Microbiota and Non-Alcoholic Steatohepatitis: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Ana Isabel Álvarez-Mercado.

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Non-alcoholic fatty liver disease (NAFLD), which is characterized by an increase in fat accumulation in the form of micro and macro vacuoles of lipids into hepatocytes (named steatosis), is the most common liver disorder worldwide. Steatosis is classified as mild (5–33%), moderate (34–66%), or severe (more than 66%) depending on the fat number in vacuoles within the cytoplasm of hepatocytes. Additionally, other histopathological features should be taken into account in the presence of steatosis including inflammation, fibrosis, and ballooning degeneration.

  • non-alcoholic steatohepatitis
  • intestinal permeability
  • microbiota

1. Microbiota and Non-Alcoholic Steatohepatitis

The microbiome involves all of the genetic information inside the microbiota defined as “the full collection of microbes, i.e., bacteria, fungi, virus, etc., that naturally exists within a particular biological niche such as an organism, soil or a body of water, among others” [28,37][1][2]. Indeed, the word “microbiome” is also referred to as the metagenome of the microbiota [38][3]. The mutual communication between the microbiota and the liver is performed through the portal vein, which transports gut-derived products to the liver, and the feedback of bile and antibodies from the liver to the intestine [28,37][1][2].

The mucus barrier composition is determined by the microbiota as indicated through studies on germ-free mice that when colonized with the microbiota acquire similar mucus from donors [39][4]. This probably is due to the capability of goblet cells to sense the presence of bacterial products and to produce Muc2 after triggering the NLRP (Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin-domain containing proteins)-6-inflammasome pathway [40][5]. Besides, studies performed in animals have shown alterations in TLR signaling related to the leaky gut syndrome by the action of bacterial lipopolysaccharide (LPS). In humans, modifications in the profile of the gut microbiota associated with alterations in intestinal permeability have also been related to liver disease [28][1]. In consequence, metabolites produced by the microbiota, the immune system, and the liver show a strategic function in the pathogenesis of alcoholic liver disease and NAFLD/NASH [37][2]. Gut barrier impairment (which induces intestinal permeability) is the dynamic variable that enables portal influx of pathogen-associated molecular patterns (PAMPs), e.g., LPS, and microbiome-derived metabolites to the liver, activating a pro-inflammatory cascade that exacerbates hepatic inflammation [41][6].

Metagenomic analyses reveal that NASH and cirrhosis are related to changes in the gut microbiota composition [42,43][7][8]. In particular, it has been shown that Eubacterium rectale and Bacteroides vulgates enhancement is associated with NAFLD, probably through damaging metabolic intermediaries in the altered microbiome of the host [44][9].

Patients with NASH showed augmented intestinal permeability and decreased intestinal bacterial overgrowth that are correlated with the severity of steatosis [45][10]. Likewise, mice deficient in junctional adhesion molecule A (Jam-A), an essential constituent of tight junctions that regulate the paracellular route of solutes avoiding molecules such as LPS cross the epithelium [46][11], are also more susceptible to NASH development [47][12]. Some authors have reported that just below the epithelium there is another cellular barrier-dominated gut vascular barrier that senses the entry to the liver and portal circulation [48,49][13][14]. Enteric pathogens such as Salmonella typhimurium have proven tactics to evade this gut vascular barrier via delaying the WNT/b-catenin signaling pathway [50][15]. In this regard, preventing the gut vascular barrier disruption with obeticholic acid treatment might prevent the development of NASH [50][15]. In addition, a recent study in a heterodimeric integrin receptor has shown that by blocking this integrin receptor known as α4β7, the recruitment of CD4+ T cells to the intestine and liver not only reduces hepatic inflammation and fibrosis but also protects the metabolic imbalances related to NASH [51][16].

