He and Shi Cell Biosci (2017) 7:54 DOI 10.1186/s13578-017-0183-1 Cell & Bioscience

REVIEW Open Access Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics Mingqian He and Bingyin Shi*

Abstract Metabolic syndrome (MS) comprises central obesity, increased plasma glucose levels, hyperlipidemia and hyperten- sion, and its incidence is increasing due to changes in lifestyle and dietary structure in recent years. MS has been proven to be associated with an increased incidence of cardiovascular diseases and type 2 diabetes mellitus, leading to morbidity and mortality. In this manuscript, we review recent studies concerning the role of the gut microbiota in MS modulation. Manipulation of the gut microbiota through the administration of prebiotics or probiotics may assist in weight loss and reduce plasma glucose and serum lipid levels, decreasing the incidence of cardiovascular diseases and type 2 diabetes mellitus. To the best of our knowledge, short-chain fatty acids (SCFAs), bile salt hydrolase (BSH), metabolic endotoxemia and the endocannabinoid (eCB) system are essential in regulating the initiation and pro- gression of MS through the normalization of adipogenesis and the regulation of insulin secretion, fat accumulation, energy homeostasis, and plasma cholesterol levels. Therefore, the gut microbiota may serve as a potential therapeutic target for MS. However, further studies are needed to enhance our understanding of manipulating the gut microbiota and the role of the gut microbiota in MS prevention and treatment. Keywords: Metabolic syndrome, Gut microbiota, Probiotics, Prebiotics, Potential therapeutic target

Background morbidity and mortality caused by metabolic diseases are Our lifestyle and dietary structure have signifcantly signifcant. changed due to rapid economic development and To date, the human intestinal microbiota has gained improvements in quality of life, leading to the rapid increasing interest for its equivocal impact on human occurrence of MS in recent years. MS is closely related health, such as its comprehensive physiological and path- to lifestyle and central obesity, serving as a risk factor ological functions [1–4]. A plethora of microorganisms for metabolic diseases, such as type 2 diabetes and car- have colonized the gastrointestinal (GI) tract by the time diovascular disease. MS can be defned by the presence that we are born, and they play a crucial role in building of abdominal obesity and any 2 of the following factors: our future physiology and immunity, leading to homeo- increased fasting plasma glucose, increased TGs, reduced stasis of the internal environment. Te role of bacte- HDL cholesterol, and hypertension. In recent years, MS ria in shaping immunity and gut structure has emerged has spread across the globe. People with MS are twice over the last decades. Te human intestinal microbiota as likely to die and three times as likely to have a heart composition is the result of a bi-directional interaction attack or stroke than people without the syndrome. Tus, between the host and its microbial consortium. Immune preventative and therapeutic strategies to reduce the factors, such as secretory IgA and endogenous secretions, end up in the intestine and have been proven to afect the composition of the intestinal microbiota [5, 6]. In *Correspondence: [email protected] addition to these endogenous modulations, the compo- Department of Endocrinology, The First Afliated Hospital of Xi’an sition and stability of the intestinal microbiota are deter- Jiaotong University, 277 West Yanta Road, Xi’an 710061, Shaanxi, People’s Republic of China mined by nutrition or other factors, such as probiotics,

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prebiotics, antibiotics, drugs, and diseases. Current stud- Te gut microbiota was thought to possess a variety of ies suggest that manipulation of the gut microbiota could functions in human physiology and pathology. For exam- be a promising approach for the prevention and manage- ple, it aids in host nutrition and energy harvest, vitamin ment of metabolic syndrome [7]. production, and the fermentation of food components Probiotics (mainly bifdobacteria and lactobacilli) that are otherwise indigestible by the host [10–13]. It reside in the human colon, where they exert actions also contributes to intestinal epithelial homeostasis, such as modulating colon micro-fora and immunogenic the development of the immune system, drug metabo- responses and producing certain materials; altogether, lism, and protection against pathogens [14–17]. Te gut these functions improve the host’s health. Probiotics may microbiota can perform defensive functions in healthy help prevent infections, reduce cholesterol levels, pro- individuals directly by impeding colonization by patho- mote vitamin and cytokine synthesis and inhibit cancer gens that are competing for space and nutrients or indi- progression. Te safety and efcacy of a given strain in the rectly by producing antimicrobial compounds, volatile context of these properties must be scientifcally demon- fatty acids and chemically modifed bile acids. In this strated for it to be considered a probiotic. Prebiotics are way, the indigenous gut bacteria are able to modify described by Gibson and Roberfroid as non-digestible adverse conditions for the inoculation and development poli- or oligosaccharides (OS) that benefcially afect the of enteric pathogens through the barrier efect or colo- host by selectively stimulating the growth and/or activ- nization resistance. Tey also exert a signifcant role in ity of one or a limited number of benefcial bacteria in the pathogenesis of metabolic syndrome, as confrmed the colon [8]. In combination, prebiotics and probiotic by studies conducted on humans and in animal models. bacteria create synbiotics, which can provide even more An impairment of the fne balance between gut microbes benefts than probiotics or prebiotics alone. Here, we have and the host’s immune system could culminate in the reviewed recent studies concerning the role of the gut intestinal translocation of bacterial fragments and the microbiota in metabolic syndrome and the efects of pro- development of “metabolic endotoxemia” (caused by biotic bacterial strains and prebiotics on the prevention bacteria and/or bacterial fragments, such as lipopoly- or treatment of metabolic syndrome, such as their anti- saccharides, which pass through the gut barrier into obesity and anti-infammatory efects and their ability to the blood), leading to systemic infammation. Because improve glycemic control and modulate serum lipids. these molecules can stimulate macrophage infltration and activate the synthesis of infammatory cytokines, an Gut microbiome and metabolic syndrome increase in cytokine signaling can inhibit protein synthe- A wide variety of commensal microbes colonize our body sis and enhance catabolism. Current views suggest