated with Barnesiella and Roseburia (from the Bacteroidetes and Firmicutes genera, respectively); after 16 weeks of high-fat diet administration, an increase in Barnesiella and Allobaculum and a decrease in Lactobacilli were observed. In general, the Firmicutes phylum was more represented in mice developing NAFLD [77][14]. Overall, the increase in Firmicutes/Bacteroidetes has been associated with NAFLD progression, even though there is not a complete consensus. In this last regard, in another work, Firmicutes and Verrucomicrobiota phyla were instead found to be more represented in mice not developing NAFLD and, at the genus level, Bacteroidia and Flavobacteriia were increased in mice developing NAFLD [79][15]. The administration of VSL#3, a high-concentration mixture of Bifidobacteria, Lactobacilli, and Streptococcus thermophilus improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase levels in mice fed with high-fat diet. The histological and biochemical improvement were associated with lower levels of two nuclear factors regulated by tumor necrosis factor (TNF): Jun N-terminal kinase (JNK) and nuclear factor B (NF-B), both involved in the development of insulin resistance [84][16]. In mice fed with the MCD diet for 2 and 4 weeks, the phylum of Tenericutes was more abundant compared with that of the respective control groups, while Verrucomicrobia were consistently less abundant. After 2 weeks of MCD diet, a significantly higher abundance of Firmicutes and a significantly reduced content of Proteobacteria were seen; at 4 weeks, a decrease in Actinobacteria was observed. At the family level, Rikenellaceae, Desulfovibrionaceae, and Verrucomicrobiaceae were persistently reduced in the MCD group when compared with the 4-week control group [82][17]. After 8 weeks, MCD feeding resulted in a strong overall decrease of the microbiota diversity and in a reduction in the potentially probiotic Lactobacillus, as well as Akkermansia, and an increase in the Ruminococus, which has been linked to liver fibrosis [83][18].

3. Association between Gut Microbiota and NAFLD Development in Humans

Several large human studies have investigated a microbial signature possibly predicting the risk of progression from simple steatosis toward more advanced disease stages [76][19]; however, a certain level of discrepancy was found among studies, with divergent results concerning phylum, family, genus, and species. The phyla of Firmicutes and Bacteroidetes are the most represented in the gut microbiome; consequently, many animal and human studies focused on the relative abundance of these two groups. Similarly to what had been found in animal studies [77[13][14][20],91,92], it was originally proposed that an increase in the Firmicutes-to-Bacteroidetes ratio was associated with a higher energy harvest and more severe NAFLD manifestations in obese individuals [93][21]; however, this notion was challenged by more recent findings [94,95,96][22][23][24]. Specifically, in NAFLD patients, Firmicutes were found to be increased in studies by Del Chierico (2017) and Loomba (2017) [97,98][25][26], decreased in studies by Wang [99][27] and Zhu [94][22], and unaltered in those by Raman (2013) and Alferink [96,100][24][28]. Bacteroidetes were more represented in NAFLD patients in the studies by Wang [99][27] and Zhu [94][22], decreased in the studies by Del Chierico [97][25] and Shen [95][23], and unaltered in the studies from Alferink [96][24]. It has been proposed that using higher phylogenetic levels (i.e., phylum) to distinguish disease states naturally leads to discrepancies; therefore, the studies should focus on lower levels, such as the genus [100][28]; however, discrepancies have also been found when considering the genus level, with regard to Prevotella, Oscillibacter, Bifidobacterium, Blautia, Lactobacillus, and Roseburia [72][29]. These discrepancies may originate from the fact that NAFLD is heterogeneous by nature, and the studies often include patients at different stages of disease severity, with compensated or decompensated cirrhosis [72][29]. Nonetheless, concordant changes were found in patients with NAFLD and NASH, in comparison with healthy individuals. Indeed, the phylum of Proteobacteria was increased [95,98,100][23][26][28]; at the family level, Enterobacteriaceae were increased [94[22][23],95], while Rikenellaceae [94,97][22][25] and Ruminococcaceae [95,100][23][28] were decreased; the genera Faecalibacterium [94][22], Coprococcus [94[22][27],99], and Anaerosporobacter [99][27] were also decreased, while Dorea was increased [97,100][25][28]. An increase in the genera Escherichia and Peptoniphilus was specific to NAFLD patients without NASH [94[22][25],97], as well as a decrease in Prevotella [101][30].

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