Quercetin and Akkermansia muciniphila: facing NAFLD & obesity: Comparison
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Obesity is a disease characterized by an excessive body fat accumulation and by the presence of a subclinical chronic inflammation. It is related to many comorbidities, such as non-alcoholic fatty liver disease (NAFLD), the predominant cause of chronic liver disease in many parts of the world. NAFLD is a disease spectrum which starts with simple steatosis (the accumulation of fat in the liver) and could progress to steatohepatitis, cirrhosis or even hepatocarcinoma, mainly due to sedentary lifestyle. 

Gut microbiota is a metabolic organ involved in physiological homeostasis and is defined as all the microorganisms that habit along the digestive tract. The alteration of its composition and functionality, called dysbiosis, has been associated with many pathologies, such as obesity and non-alcoholic fatty liver disease (NAFLD) development. Gut microbiota emerges as a therapeutic target, in which probiotics or prebiotics play a central role. Probiotics are live microorganisms that have beneficial effects on health status when are consumed in proper doses, whereas prebiotics are non-digestible ingredients which promote the growth of beneficial microorganisms in the gut. A synbiotic is a combination of prebiotics and probiotics that confers a healthy benefit on the host. 

  • Akkermansia muciniphila
  • childhood obesity
  • gut microbiota
  • quercetin
  • synbiotic

1. Introduction

Nowadays, obesity is a worldwide epidemic with a 13% of prevalence in adults and with a rising trend in children and adolescents [1]. In its multifactorial pathogenesis, the sedentary patterns and the unhealthy habits have an important role. Moreover, obesity is associated with many comorbidities, such as non-alcoholic fatty liver disease (NAFLD) [2], one of the commonest manifestations of chronic hepatic disease with a worldwide prevalence of 20–30% [3]. The pathogenesis of NAFLD, according to the multiple-hit hypothesis [4], is explained by the concurrent action of many factors. In the last few years, gut microbiota has been identified as a key factor in NAFLD and obesity development [5][6][7]. Gut microbiota is a metabolic organ with an essential role in human homeostasis, which carries out many indispensable functions such as fermentation of carbohydrates and its transformation in short-chain fatty acids (SCFAs) and transformation of primary bile acids (BAs) into secondary metabolites [8].

Currently, the main strategy to manage NAFLD and obesity is to change lifestyle towards healthy patterns [3]. However, obesity-related NAFLD patients usually have a low adherence to these interventions, being necessary to search for new strategies in the treatment of these pathologies [9][10]. Due to the role of gut microbiota alterations in the development of NAFLD and obesity, the administration of probiotics or prebiotics are reasonable therapies in the treatment of these diseases. Additionally, the combination of both, namely synbiotics, may potentiate the efficacy of the intervention [11][12]. The flavonoid quercetin, with antioxidant and anti-inflammatory properties, has been reported to counteract NAFLD in in vivo models through a possible and additional prebiotic effect [7][13]. Moreover, the bacteria Akkermansia muciniphila has been pointed out as a potential probiotic due to its protective effect in obesity development [14][15][16].

Therefore, the aim of this study is to evaluate the combinatory effect of a nutritional intervention together with quercetin supplementation and A. muciniphila administration on early obesity and NAFLD development in an in vivo model.

2. Methods

To carry out this study, as it is shown in Figure 1, 21-day-old Wistar rats were fed with control or high fat diet (HFD) for 6 weeks. After that, blood and faecal samples were collected and all animals were fed with control diet supplemented with quercetin, A. muciniphila or the combination of both for 3 weeks. Finally, animals were sacrificed and samples were collected. Histopathological and biochemical parameters as well as gut microbiota composition were analyzed. Moreover, plasma BAs quantification was carried out.

Figure 1. Experimental design.Figure 1. Experimental design.

 

3. Results and Discussion

After 6 weeks of HFD feeding, juvenile rats manifested higher body weight and food intake in comparison with the control group. Besides, biochemical analysis showed important alterations in plasma such elevated alanine aminotransferase (ALT), cholesterol and incremented insulin concentration and HOMA‐IR index, which is closely linked to hepatic insulin resistance in NAFLD [17].