that surfaces and gut lumen. For example, there are more low-grade chronic systemic infammation contributes to than 100 trillion commensal microbes classifed into at the development of insulin resistance, diabetes, and obe- least 1000 diferent species in our gastrointestinal tract. sity. Te relative proportion of some major phyla of gut Nevertheless, our understanding of the diversity of the bacteria, such as Bacteroidetes and Firmicutes (a lower gut microbiota was largely limited and biased, and it proportion of Bacteroidetes and higher abundance Fir- showed that the gut microbiota is mainly composed of micutes), was associated with metabolic syndrome [18]. four phyla, namely, Firmicutes, Bacteroidetes, Actinobac- Ferrer et al. conducted an investigation of gut microbial teria, and Proteobacteria. Te number of microbes in the communities in fecal samples taken from an obese ado- gut microbiota is approximately ten times that of somatic lescent and a lean adolescent by analyzing the diversity of cells in our body, and these microbes participate in 16S rDNA amplicons, 22 Mbp of consensus metagenome most metabolic activities in vivo with noticeable efects. sequences and the expression profles of 613 distinct pro- Moreover, the gut microbiota contains 600,000 genes [9], teins. Tey found that in the obese gut, the phylum Firm- which is approximately 25 times more than the number icutes (94.6%) was more abundant in the total microbiota of genes in our own genome, highlighting the existence of than Bacteroidetes (3.2%), whereas the lean gut showed a highly complex microbiota ecosystem with the poten- a remarkable shift towards Bacteroidetes (18.9% of total tial for profound efects on metabolism and immune 16S rDNA), which became the most active fraction (81% function. Intestinal immune, nerve, and endocrine cells of proteins) [18]. Tese facts generally implicated the role are tightly interlinked and form a highly complex gut of the gut microbiota in the pathophysiology of meta- ecosystem, along with the gut microbiota, through host- bolic syndrome. microbial crosstalk, which contributes to homeostatic Diet-induced weight loss and bariatric surgery pro- balance in the host. Terefore, it was vital to understand moted signifcant changes in gut microbial composition the gut ecosystem by comprehensively analyzing the and thus changed treatment strategies. Manipulation host, the gut microbiota, and their interactions. of the gut microbiota through the administration of He and Shi Cell Biosci (2017) 7:54 Page 3 of 14

prebiotics or probiotics can reduce intestinal low-grade demonstrated selective stimulation of bifdobacteria infammation and improve gut barrier integrity, thus growth, and in some cases, lactobacilli lead to a signif- ameliorating metabolic balance and promoting weight cant change in gut microbiota composition. Te prebiotic loss. Terefore, a comprehensive understanding of the concept and its health efects were extensively reviewed gut microbiota manipulation and an assessment of risk by Gibson and Roberfroid in 2010 [21]. To date, the most factors in related disorders was necessary to generate studied prebiotics are the fructooligosaccharides (FOS) therapeutic approaches to cure these diseases. inulin and oligofructose [22, 23]. Nevertheless, many other OS, such as xylo-oligosaccharides (XOS), pectic History of probiotics and prebiotics oligosaccharides (POS), cyclodextrins, palatinose and OS One approach to modulating the gut microbiota was the from pullulan, are also important prebiotic candidates. ingestion or administration of probiotics. Te term “pro- Because of these health efects stemming from the biotic” originated from the Greek word meaning “for life” alteration of intestinal microbial balance, probiotics and [19]. Probiotics are defned as living microorganisms that prebiotics began to blossom in the late 1800s and early can exert benefcial health efects on the host by improv- 1900s. Tere is a long history of human consumption of ing their intestinal microbial balance after entering the probiotics (particularly lactic acid bacteria and bifdo- gut. Te defnition originally came from Elie Metchnikof bacteria) and prebiotics as natural components of food at the beginning of the 20th century. Elie Metchnikof, or as fermented foods. Tis longstanding use highlights a the father of the probiotics concept, frst referred to the growing recognition of the role of probiotics and prebiot- properties of fermented milk (containing lactic acid bac- ics in modulating the metabolic activities of the human teria) used by native, long-living Bulgarian populations gut microbiota and regulating the immune system, thus and linked it to increased well-being. In his book, ‘Te improving the host’s health. Probiotic manipulation of Prolongation of Life’, he illustrated the efects of respon- the microbiota may therefore be complementary to the sible microorganisms, and his work laid the foundation application of prebiotic supplementation. Te combina- for further studies on the positive efects of bacteria. Te tion of both pre- and probiotics, also referred to as synbi- discovery of bifdobacteria in the microbiota of human otics, constitutes another nutritional tool for modulating milk-fed infants by Henri Tissier at the Pasteur Institute the microbiota. Ishizuka et al. demonstrated a synergistic led to the recommendation to administer bifdobacteria efect of synbiotics in combination with Bifdobacterium to infants with diarrhea in the 1950s [20]. To date, the breve and rafnose on intestinal epithelial proliferation in discovery and development of new probiotics still greatly rats. relies on experiments, regardless of the fact that humans have been using probiotics for a long time. Bifdobacteria Probiotic and prebiotic consumption can and/or lactobacilli, as well as other lactic acid bacteria, ameliorate MS components such as lactococci and streptococci, can be found in most The anti‑obesity efect of today’s probiotic products. Other promising probiotic Most studies regarding the “anti-obesity” efect of probi- strains include organisms of the bacterial genera Bacillus, otics performed in rodents were achieved with members Enterococcus, Escherichia, and Propionibacterium and of the genus Lactobacillus. Lactobacillus strain admin- of the yeast genus Saccharomyces. Generally, probiotics istration led to several metabolic benefts in rodents: a are considered essentially innocuous for human ingestion reduction in adipocyte cell size and body fat in high-fat with limited reported cases of adverse events. diet fed mice [24], a reduction in fat mass, and restriction In addition to probiotics, the gut microbiota can be of excessive body weight gain [25]. Diet-induced obese modulated via the administration of prebiotics. Gibson mice and diet-induced overweight rats showed a reduc- and Roberfroid put forward the prebiotic concept in 1995 tion in body weight