Under healthy conditions, the gut microbiota composition is mostly stable, showing dissimilarities mainly at the species level. However, studies in humans revealed that the microbiota differs in patients with NASH. Accordingly, Enterobacteria and Proteobacteria present increased abundance relative, whereas anti-inflammatory bacterial strains such as Faecalibacterium prausnitzii are diminished [52][17]. In addition, important variables are related to the gut microbiota in the characterization of NASH, such as the serum bile acid profile and the hepatic gene expression pattern that support an increased bile acid production in NASH patients [53][18].

A better understanding of the patient microbiota interactions and the response to different actions/managements will be essential for the enhancement of NASH therapies and the elaboration of novel approaches targeting the alterations in microbiota associated with NASH.

2. Research Studies on Gut Microbiota and Non-Alcoholic Steatohepatitis

The global burden of NASH is high, affecting one in four adults and presenting a substantial geographic variation in prevalence [54][19]. Liver-detailed mortality of NASH patients was estimated to be 15.44/1000 person-years. Moreover, the impact of NASH as a cause of liver-related mortality may increase several-fold as the age at onset of disease decreases not just to childhood but to the in-utero state [55][20]. Indeed, this may potentially increase the duration and progression of liver disease. Another important factor is genetic susceptibility which means and unquestionable causal issue, e.g., despite the much lower daily caloric intake in Central and South America than in North America and western Europe, the prevalence of NASH is higher in these regions probably due to the association of this population with an increased prevalence of the rs738409 G allele of the PNPLA3 gene [56][21].

2.1. Animal Studies

Animal studies have mostly been performed in rodents, revealing a potential causal role of gut microbiota in NAFLD. Several studies performed in animal models evaluating the implication of several genes in microbiota alteration and NASH pathogenesis have been recently reported. For instance, hepatic MyD88 regulates the production of bioactive lipid compounds that are implicated in glucose, inflammation, and lipid metabolism. The deletion of MyD88 in mice fed with a normal diet provoked changes in the gene expression, plasma, and liver metabolome. Moreover, gut microbes similar to those reported have been observed in diet-induced obesity and diabetic subjects [57][22].

On the other hand, it is well known that Sirtuin 3 (SIRT3) shows a defensive function against NAFLD by refining hepatic mitochondrial dysfunction [58,59][23][24]. SIRT3 knockout mice fed with a chow diet or high-fat diet were used to evaluate the relationship between gut microbiota and SIRT3 in NAFLD development. Results from this study showed that SIRT3 deletion accelerated gut microbial dysbiosis after a high-fat diet with augmented levels of Desulfovibrio and Oscillibacter and reduced Alloprevotella abundance. In addition, these mice had augmented LPS levels and dysfunction of cannabinoid receptor 1 and 2 expressions in both the colon and the liver, which were significantly linked to the variations observed in gut microbiota [58][23].

The disruption of the gene F11r encoding Jam-A has showed deficiencies in intestinal epithelial permeability in mice fed with a normal diet or a diet high in saturated fat, fructose, and cholesterol. Mice with F11r gene knockout developed NASH features and increased levels of inflammatory microbial taxa related to Firmicutes and Proteobacteria compared with wild type mice [47][12].

To note, contemporary studies have proposed a key function for the inflammasome/caspase-1 in NASH development. Knockout mice (caspases 1/11 and Nlrp3) were evaluated with a standard fat diet or a high-fat diet. Caspases 1/11 knockout mice were predisposed to hepatic steatosis irrespective of the type of diet received. The lack of caspases 1/11 was also linked to higher hepatic triacylglycerol levels. Additionally, increased levels of Proteobacteria and a higher Firmicutes/Bacteroidetes ratio were found in the gut of caspases 1/11 knockout mice nourished with a high-fat diet [60][25]. To evaluate the implication of Nlrp3 in the development of NAFLD, Nlrp3 knockout mice were fed with a Western-lifestyle diet with fructose in drinking water or a chow diet. Knock-out Nlrp3 mice showed increased peroxisome proliferator-activated receptor-γ2 expression and triglyceride contents, greater adipose tissue inflammation and histological liver damage, as well as dysbiotic microbiota with bacterial translocation, related to an increase in TLR4 and TLR9 hepatic expression. After antibiotic treatment, the abundance of Gram-negative species and translocation of bacteria were reduced, and adverse effects were repaired both in the liver and adipose tissue [61][26]. Higher TLR4, TLR9, MyD88, Casp1, and NLPR3 expression levels were also found in animals that received a high-fat and choline-deficient diet. Concerning the composition of gut microbiota, the number of operational taxonomic units and the Bray-Curtis dissimilarity index were significantly different compared with the control group [62][27].

