The anti-obesity effect

Most studies regarding the “anti-obesity” effect of probiotics performed in rodents were achieved with members of the genus Lactobacillus. Lactobacillus strain administration led to several metabolic benefits in rodents: a reduction in adipocyte cell size and body fat in high-fat diet fed mice [24], a reduction in fat mass, and restriction of excessive body weight gain [25]. Diet-induced obese mice and diet-induced overweight rats showed a reduction in body weight gain after they were fed specific Lactobacilli [26, 27]. It was reported that the administration of Lactobacillus gasseri BNR17 could reduce body weight and fat mass gain in high-sucrose diet-induced obese rodents and fasting glycemia in db/db mice. Other studies showed that L. gasseri SBT2055 (LG2055) could decrease fat mass and adipocyte size in rodents [28,29,30]. For example, Miyoshi et al. revealed that LG2055 administration resulted in a significant reduction in body weight and fat tissue mass (epididymal and perirenal/retroperitoneal) and inhibited the up-regulation of pro-inflammatory gene expression in adipose tissue, which might be a possible mechanism underlying the anti-obesity effect of LG2055 [29]. Other in vivo studies showed that L. rhamnosus GG or L. sakei NR28 administration could decrease body weight gain and adipose tissue weight in mice. Both strains could down-regulate lipogenic gene expression in the liver [31]. These results suggested that in addition to effects on body weight and fat mass, the administration of probiotics could counteract some metabolic diseases related to obesity.

In addition to studies utilizing Lactobacillus species, several studies used specific Bifidobacterium strains alone, such as Bifidobacterium longum, B. adolescentis and a combination of Bifidobacterium species (B. pseudocatenulatum SPM1204, B. longum SPM1205, and B. longum SPM1207). These studies showed that Bifidobacterium spp. could decrease body weight gain and adipose tissue in high-fat diet (HFD)-induced obese rats [32,33,34]. A recent study also demonstrated that administration of the strain B. pseudocatenulatum CECT7765 could ameliorate metabolic and immunologic obesity-associated alterations by reducing liver steatosis and the number of larger adipocytes and fat micelles in the enterocytes of obese mice [35].

The “anti-obesity” effects of probiotic use can interfere with intestinal functions. An example was the administration of engineered NAPE-expressing Escherichia coli Nissle 1917 bacteria for 8 weeks. Chen et al. demonstrated that incorporation of these modified bacteria in the drinking water of mice fed a high-fat diet resulted in dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis, whereas weight gain was inhibited in a polygenic mouse model of obesity (TallyHo mice) [36].

Prebiotic supplementation of obese animals (ob/ob mice, diet-induced obesity, obese Zucker or JCR:LA-cp rats) also decreased body weight gain, adipocyte size, adiposity, and insulin resistance [37, 38]. A high-fat diet-induced an accumulation of large adipocytes, promoted peroxisome proliferator activated receptor gamma (PPARγ)-activated differentiation factors and led to a huge increase in G-protein-coupled receptor 43 expression in subcutaneous adipose tissue. In HFD-fed mice, dietary supplementation with non-digestible/fermentable carbohydrates, such as ITF or arabinoxylans, could lessen adiposity [39]. Prebiotic treatment could lower adiposity by changing the gene expression pattern in white adipose tissue of obese mice (by acting on PPARγ and GPR43), leading to increased lipolysis, decreased adipogenesis, and an increased metabolic response to hormones such as leptin [37, 40]. In obese animals fed ITF (10% in the diet), a decrease in food intake and an increase in anorexigenic peptides [peptide YY (PYY) and glucagon-like peptide-1 (GLP-1)] through modulation of the production of gastrointestinal peptides could be detected. The increase suggested that the improvement of obesity and related diseases by fermentable carbohydrates could be mediated through modulation of the endocrine function of the gut. Recently, Dewulf et al. reported that ITF supplementation in high-fat diet fed male C57BL/6J mice increased fermentation in the cecum, which paradoxically counteracted HF diet-induced GPR43 overexpression in adipose tissue; this phenomenon correlated with a beneficial effect on adiposity and a potential decrease in PPARγ-activated processes [37].

Only a small number of studies focusing on human interventions were designed to analyze the effect of probiotic administration on body fat and weight [41, 42]. In a multicenter, double-blind, randomized, placebo-controlled clinical intervention trial, 87 subjects with a higher body mass index (BMI) (24.2–30.7 kg/m2) and abdominal visceral fat area (81.2–178.5 cm2) were randomly assigned to receive either fermented milk (FM) containing LG2055 (active FM; n = 43) or FM without LG2055 (control FM; n = 44); then, they were asked to consume 200 g/day of FM for 12 weeks. In the active FM group, abdominal visceral and subcutaneous fat areas significantly (P < 0.01) decreased from baseline by an average of 4.6 and 3.3%, respectively. Of these parameters, the reduction in visceral fat stood out because an excess accumulation of visceral fat was primarily involved in metabolic disorders, and visceral fat was more strongly correlated with most metabolic risk factors than subcutaneous fat. Body weight and other measures also decreased significantly (P < 0.001) as follows: body weight, 1.4%; BMI, 1.5%; waist, 1.8%; and hip, 1.5%. None of these parameters significantly decreased in the control group. The outcome of this study indicated that the probiotic LG2055 lowered abdominal adiposity, body weight and other measures, suggesting its beneficial influence on metabolic disorders [42].