gain after they were fed specifc Lac- [8]. Tereafter, the employment of specifc non-digestible tobacilli [26, 27]. It was reported that the administration carbohydrates (NDO) devoted to modulation of the gut of Lactobacillus gasseri BNR17 could reduce body weight microbiota raised researchers’ attention. In 2008, the and fat mass gain in high-sucrose diet-induced obese most recent defnition of a prebiotic was formulated as rodents and fasting glycemia in db/db mice. Other studies a selectively fermented dietary ingredient that resulted showed that L. gasseri SBT2055 (LG2055) could decrease in specifc changes in the composition and activity of fat mass and adipocyte size in rodents [28–30]. For the gastrointestinal microbiota, thus conferring ben- example, Miyoshi et al. revealed that LG2055 adminis- efts on host health. Most scientifc data were obtained tration resulted in a signifcant reduction in body weight using food ingredients/supplements belonging to two and fat tissue mass (epididymal and perirenal/retroperi- chemical groups, namely, inulin-type fructans (ITF) and toneal) and inhibited the up-regulation of pro-infamma- galacto-oligosaccharides (GOS). Tese data repeatedly tory gene expression in adipose tissue, which might be a He and Shi Cell Biosci (2017) 7:54 Page 4 of 14

possible mechanism underlying the anti-obesity efect of gastrointestinal peptides could be detected. Te increase LG2055 [29]. Other in vivo studies showed that L. rham- suggested that the improvement of obesity and related nosus GG or L. sakei NR28 administration could decrease diseases by fermentable carbohydrates could be mediated body weight gain and adipose tissue weight in mice. Both through modulation of the endocrine function of the gut. strains could down-regulate lipogenic gene expression in Recently, Dewulf et al. reported that ITF supplementa- the liver [31]. Tese results suggested that in addition to tion in high-fat diet fed male C57BL/6J mice increased efects on body weight and fat mass, the administration fermentation in the cecum, which paradoxically coun- of probiotics could counteract some metabolic diseases teracted HF diet-induced GPR43 overexpression in adi- related to obesity. pose tissue; this phenomenon correlated with a benefcial In addition to studies utilizing Lactobacillus species, efect on adiposity and a potential decrease in PPARγ- several studies used specifc Bifdobacterium strains activated processes [37]. alone, such as Bifdobacterium longum, B. adolescentis Only a small number of studies focusing on human and a combination of Bifdobacterium species (B. pseu- interventions were designed to analyze the efect of pro- docatenulatum SPM1204, B. longum SPM1205, and B. biotic administration on body fat and weight [41, 42]. longum SPM1207). Tese studies showed that Bifdobac- In a multicenter, double-blind, randomized, placebo- terium spp. could decrease body weight gain and adipose controlled clinical intervention trial, 87 subjects with a tissue in high-fat diet (HFD)-induced obese rats [32–34]. higher body mass index (BMI) (24.2–30.7 kg/m2) and A recent study also demonstrated that administration of abdominal visceral fat area (81.2–178.5 cm2) were ran- the strain B. pseudocatenulatum CECT7765 could ame- domly assigned to receive either fermented milk (FM) liorate metabolic and immunologic obesity-associated containing LG2055 (active FM; n = 43) or FM without alterations by reducing liver steatosis and the number of LG2055 (control FM; n = 44); then, they were asked to larger adipocytes and fat micelles in the enterocytes of consume 200 g/day of FM for 12 weeks. In the active FM obese mice [35]. group, abdominal visceral and subcutaneous fat areas Te “anti-obesity” efects of probiotic use can interfere signifcantly (P < 0.01) decreased from baseline by an with intestinal functions. An example was the admin- average of 4.6 and 3.3%, respectively. Of these param- istration of engineered NAPE-expressing Escherichia eters, the reduction in visceral fat stood out because coli Nissle 1917 bacteria for 8 weeks. Chen et al. demon- an excess accumulation of visceral fat was primar- strated that incorporation of these modifed bacteria in ily involved in metabolic disorders, and visceral fat was the drinking water of mice fed a high-fat diet resulted in more strongly correlated with most metabolic risk factors dramatically lower food intake, adiposity, insulin resist- than subcutaneous fat. Body weight and other measures ance, and hepatosteatosis, whereas weight gain was also decreased signifcantly (P < 0.001) as follows: body inhibited in a polygenic mouse model of obesity (TallyHo weight, 1.4%; BMI, 1.5%; waist, 1.8%; and hip, 1.5%. None mice) [36]. of these parameters signifcantly decreased in the control Prebiotic supplementation of obese animals (ob/ group. Te outcome of this study indicated that the pro- ob mice, diet-induced obesity, obese Zucker or JCR:LA- biotic LG2055 lowered abdominal adiposity, body weight cp rats) also decreased body weight gain, adipocyte and other measures, suggesting its benefcial infuence on size, adiposity, and insulin resistance [37, 38]. A high-fat metabolic disorders [42]. diet-induced an accumulation of large adipocytes, pro- It was proven that prebiotics contributed to weight moted peroxisome proliferator activated receptor gamma loss and improved metabolic parameters, such as insu- (PPARγ)-activated diferentiation factors and led to a lin resistance, in overweight or obese individuals [43]. huge increase in G-protein-coupled receptor 43 expres- Moreover, satiety, reduced energy and food intake, and sion in subcutaneous adipose tissue. In HFD-fed mice, increased levels of satiety peptides also resulted from dietary supplementation with non-digestible/fermentable the consumption of prebiotics in healthy human subjects carbohydrates, such as ITF or arabinoxylans, could lessen [44]. For example, ingestion of ITF (8 g/day) for 1 year adiposity [39]. Prebiotic treatment could lower adiposity showed signifcant reductions in BMI and fat mass in by changing the gene expression pattern in white adipose non-obese young adolescents [45]. tissue of obese mice (by acting on PPARγ and GPR43), In clinical experiments, benefcial efects of prebiotic leading to increased lipolysis, decreased adipogenesis, administration were observed, such as a reduction in and an increased metabolic response to hormones such BMI, waist circumference, fat mass, and insulin resist- as leptin [37, 40]. In obese animals fed ITF (10% in the ance [21, 45, 46]. Te daily intake of yacon syrup in diet), a decrease in food intake and an increase in anorex- obese pre-menopausal women, which delivered 0.14 g igenic peptides [peptide YY (PYY) and glucagon-like pep- of fructooligosaccharides per kg per day over 120 days, tide-1 (GLP-1)] through modulation of the production of increased satiety sensation and defecation frequency and He and Shi Cell Biosci (2017) 7:54 Page 5 of 14