A recent study [63][28] reported that bile acids modulated through microbial modulation were critical to normalize obesity-induced metabolic disorders in hamsters. In addition, these authors found that the elimination of the gut microbiota increased hepatic bile acid synthesis and inhibited the microbial dihydroxylation and deconjugation in the gut [63][28]. Mice fed with either a low-fat diet with casein or a high fat-diet with casein, fish, or mutton protein were analyzed. The different types of protein in the high-fat diet significantly impacted the gut microbiota composition, with changes in Prevotellaceae UCG-003, Ruminococcaceae UCG-005, Desulfovibrio, the Lachnospiraceae NK4A136 group, Lactobacillus, and Akkermansia, intestinal inflammatory gene expression, serum endotoxin level, and changes in nine metabolites associated with hepatic MetS [64][29]. The hepatocyte-specific loss of the bacterial wall sensor nucleotide-binding oligomerization domain-containing (NOD) 2 transformed the gut microbiota composition, augmenting Clostridiales and diminishing Erysipelotrichaceae, among other taxa, verifying that NOD2 protects diet-induced NAFLD in mice [65][30]. Rats fed a high-fat and choline-deficient diet (a well-established nutritional model of NASH) showed a significantly higher delta Lee index, abdominal adipose tissue, and abdominal circumference, as well as other biochemical parameters compared to control standard diet animals. In this line, the methionine–choline-deficient diet induced steatohepatitis and a decrease in the gut microbiota diversity although these changes in gut microbiota differ from those observed in human subjects with NASH [66][31]. Using a different nutritional model, a high-fat high-cholesterol diet stimulated fatty liver, steatohepatitis, fibrosis, and NAFLD–HCC development, while a high-fat low-cholesterol diet induced only hepatic steatosis in mice. Microbiota composition was also altered in this model, showing an increase in Mucispirillum, Desulfovibrio, Anaerotruncus, and Desulfovibrionaceae and low levels of Bifidobacterium and Bacteroides in the high-fat high-cholesterol diet-fed group. In addition, dietary cholesterol induced changes in gut bacterial metabolites with augmented levels of taurocholic acid and decreased 3-indole propionic acid [67][32].

The recognized translational model for NAFLD/NASH, i.e., Leiden mice [68[33][34],69], was used by Gart et al. to test several energy-dense diets. Animals were fed with chow, butterfat–fructose, lard fat–sucrose, or a diet with lard fat–sucrose and fructose water. General variations in microbiota were detected in all groups as well as modifications in plasma short-chain fatty acids (SCFAs) [70][35].

On the other hand, proton pump inhibitors have been shown to stimulate the progression of alcoholic liver disease, NAFLD, and NASH in mice by growing Enterococcus spp. and Enterococcus faecalis [71][36].

Germ-free mice received microbiota from four donors subjected to different diets, i.e., (1) control diet, (2) high-fat diet-responders, (3) high-fat diet non-responders, and (4) a quercetin-supplemented high-fat diet to investigate changes in NAFLD development. The high-fat diet non-responders and quercetin-supplemented high-fat diet groups had higher levels of Desulfovibrio and Oscillospira, diminished levels of Bacteroides and Oribacterium, higher stimulation of hepatic bile acid transporters, and suppression of hepatic lipogenic and bile acid synthesis genes. The authors suggested a hepatoprotective effect in the high-fat diet non-responders and of the quercetin-supplemented high-fat diet [72][37].