Moreover, 6-week HFD fed rats presented lower concentration of total bacteria DNA and a modified gut microbiota profile not only at phylum level, but also at class and genus level, highlighting higher abundance of Lactobacillus and Blautia in contrast with control group. In this sense, high levels of Lactobacillus has been identified in obesity and NAFLD [5][18][19], whereas Blautia increasement has been related with NAFLD in pediatric patients [20].

After 3 weeks of dietary intervention and administration of A. muciniphila and quercetin, the synbiotic reduced the concentration of fasting blood glucose, plasma insulin concentration and HOMA-IR index observed at 6 weeks of HFD intake, remarking their beneficial effects to counteract insulin resistance as previously described [7][15]. Also, reduced white adipose tissue and higher leptin concentration in plasma were observed after synbiotic administration. In absence of insulin resistance or metabolic disorders, high leptin concentration could promote energy expenditure and control food intake to compensate the metabolic disorders caused by HFD diet [21].

Regarding white adipose tissue status, relative expression of Ppary and Plin2 were reduced after the synbiotic, which has been associated to a protective role against insulin resistance and obesity and NAFLD development [22][23]. Additionally, the relative expression of Cebpa, Dgat2 and Srebp2 involved in the novo lipogenesis were upregulated by HFD-diet and this increment was counteracted by the synbiotic administration [17][24]. Moreover, Pparα upregulation, which modulates lipid metabolism and has a role in fatty acid beta-oxidation and regulation of their circulation [25][26], may result in a decrease of triglyceride synthesis and NAFLD progression. Regarding inflammation status, a protective role of the synbiotic administration was observed in the reduced relative expression of proinflammatory cytokines (Tlr2, Il6 and Il1β), confirming the effect of quercetin or A. muciniphila supplementation previously reported [7][15].

Beneficial effects of the synbiotic were also reflected in the gut microbiota composition. At phylum level, the relative abundance of Cyanobacteria was increased after synbiotic administration whereas Actinobacteria, a common marker of obesity [27], was decreased.   At genus level, Blautia (highly detected in NAFLD adult and pediatric patients [20][28]) and Coprobacillus (previously associated with HFD [29]) were reduced in all quercetin-supplemented experimental groups. Besides, after synbiotic administration, Lactobacillus and Lactococcus, which correlate positively with fasting plasma insulin [28][30], reduced their relative abundance. On the contrary, Oscillospira, which negatively correlates with hepatic fat deposition and less expression in NAFLD and obese patients [31][32], was increased in both control and HFD groups. All of these results support the capacity of the synbiotic on gut microbiota reshaping and its beneficial effect counteracting obesity and NAFLD.

Also, changes in gut microbiota composition caused by the synbiotic promote beneficial modifications in bile acid (BA) composition, synthesis and transport in the liver. The intervention along with A. muciniphila and quercetin increased the total plasma BA pool mainly primary and unconjugated hydrophilic BAs, establishing a healthier hydrophilic BA profile [33]. Moreover, the increased gene expression of BA synthesis genes such as Cyp7a1 and Cyp8b1 and BA transport genes like Nctp, Bsep, Mdr2 and Mrp2 suggested an enhancement on BAs synthesis and bile flux linked to the synbiotic administration.

All these results were subjected to a correlation analysis, showing a whole network in which the synbiotic seems to induce changes in gut microbiota, that in turn are related to the improvement observed in our in vivo model.

In conclusion, the modulation of the BA profile, the upregulation of its synthesis and transport flux, as well as a modulation in hepatic inflammatory status and lipogenesis process in white adipose tissue could denote innovative mechanisms behind the beneficial effects of A. muciniphila in metabolic disease and support its use in combination with quercetin as a possible treatment of NAFLD and obesity development (Figure 2).

Figure 2. Graphical abstract.Figure 2. Graphical abstract.

This entry is adapted from: https://doi.org/10.3390/antiox10122001

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