decreased body weight, waist circumference and body Te benefcial efects of the consumption of multispe- mass index [46]. In a subsequent clinical trial, short-chain cies probiotic supplements on insulin resistance and inulin-type fructans given as a supplement for 12 weeks metabolic profles, including high-sensitivity C-reactive (21 g/day) decreased food intake, body weight gain and protein (hs-CRP), were also reported in diabetic patients. fat mass development, and an increase of plasma PYY Asemi et al. utilized an oral supplement comprising levels and a drop in ghrelin after a meal were detected in seven viable and freeze-dried strains: L. acidophilus, L. otherwise healthy adults with a body mass index > 25 kg/ casei, L. rhamnosus, L. bulgaricus, Bifdobacterium breve, m2, providing evidence that oligofructose supplementa- B. longum, Streptococcus thermophilus, and 100 mg of tion has the potential to promote weight maintenance fructooligosaccharide. Fifty-four diabetic patients aged [43]. 35–70 years were randomly assigned to take either a As previously known, the gut microbiota regulated multispecies probiotic supplement (n = 27) or a pla- obesity-related biological systems, such as nutrient sup- cebo (n = 27) for 8 weeks. Between-group comparisons ply, fat accumulation and energy storage [47, 48]. In addi- of fasting plasma glucose (FPG) revealed that consump- tion, gut ecology could be infuenced by insulin-type tion of probiotic supplements prevented a rise in FPG fructans, which also activated immune cells. Accumu- (+ 28.8 ± 8.5 for placebo vs. + 1.6 ± 6 mg/dl for pro- lating studies have indicated that insulin-type fructans biotic group, P = 0.01). Mean changes in serum hs-CRP decreased fat accumulation and body weight in vivo, such were signifcantly diferent between the two groups as in obese individuals [49–51]. (− 777.57 for the probiotic group vs. + 878.72 ng/ ml for the placebo group, P = 0.02). Probiotic supple- The efect on improving glycemic control mentation led to a signifcant increase in plasma GSH Oral administration of probiotics and/or prebiotics could levels compared to those with the placebo (240.63 vs. decrease serum glucose levels. Specifc animal models − 33.46 µmol/l, P = 0.03). Te results of this study indi- using diet-induced obese mice or diabetic mice have been cated that multispecies probiotic supplementation for commonly applied to evaluate the efects of probiotics on 8 weeks in diabetic patients prevented a rise in FPG and the characteristics of type 2 diabetes mellitus (T2DM) to resulted in a decrease in serum hs-CRP and an increase report the benefcial efects of various strains of Lactoba- in plasma total glutathione, r-glutamyl cysteinyl + gly- cilli [52]. In high-fructose fed rats, the anti-diabetic efect cine (GSH) compared with placebo [56]. of probiotics was measured by feeding them probiotics Probiotic yogurt supplementation controlled glycemic containing Lactobacillus acidophilus and Lactobacil- level (reduced fasting blood glucose and glycated hemo- lus casei [53]. Recently, Naito et al. described both the globin) in type 2 diabetic patients. After consuming pro- anti-diabetic and anti-infammatory efects of L. casei in biotic yogurt (L. acidophilus La5 and Bifdobacterium diet-induced obese mice. Yadav et al. also demonstrated lactis Bb12) for 6 weeks at the dose of 300 g/day, T2D that administration of dahi (yogurt on the Indian subcon- patients experienced a decrease in fasting blood glucose tinent) containing probiotic L. acidophilus and L. casei and HbA1. Additionally, probiotics could promote anti- in male diabetic rats (induced by feeding 21% fructose in oxidation in T2DM patients. An increase in erythrocyte water) for 8 weeks signifcantly delayed the onset of glu- superoxide dismutase, glutathione peroxidase activities, cose intolerance, hyperglycemia, hyperinsulinemia, and and total antioxidants could be detected in the group dyslipidemia and decreased oxidative stress [53]. supplemented with probiotic yogurt [57]. Akkermansia muciniphila was of interest among the Sasaki et al. showed that type 2 diabetic patients bacteria that could potentially be used for the ameliora- treated with transglucosidase (which generates prebiotic tion of type 2 diabetes. Te direct benefcial efects of fbers, including oligosaccharides, from dietary starch in this bacterium on glucose metabolism were identifed the human GI tract) experienced reduced levels of hyper- in a diet-induced type 2 diabetes mouse model using A. glycemia and body weight gain. Tese efects were medi- muciniphila MucT (ATTC BAA-835) [54]. First, A. ated by increased gut production of oligosaccharides and muciniphila decreased glucose-6-phosphatase (G6pc) alteration of the gut microbiota composition (increased mRNA expression to counteract fasting hyperglycemia Bacteroidetes-to-Firmicutes ratio) [58]. in the mouse model [54]. Tis implied that A. mucin- iphila decreased gluconeogenesis in a diabetic mouse The efect on modulating serum lipids model. Furthermore, administration of live A. muciniph- Ann and Spoerry observed the hypocholesterolemic ila could also alleviate glucose intolerance [54, 55]. How- activity of fermented milk in a Maasai tribe located ever, additional studies were needed to clarify whether A. in Kenya. Animal and human models have since been muciniphila could be used as a probiotic for type 2 diabe- used to evaluate the efects of probiotic microorganisms tes patients or not. on serum lipid levels, and probiotic benefts have been He and Shi Cell Biosci (2017) 7:54 Page 6 of 14

emphasized over the last 40 years. Accumulating studies 6 weeks, blood cholesterol rates were signifcantly low- have shown that well-established probiotics, prebiotics ered, whereas other blood lipid indices did not show any and synbiotics possess hypocholesterolemic efects and signifcant diferences compared with those of the group other efects that modulate serum lipids in humans and that consumed traditional yogurt [66]. Similarly, Jones animals. et al. demonstrated that the consumption of a yogurt con- It was reported that probiotic administration could taining microencapsulated bile salt hydrolase-active Lac- modulate lipid metabolism in animal models, such as tobacillus reuteri NCIMB 30242, which was taken twice in diet-induced obese mice, hypocholesterolemic mice, per day during a 6-week period, was efective at reduc- and hypercholesterolemic rats. Kumar et al. suggested ing LDL-cholesterol, total cholesterol and non-HDL cho- that the indigenous Lactobacillus plantarum Lp91 lesterol in hypercholesterolemia adults; this treatment strain had the potential to be explored as a probiotic in appeared to be superior to traditional probiotic therapy the management of hypercholesterolemia by reporting [67]. Anderson et al. utilized a probiotic called L. acido- the hypocholesterolemic efect of L. plantarum