Initial infant gut colonization through microbes plays an important role in immunity and metabolic function [73][38]. Germ-free mice were colonized with stool microbes from 2-week-old human infants born to obese or normal-weight mothers. The stool from infants had higher hepatic gene expression for endoplasmic reticulum stress and innate immunity together with periportal inflammation histological signs, similar to pediatric cases of NAFLD. These results postulate useful data supporting the role of maternal obesity-associated infant dysbiosis in children with obesity and NAFLD [73][38].

Bearing in mind all the aforementioned, studies in animals seem to be a good tool to explore the implication of microbiota in NAFLD/NASH even when many limitations to extrapolating information to humans have to be considered. Overall, animal models are very helpful to shed light on the effect of alterations in the gut microbiota in hepatic disease, especially when NAFLD patients present different severities, heterogeneous lesions, and variable demographic characteristics (e.g., age, sex, or ethnicity). Additionally, the complexity of human behavior, diet, physical activity, environment, psychological stress, or genetics affects the gut microbiota, which may lead to discrepancies and controversial results.

Although animal models of NAFLD/NASH do not always show all the histological alterations compared with humans (e.g., hepatocyte ballooning) and the microbiota are not strictly the same between species, the effect of an unbalanced microbiota on hepatic disease or the possibly of providing proof of concept may be more reasonable through appraisal of experimental models. Moreover, animal studies have advantages such as reduced biological variation or easy housing and monitoring or control of the diet/environment—all factors with a great impact on the microbiota profile.

2.2. Human Studies (Adults and Children)

It has been described that the relationship between Bacteroides and a Western-type diet has a pro-inflammatory effect related to the pathogenesis of NASH [44][9]. In addition, it is known that patients with NAFLD show a different bacterial community with lower biodiversity compared with healthy individuals [74][39]. Non-virulent endotoxin-producing strains of pathogenic species overgrowing in the gut of patients with obesity can act as contributory agents for the initiation of NAFLD. The most important molecular mechanism is mediated through the TLR4 receptor; this receptor can modulate the different steps in NAFLD evolution and related metabolic disorders [75][40]. Concerning the NASHmicrobiota association, Bacteroides abundance was significantly increased in NASH patients, whereas Prevotella was reduced. Ruminococcus was higher in patients with fibrosis, and the Bacteroides relative abundance was independently related to NASH. Alterations in metabolic pathways were associated with carbohydrate, lipid, and amino acid metabolism [76][41].

Metagenomic analyses of diagnosed patients with NAFLD, NASH, and obesity compared with control individuals revealed an increase in Actinobacteria and reduced Bacteroidetes in NAFLD patients. In NASH patients, low Oscillospira levels were related to high Dorea and Ruminococcus and high 2-butanone and 4-methyl-2-pentanone levels [42][7]. In the same line, another study reported decreased Bacteroidetes and Ruminococcaceae as well as increased Lactobacillaceae and Veillonellaceae and Dorea abundances in NAFLD patients [77][42]. In addition, in patients with advanced fibrosis, serum and fecal bile acid quantities increased, with serum glycocholic acid fecal deoxycholic acid levels associated with Bacteroidaceae and Lachnospiraceae [78][43]. In concordance with these results, Ruminococcaceae and Veillonellaceae were the central microbiota related to fibrosis severity in non-obese subjects, and bile acids and propionate were elevated in non-obese patients with significant fibrosis [79][44]. In the same line, a prospective cross-sectional study was conducted to characterize the differences between non-obese adults with and without NAFLD in fecal microbiota. It revealed that NAFLD patients presented additional Bacteroidetes and fewer Firmicutes that produced SCFAs, and 7α-dehydroxylating bacteria decreased. By contrast Gram-negative bacteria were predominant in NAFLD patients [80][45].

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