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.