in rats philus L1 and showed that daily consumption of 200 g fed a hypocholesterolemic diet [59]. In addition, Moha- of fermented milk (FM) containing L. acidophilus L1 for nia et al. observed that the supplementation of probi- 3 weeks was accompanied by a 2.4% (P < 0.05) reduction otic dahi prepared by L. plantarum Lp9 might have the of serum cholesterol concentration compared to that of therapeutic potential to decrease plasma, hepatic, and the placebo group [68]. Fukushima et al. indicated that aortic lipid profles and attenuate diet-induced hyper- a mixture of organisms (a probiotic mixture) comprised cholesterolemia in rats fed a hypercholesterolemic basal of Bacillus, Lactobacillus, Streptococcus, Clostridium, diet [60]. Nguyen et al. demonstrated that total serum Saccharomyces, and Candida efectively reduced total cholesterol and triglycerides were signifcantly reduced cholesterol and liver cholesterol compared to individual (by 7 and 10%, respectively) in hypocholesterolemic bacteria strains. Te supplied mixed-bacteria and L. aci- mice that ingested L. plantarum PH04 for 14 days [61]. dophilus groups exhibited a 23–57% decrease in choles- Te administration of probiotic strain Lactobacillus cur- terol concentrations in the liver. Additionally, the serum vatus HY7601(CU), combined or not combined with L. total cholesterol in the supplied mixed-bacteria group plantarum KY1032(PL), reduced plasma cholesterol was reduced by 15–33% compared with that in the sin- levels and hepatic lipid content (TGs and cholesterol) in gle-bacteria supplemented groups [69]. mice fed a high-fat high-cholesterol diet (HFCD) [62]. Consumption of prebiotics was shown to improve lipid Another focus of the research community was the role metabolism in healthy volunteers. Brighenti et al. showed of prebiotics in the prevention of cardiovascular disease that inulin seemed to have a lipid lowering potential in (CVD) in animal models. Studies by Rault-Nania et al. normolipidemic men. When normolipidemic individu- on apo E-defcient mice demonstrated that the addi- als consumed cereal containing 18% inulin on a daily tion of long-chain inulin in the diet of mice inhibited the basis without any other dietary restrictions, total plasma formation of atherosclerotic plaques; this efect is prob- cholesterol and triacylglycerols decreased by 7.9 ± 5.4% ably related to changes in lipid metabolism. Both long- (P < 0.05) and 21.2 ± 7.8% (P < 0.005), respectively chain inulin and an oligofructose-enriched inulin [70]. Recently, Russo et al. concluded that an intake of signifcantly lowered hepatic cholesterol concentrations 11% inulin-enriched pasta in healthy young male volun- compared with the control diet (P < 0.05) [63]. Te addi- teers for 5 weeks improved HDL cholesterol and the total tion of inulin in the diet of rats induced higher excretions cholesterol/HDL-cholesterol ratio [71]. of fecal lipids and cholesterol compared to the excre- A signifcant reduction in serum total- and LDL-choles- tions of rats in the control group. Tis increased level of terol levels was also seen with intake of a synbiotic con- excretion was attributed primarily to reduced cholesterol taining L. gasseri and inulin among hypercholesterolemic [64]. Te administration of a synbiotic food containing L. patients after 12 weeks. Schaafsma et al. found that con- acidophilus ATCC 4962, fructooligosaccharide, inulin sumption of milk (fermented by yogurt starters and L. and mannitol in hypercholesterolemic pigs for 8 weeks acidophilus and containing 2.5% fructooligosaccharides) resulted in reductions in serum triglycerides and total- by adult male volunteers for 3 weeks signifcantly low- and low density lipoprotein (LDL)-cholesterol levels as ered values of serum total cholesterol (P < 0.001), LDL- well as an increased HDL-cholesterol concentration [65]. cholesterol (P < 0.005), and the LDL/HDL-ratio (P < 0.05) Ataie-Jafari et al. evaluated a group of people with mild by 4.4, 5.4 and 5.3%, respectively [72]. to moderate hypercholesterolemia and reported that Some researchers have investigated the efects of after consumption of probiotic yogurt (fermented with a prebiotics on cholesterol levels, but the results have not starter composed of L. acidophilus and Bifdobacterium been consistent. Balcázar-Muñoz et al. reported that lactis in addition to the bacteria in ordinary yogurt) for the oral consumption of inulin (7 g/day) for 4 weeks by He and Shi Cell Biosci (2017) 7:54 Page 7 of 14

dyslipidemic obese subjects led to a signifcant reduction Bacteroidetes) [40, 81]. Laminarin or fucoidan sup- of total cholesterol (248.7 ± 30.5 and 194.3 ± 39.8 mg/ plementation reduced Enterobacteriaceae population dl; P = 0.028), LDL, cholesterol (136.0 ± 27.8 and and abundance, which were clarifed as attaching and 113.0 ± 36.2 mg/dl; P = 0.028), very low density lipo- efacing E. coli strains. Further studies confrmed that proteins (VLDL) (45.9 ± 18.5 and 31.6 ± 7.2 mg/dl; prebiotic supplementation could improve gut barrier P = 0.046) and triglyceride concentrations (235.5 ± 85.9 functions in pigs. Tese prebiotics also markedly down- and 171.1 ± 37.9 mg/dl; P = 0.046) [73]. Other prebiotics, regulated the colonic mRNA expression of pro-infam- such as oligodextrans, lactose, resistant starches and their matory cytokines [82]. Increased expression levels of derivatives, lactoferrin-derived peptides, and N-acetyl circulating GLP-1 and GLP-2 were observed in mouse chitooligosaccharides have also been identifed as hav- models developed by diet control [44]. Prebiotic intake ing the ability to maintain hypocholesterolemic efects might also regulate enteroendocrine L-cell diferentia- in people with T2DM who are at high risk of developing tion and the GLP-1 response [83, 84]. Increased GLP-2 CVD [74]. On the other hand, Giacco et al. reported that production following a prebiotic diet was associated with daily intake of 10.6 g of short-chain-fructooligosaccha- an increased number of benefcial gut bacteria, improved rides (sc-FOS) for 2 months by mild hypocholesterolemic integrity of the intestinal barrier, and lowered metabolic individuals had no major efects on lipid metabolism infammation and endotoxemia. However, these efects compared with placebo groups (maltodextrin plus aspar- have not been unraveled in humans [44, 83, 85–89]. Sev- tame, 15 g/day) [75]. However, Kellow et al. emphasized eral studies have suggested that the gut microbiota can that the results of these studies were limited because mediate the low-grade infammation classically associ- they evaluated relatively short-term prebiotic interven- ated with metabolic disorders related to obesity by exert- tion periods and that large-scale trials of longer duration ing an interesting “anti-infammatory” efect [84, 90, 91]. would be required to draw stronger conclusions [76]. Increased pro-infammatory cytokine production was associated with aging [92], and