INTRODUCTION
Metabolic syndrome is one of the public health problems of our time. It affects 25% of the worldwide population, and its prevalence is constantly increasing (Saklayen, 2018). Metabolic syndrome is characterized by the concurrence of several metabolic dysfunctions including insulin resistance, obesity, hypertension, impaired glucose tolerance, hyperglycemia and dyslipidemia (Eckel, Alberti, Grundy & Zimmet, 2010). Among them, obesity is considered the central axis of metabolic syndrome (Rogero & Calder, 2018). This condition is developed as a consequence of an energy imbalance due to an excessive energy intake and low expenditure, leading to an abnormal accumulation of lipids in metabolic tissues, mainly adipose tissue and liver (Ding et al., 2010; Esser, Legrand-Poels, Piette, Scheen & Paquot, 2014). This results in the development of a low-grade systemic inflammatory state, associated with the secretion of pro-inflammatory mediators, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Thus, it promotes the recruitment of macrophages to adipose tissues and contributes to the metabolic dysfunctions and obesity-related diseases in these patients (Jang, Han, Kim, Oh, Jang & Kim, 2019; Lee, Shin & Choue, 2010). Nowadays, the management of obesity usually implies drastic changes in lifestyle, including dietary restrictions and exercise. In addition, different anti-obesity drugs are available. The most frequently used are phentermine, orlistat, lorcaserin, bupropion and liraglutide, but most of them present limited effectiveness and significant side effects (Saunders, Umashanker, Igel, Kumar & Aronne, 2018). Therefore, and considering the prevalence of obesity and its co-morbidities, there is a clear demand for more effective and safer strategies for its management.
During the two last decades, different studies have revealed that gut microbiota seems to play an important role in the development of obesity and obesity-associated disorders (Festi, Schiumerini, Eusebi, Marasco, Taddia & Colecchia, 2014). Obesity has been linked to an altered intestinal microbiota composition, also known as dysbiosis, together with increased gut permeability that promotes bacterial endotoxins translocation, including lipopolysaccharide (LPS), into the systemic circulation, which clearly contributes to the obesity-associated low-grade systemic inflammation (Cani et al., 2007; Teixeira et al., 2012). Considering this, modulation of gut microbiota can result in amelioration of the pathogenic mechanisms involved in obesity, like modulation of the inflammatory response and enhancement of the intestinal barrier function (Gil-Cardoso, Gines, Pinent, Ardevol, Blay & Terra, 2016). In this context, special attention should be paid to the use of probiotics for the prevention and treatment of obesity-associated metabolic disorders and related diseases, as it has been recently explored (Tenorio-Jimenez, Martinez-Ramirez, Gil & Gomez-Llorente, 2020).
Probiotics are defined as live microorganisms that confer a health benefit to the host when administered in adequate amounts (Backhed et al., 2004). Among probiotics,Lactobacillus spp. (L. casei strain Shirota (LAB13) ,L. gasseri , L. rhamnosus , and L. plantarum , among others) and Bifidobacterium spp. (mainly B. infantis ,B. longum , and B. breve B3 ) are the most relevant in the treatment of metabolic syndrome, demonstrating considerable anti-obesity effects, both in rodents and humans, by modulating weight gain, improving glycemic and lipid metabolism, as well as decreasing insulin resistance (Tenorio-Jimenez, Martinez-Ramirez, Gil & Gomez-Llorente, 2020). Different mechanisms may be involved in their beneficial effects, including increased short-chain fatty acid (SCFA) production, regulation of bile acid metabolism and host protection from metabolic endotoxemia, most probably through modulation of gut microbiota composition (Daniali, Nikfar & Abdollahi, 2020). However, a recent systematic review of randomized clinical trials concluded that, up to date, administration of probiotics to patients with metabolic syndrome just produces a discrete improvement, especially when considering their impact on the metabolic profile and the inflammatory biomarkers associated with this condition (Tenorio-Jimenez, Martinez-Ramirez, Gil & Gomez-Llorente, 2020). For this reason, there is a great interest in the search of new probiotic-based treatments for human metabolic syndrome that combine efficacy and safety. Among these, the emerging next generation probiotics have started to be studied against these conditions, including Prevotella copri , Christensenella minuta , Parabacteroides goldsteinii , Akkermansia muciniphila or Bacteroides thetaiotaomicron , among others (Chang et al., 2019). However, technological and regulatory limitations can hinder their development for human therapy (El Hage, Hernandez-Sanabria & Van de Wiele, 2017). Meanwhile, the characterization of other conventional probiotic strains, not previously tested for metabolic syndrome can be an interesting approach. In this context, L. fermentum CECT5716, a probiotic strain originally isolated from human breast milk (Martin et al., 2003) with proven safety and tolerance in infants and mothers (Bond, Morris & Nassar, 2017), could be of interest. L. fermentum CECT5716 has been shown to display immunomodulatory properties that can be involved in the beneficial effects obtained in experimental models of colitis (Rodriguez-Nogales et al., 2017; Rodríguez-Nogales et al., 2015) and hypertension (Robles-Vera et al., 2018; Toral et al., 2019). Furthermore, these studies highlight the ability of this probiotic to ameliorate gut microbiota dysbiosis and improve the impaired intestinal barrier function, common features of metabolic syndrome (Fasano, 2017; Festi, Schiumerini, Eusebi, Marasco, Taddia & Colecchia, 2014). Noteworthy, the anti-obesity effects ofL. fermentum CECT5716 have been previously reported in experimental obesity (Rivero-Gutierrez et al., 2017), although the probiotic was administered with fructooligosaccharides as a synbiotic, being difficult to clearly establish which effects were derived from probiotic administration. Furthermore, other strains of L. fermentum have shown beneficial effects in different experimental models of obesity. Thus, the administration of L. fermentum NCIMB5221 to Zucker diabetic fatty (ZDF) rats improved insulin resistance and lipid metabolism (Tomaro-Duchesneau et al., 2014). Similarly, L. fermentum CQPC05 inhibited high-fat diet (HFD)-induced obesity in mice, an effect associated with an improvement of lipid metabolism (Zhu, Tan, Mu, Yi, Zhou & Zhao, 2019); while L. fermentum 296 showed protective effects on cardiovascular dysfunction in HFD-treated rats (Cavalcante et al., 2019). Therefore, the aim was to evaluate the effects of the probiotic L. fermentumCECT5716 in a model of diet-induced obesity in mice, and to establish a link between the anti-obesity effect, and its impact on gut dysbiosis, inflammatory status and endothelial dysfunction.