the low-grade infam- The anti‑infammatory efect mation that is usually found in older people infuenced Gut permeability can be modifed by an unbalanced the incidence of several age-associated diseases [22, 93]. intestinal microbiota, and bacteria and/or bacterial Probiotics can modulate the immune system through fragments, such as lipopolysaccharides (LPS), passing phagocytosis, TH1 responses and pro-infammatory through the gut into the blood can lead to metabolic cytokine production utilizing interleukin-10 (IL-10) [94]. endotoxemia [77, 78]. LPS then binds to the cytokine Decreased IL-6 production can be detected in peripheral receptors located in hepatocytes and adipocytes, thereby blood mononuclear cell (PBMC) in older people. In addi- inducing pro-infammatory cytokine release and insulin tion, a related prebiotic galacto-oligosaccharide mixture resistance. Tese molecules induce macrophage infltra- was shown to decrease Tumor Necrosis Factor-α (TNF- tion and result in the synthesis of infammatory cytokines α), IL-1β and IL-6 and increase the production of IL-10 [77, 79], and induced cytokine signaling can then inhibit and natural killer cells [95]. An increase in serum CRP, protein synthesis in order to enhance catabolism [79, 80]. which has been shown to correlate with circulating IL-6, Probiotics and prebiotics can enhance intestinal barrier can be evidence of systemic infammation [96]. Several functions, thus promoting the proliferation rate of ben- studies confrmed that the production of IL-6 was down- efcial or commensal gut microbes and impeding the regulated and that the number of apoptotic T cells was progression of several gram-negative pathogens. In addi- increased in the lamina propria by the interaction of tion, probiotics and prebiotics can reduce LPS leakage probiotics with infamed intestinal tissues. A number and decrease pro-infammatory cytokine production in of probiotic strains passing through the gastrointestinal adipose tissues. In total, we have acknowledged the need tract can also induce anti-infammatory cytokine pro- for future studies to evaluate whether this probiotic/syn- duction. Te study advocated that this probiotic strain or biotic treatment can lead to a reduced pro-infammatory its symbiotic combination can be benefcial by prevent- state. ing lifestyle-associated, infammation-associated, or gut Moreover, gut microbiota composition can be medi- microbiome-associated metabolic disorders through the ated through probiotic supplementation by restoring glu- amelioration of infammatory status and gut microbial cose transporter-4 (GLUT4), PPAR-γ and lipogenic genes populations. and pro-infammatory marker (IL-6, TNF-α) expression in high-fructose fed rats. In mouse models, prebiotic Mechanisms of action supplementation can reduce low-grade infammation Currently, there is existing evidence from animal and caused by altered gut microbiota composition (decreased human studies demonstrating the interaction between number of Firmicutes and increased abundance of the modulation of the gut microbiota and various He and Shi Cell Biosci (2017) 7:54 Page 8 of 14

components of metabolic syndrome. Given that diferent stimulated the release of intestinal hormone secre- strains and product formulations exist, the correspond- tion, such as 5-hydroxytryptamine (5-HT), GLP-1 and ing mechanisms are quite complex. In any event, the ef- PYY secretion. 5-HT is an important neurotransmit- ciency and mechanisms of probiotic efects are crucially ter involved in regulating gastrointestinal motility and determined by the link between probiotics and either the secretory functions, which regulate intestinal permeabil- microbiota of the host or the immunocompetent cells of ity, promote intestinal peristalsis, and reduce the body’s the intestinal mucosa [97]. To date, several assumptions absorption of food energy. GLP-1 had numerous physi- about the mechanistic actions of probiotics and prebiot- ological efects, including stimulation of glucose-depend- ics that ameliorate MS, including modifcations of gut ent insulin secretion, augmentation of β-cell mass, and microbial composition, involvements with energy home- inhibition of glucagon release, gastric emptying, and food ostasis, the stimulation of insulin signaling, modulations intake. Many investigations demonstrated that prebiotics of infammatory signaling pathways, interference with increased GLP-1 release and improved metabolic infam- the immune system, and the down-regulation of choles- mation and insulin resistance [87, 99, 100]. GLP-2 was terol levels, have been presented. Among the molecular co-secreted with GLP-1 and could enhance intestinal epi- mechanisms, this review focuses on short-chain fatty thelial proliferation and reduce gut permeability [101]. In acids (SCFAs), bile-salt hydrolase (BSH), metabolic endo- addition to the roles of GLP-2 in maintaining gut barrier toxemia and the endocannabinoid (eCB) system, which integrity, slowing gastric emptying and intestinal motility, are associated with the normalization of adipogenesis improving nutrient absorption, and enhancing immune and the regulation of insulin secretion, fat accumulation, function, GLP-2 in central neurons enhanced hepatic energy homeostasis, and plasma cholesterol levels, thus insulin sensitivity and played a key role in the control of resulting in anti-obesity and anti-infammatory efects, glucose homeostasis [102]. PYY had several biological improving glycemic control and modulating serum lipids, actions, including vasoconstriction, inhibition of gastric as previously stated. acid secretion, reduction of pancreatic and intestinal secretion, regulation of appetite and inhibition of gastric SCFAs motility [103, 104]. It was reported that when probiotics settle in the gut, Additional studies indicated that SCFAs were involved they ferment indigestible carbohydrates from food. in the regulation of hepatic cholesterol synthesis [105, Teir action raises the level of SCFAs in the gut, princi- 106] and that the ingestion of SCFA-producing probi- pally acetate, propionate, and butyrate. Host recovery of otics could increase SCFA infux into the liver, leading SCFAs is generally efcient and occurs by both passive to the down-regulation of angiopoietin-like protein 4 difusion and mono-carboxylic acid transporters. (ANGPTL4). ANGPTL4 inhibited circulating lipopro- In the liver, butyrate can be metabolized into glutamate, tein lipase (LPL), which promoted lipid clearance [105, glutamine and acetoacetate. Acetoacetate is a signifcant 107]. ANGPTL4 is also a downstream target gene of per- fuel resource for intestinal cells, and more than 70% of oxisome proliferator activated receptors (PPARs), the the oxygen consumption in isolated colonocytes was due agonists of which are widely utilized for the treatment to butyrate oxidation. As an intestinal nutrient, butyrate of T2DM and CVD [108, 109]. PPAR-α mainly plays an promotes the regeneration of intestinal cells to repair the important role in hepatic fatty acid oxidation, whereas intestinal mucosa, initiates the diferentiation and apop- PPAR-γ is the master regulator of adipogenesis [109]. tosis of normal intestinal cells, stimulates the synthesis of intestinal mucin glycoprotein, and strengthens the pro- BSH tective efect of the mucous layer. Acetate was reported It was reported that an oral administration of probiot- to increase total cholesterol, and propionate increased ics signifcantly reduced cholesterol levels by as much as glucose in the blood and reduced the hypercholester- 22–33% and controlled elevated cholesterol levels in mice olemia response caused by acetate. Tese efects were the fed a fat-enriched diet. Enzymatic deconjugation of bile consequence of propionate decreasing its involvement in acids by BSH was proposed as an important molecular cholesterol and fatty acid synthesis in the liver. mechanism in cholesterol-lowering efects. Recently, two orphan G Protein-Coupled Receptors Bile salts can accelerate the decomposition of fat by (GPCRs), GPR41 (known as free fatty acid receptor3, increasing the acceptance area of lipase. In addition, bile FFAR3) and GPR43 (known as FFAR2), were found to salt molecules are concentrated in 3- to 6-micron diame- be receptors for SCFAs, including acetate, propionate, ter particles, called micro-particles (micelles), when they and butyrate. FFAR2 was primarily activated by acetate reach a certain concentration in the lumen. Decomposed and propionate, whereas FFAR3 was more often acti- lipid products, including fatty acids and cholesterol, are vated by propionate and butyrate [98]. FFAR2 and FFAR3 wrapped in internal micelles and form a soluble complex He and Shi Cell Biosci (2017) 7:54 Page 9 of 14

called mixed micelles. Terefore, bile salt acts a delivery bacteria are involved in the onset and progression of the vehicle, carrying insoluble decomposed lipid products to infammation related to MS by modulating plasma LPS the surface of the intestinal mucosa, and these products levels. For instance, Cani et al. defned gut microbiota- are benefcial to the assimilation of digestive fat products derived LPS as a triggering factor in the early progress in the intestine. of infammation and metabolic diseases, which was sub- Deconjugated bile salts are less efciently reabsorbed sequently investigated in genetically and nutritionally than conjugated bile salts, resulting in the excretion of obese mice by specifcally modulating the composition of larger amounts of free bile acids in feces. In addition, the gut microbiota. Altogether, they indicated that spe- free bile salts are less efcient in the solubilization and cifc microbe-associated molecular patterns (MAMPs), absorption of lipids in the intestine. Terefore, decon- such as LPS, play a critical role in the onset the diseases jugation of bile salts could lead to a reduction in serum related to MS [40, 49, 83–85, 100, 112]. cholesterol either by increasing the demand for choles- Te host symbiotic bacteria afect the immune sys- terol during de novo synthesis of bile acids to replace tem through the interaction between their pathogen- those lost in feces or by reducing cholesterol solubility associated microbial patterns (PAMPs) (including LPS, (and thereby cholesterol absorption through the intesti- lipoteichoic acids (LTK) of cell walls of bacteria, fagellin nal lumen). and single- or double-stranded RNA and DNA) and spe- It was reported that BSH activity could hydrolyze con- cifc toll-like receptors (TLRs) of epithelial and dendritic jugated glycodeoxycholic acid and taurodeoxycholic acid, cells (DCs) of the digestive tract [94, 113, 114]. TLRs are leading to the deconjugation of glyco- and taurobile acids. a member of the integral membrane pattern-recognition Jones et al. evaluated the cholesterol-lowering efect of receptor family, which plays a major role in innate immu- BSH utilizing L. plantarum 80 and L. reuteri, whereupon nity by integrating signals from microbiota-host inter- it was shown that the enzyme responsible for bile salt actions; these interactions are vital to maintaining this deconjugation in the enterohepatic circulation could be balance [115]. In summary, the innate immune system detected in probiotics indigenous to the gastrointestinal detects LPS via its interaction with the CD14/TLR4 com- tract [110, 111]. Micelles, which play a role in the absorp- plex at the surface of innate immune cells. tion of cholesterol in the intestine, are produced by bile A series of studies indicated that modulation of the salts, cholesterol, and phospholipids. By producing bile gut microbiota (e.g., by probiotics) reduced metabolic acids through the deconjugation of bile salts in the small endotoxemia and the cecal content of LPS; improved intestine, probiotics prevent micelle production. When low-grade infammation, steatosis, glucose intolerance bile acid enters the enterohepatic circulation, probiotics and insulin sensitivity; decreased body weight gain; and hydrolyze the bile acid and bile salts through hydroxys- prevented the development of MS both in obese animal teroid dehydrogenases, which are conjugated bile acid models and in clinical studies [85, 116–118]. Moreover, hydrolase enzymes. In doing so, the enterohepatic circu- prebiotic-induced changes in the gut microbiota could lation of bile acids is disrupted. also abolish obesity-related metabolic features. Dietary intervention with oligofructoses could regulate the Metabolic endotoxemia composition of the gut microbiota in a complex way in Lipopolysaccharides is a constituent of gram-negative response to a high-fat diet or genetic obesity. bacterial cell walls and is the most potent inducer of Some recent studies underlined key mammalian host– infammation. Recently, Cani and Delzenne demon- gut microbial relationships, inferring that the gut micro- strated that excess dietary fat promoted an increase in biota played a vital role in metabolic pathways [119]. plasma LPS concentrations, which they called “metabolic Cani et al. suggested that plasma LPS levels interacted endotoxemia” because LPS plasma levels were much negatively with Bifdobacterium spp. among the ana- lower than those observed during septic shock [84]. lyzed gut bacteria. In other words, Bifdobacterium spp. Later, the relationship between metabolic endotoxemia supplementation was shown to improve mucosal bar- and a high-fat diet was confrmed in a series of studies. rier function and decrease intestinal endotoxin levels Considering that LPS can afect infammatory progress [120–122]. Furthermore, mice fed prebiotic dietary fber throughout the body and can interfere with both metabo- (FOS) had normal endotoxemia. Te precise mecha- lism and the function of the immune system, it has been nism by which FOS reduces metabolic endotoxemia increasingly recognized that metabolic pathways and the and systemic infammatory levels remains elusive. How- innate immune system are functionally intertwined. In ever, Bifdobacterium spp. is recognized as the main gut summary, these fndings underline the role of fat intake microbiota linked to the positive efects of FOS supple- and absorption in the growth of metabolic endotox- mentation. In fact, Bifdobacterium spp. supplementa- emia. Several independent experiments showed that gut tion has been linked to lowering bacterial translocation He and Shi Cell Biosci (2017) 7:54 Page 10 of 14

and endotoxemia, leading to decreased infammatory adipose tissue plasticity during obesity and may deter- cascade activation [120–122]. Tus, specifc strategies for mine adipose tissue physiology through LPS-eCB sys- modifying the gut microbiota by probiotics and prebiot- tem regulatory loops [89]. Recently, Cani et al. found that ics could be potential targets for reducing the impact of specifc modulation of the gut microbiota with prebiot- high-fat feeding on the occurrence of metabolic diseases. ics promotes normalization of eCB system responsive- ness in both the gut and in adipose tissue. Tese efects eCB system are deeply related to decreases in gut permeability, meta- Another potential mechanism involved in the modula- bolic endotoxemia and fat mass development. Terefore, tion of the gut microbiota on the development of MS prebiotic-induced changes in the gut microbiota reduce and other related disorders is the endocannabinoid both adipose tissue and intestinal eCB system respon- system (eCB), which is a summation of several bioac- siveness, consequently normalizing adipogenesis and tive lipids, enzymes and distinct types of receptors improving the gut barrier. [123]. Two kinds of lipids are the most studied, includ- Modulation of the intestinal microbiota with specifc ing N-arachidonoylethanolamide (anandamide; AEA) probiotics has been shown to upregulate CB2 receptor and 2-arachidonoylglycerol (2-AG) [124]. Subsequently, expression in rodents. Bermudez-Silva et al. [129] indi- there are two primary enzymes, monoacylglycerol lipase cated that CB2 receptor activation ameliorates glucose (MAGL) and fatty acid amide hydrolase (FAAH), that tolerance in rats. CB2 receptor expression is positively regulate the metabolism of AEA and 2-AG, respectively, regulated with intestinal counts of Lactobacillus supple- from cell membrane phospholipids after cell stimulation ment and negatively regulated with counts of Clostridium [83]. After their release, eCBs interact with Gi-coupled supplement. Later, Rousseaux et al. [130] demonstrated receptors, cannabinoid receptor 1 (CB1) and Go-coupled that administration of L. acidophilus increases CB2 receptors CB2, which are also targeted by the principal receptor expression in mouse colon. However, it should active component of Cannabis sativa, ∆9-tetrahydro- be noted that even if potent interrelation exists between cannabinol [125]. the composition of the gut microbiota and elements con- Several studies have shown that eCB system impacts trolling the eCB system, the direct involvement of spe- the regulation of energy homeostasis and the control of cifc gut microbes and/or of microbial metabolites needs lipid and glucose metabolism at several levels [126, 127]. further elucidation. Obesity is characterized by greater eCB system respon- siveness. In other words, hyperactivity of eCB is associ- Summary ated with altered expression of CB1 mRNA, decreased Te gut microbiota is now considered to be involved in levels of enzymes, and increased plasma eCB, adipose the regulation of multitudinous physiological pathways tissue eCB levels, and CB1 activity. Tis hyperrespon- and to impact diferent host functions [131]. Given the siveness brings about unbalanced energy intake, which is developing knowledge of how probiotics and prebiot- conducive to excessive intra-abdominal fat accumulation ics interact with the gut microbiota, there has been and is related to the development of MS [128]. a growing interest in exploring the efect of probiot- Te gut microbiota can determine gut permeability ics and prebiotics on specifc constituents of MS. Four and adipose tissue physiology through LPS-eCB system main mechanisms have been proposed in this review to regulatory loops. In other words, the massive expansion explain the action of probiotics. Te frst mechanism is of adipose tissues upon obesity is characterized by low- raising bacteria-derived SCFAs, which activates GPR-43 grade infammation, which is possibly controlled by the on L cells and triggers the secretion of GLP-1 and GLP- gut microbiota (via LPS), and LPS can stimulate eCB 2. Tese hormones exhibit an enormous variety of meta- synthesis. Te eCB system is hyper-activated in the intes- bolic and proliferative actions. Te second mechanism tine, which leads to increases in gut permeability, plasma is increasing BSH activity. Bacterial BSH enzymes in the LPS levels and systemic infammation. Te interaction gut infuence host physiological processes, resulting in between the eCB system and the gut microbiota modu- decreases in body weight gain and plasma cholesterol lates adipogenesis directly by acting upon adipose tissue levels. Te third mechanism is leveraging the anti-infam- and indirectly by increasing plasma LPS levels. matory function of probiotics, which improves low-grade Regulating the gut microbiota with prebiotics in ob/ infammation, steatosis, glucose intolerance and insulin ob mice decreases CB1 mRNA expression in adipose tis- sensitivity. Te fourth mechanism is down-regulation sue, reduces LPS levels in plasma and increases adipo- of eCB system responsiveness, which impacts the regu- cyte lipogenesis and diferentiation; these efects indicate lation of energy homeostasis and the normalization of that the gut microbiota may have critical functions in adipogenesis. He and Shi Cell Biosci (2017) 7:54 Page 11 of 14

Conclusion Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- Accumulating evidence suggests that gut microbiota lished maps and institutional afliations. plays a signifcant role in the initiation and progression of MS. Te gut microbiota was proven to modulate plasma Received: 16 June 2017 Accepted: 4 September 2017 glucose, appetite, serum lipids and pro-infammation. In addition, prebiotics or probiotics, which are widely used to manipulate the microbiota, can reduce low-grade intestinal infammation and improve gut barrier integrity References to reduce plasma glucose and serum lipid levels, induce 1. Rauch M, Lynch SV. The potential for probiotic manipulation of the gastrointestinal microbiome. Curr Opin Biotechnol. 2012;23(2):192–201. weight loss and decrease insulin resistance. Based on 2. Orlando A, Russo F. Intestinal microbiota, probiotics and human gastro- these current achievements, the gut microbiota may be intestinal cancers. 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