It was proven that prebiotics contributed to weight loss and improved metabolic parameters, such as insulin resistance, in overweight or obese individuals [43]. Moreover, satiety, reduced energy and food intake, and increased levels of satiety peptides also resulted from the consumption of prebiotics in healthy human subjects [44]. For example, ingestion of ITF (8 g/day) for 1 year showed significant reductions in BMI and fat mass in non-obese young adolescents [45].

In clinical experiments, beneficial effects of prebiotic administration were observed, such as a reduction in BMI, waist circumference, fat mass, and insulin resistance [21, 45, 46]. The daily intake of yacon syrup in obese pre-menopausal women, which delivered 0.14 g of fructooligosaccharides per kg per day over 120 days, increased satiety sensation and defecation frequency and decreased body weight, waist circumference and body mass index [46]. In a subsequent clinical trial, short-chain inulin-type fructans given as a supplement for 12 weeks (21 g/day) decreased food intake, body weight gain and fat mass development, and an increase of plasma PYY levels and a drop in ghrelin after a meal were detected in otherwise healthy adults with a body mass index > 25 kg/m2, providing evidence that oligofructose supplementation has the potential to promote weight maintenance [43].

As previously known, the gut microbiota regulated obesity-related biological systems, such as nutrient supply, fat accumulation and energy storage [47, 48]. In addition, gut ecology could be influenced by insulin-type fructans, which also activated immune cells. Accumulating studies have indicated that insulin-type fructans decreased fat accumulation and body weight in vivo, such as in obese individuals [49,50,51].

The effect on improving glycemic control

Oral administration of probiotics and/or prebiotics could decrease serum glucose levels. Specific animal models using diet-induced obese mice or diabetic mice have been commonly applied to evaluate the effects of probiotics on the characteristics of type 2 diabetes mellitus (T2DM) to report the beneficial effects of various strains of Lactobacilli [52]. In high-fructose fed rats, the anti-diabetic effect of probiotics was measured by feeding them probiotics containing Lactobacillus acidophilus and Lactobacillus casei [53]. Recently, Naito et al. described both the anti-diabetic and anti-inflammatory effects of L. casei in diet-induced obese mice. Yadav et al. also demonstrated that administration of dahi (yogurt on the Indian subcontinent) containing probiotic L. acidophilus and L. casei in male diabetic rats (induced by feeding 21% fructose in water) for 8 weeks significantly delayed the onset of glucose intolerance, hyperglycemia, hyperinsulinemia, and dyslipidemia and decreased oxidative stress [53].

Akkermansia muciniphila was of interest among the bacteria that could potentially be used for the amelioration of type 2 diabetes. The direct beneficial effects of this bacterium on glucose metabolism were identified in a diet-induced type 2 diabetes mouse model using A. muciniphila MucT (ATTC BAA-835) [54]. First, A. muciniphila decreased glucose-6-phosphatase (G6pc) mRNA expression to counteract fasting hyperglycemia in the mouse model [54]. This implied that A. muciniphila decreased gluconeogenesis in a diabetic mouse model. Furthermore, administration of live A. muciniphila could also alleviate glucose intolerance [54, 55]. However, additional studies were needed to clarify whether A. muciniphila could be used as a probiotic for type 2 diabetes patients or not.

The beneficial effects of the consumption of multispecies probiotic supplements on insulin resistance and metabolic profiles, including high-sensitivity C-reactive protein (hs-CRP), were also reported in diabetic patients. Asemi et al. utilized an oral supplement comprising seven viable and freeze-dried strains: L. acidophilus, L. casei, L. rhamnosus, L. bulgaricus, Bifidobacterium breve, B. longum, Streptococcus thermophilus, and 100 mg of fructooligosaccharide. Fifty-four diabetic patients aged 35–70 years were randomly assigned to take either a multispecies probiotic supplement (n = 27) or a placebo (n = 27) for 8 weeks. Between-group comparisons of fasting plasma glucose (FPG) revealed that consumption of probiotic supplements prevented a rise in FPG (+ 28.8 ± 8.5 for placebo vs. + 1.6 ± 6 mg/dl for probiotic group, P = 0.01). Mean changes in serum hs-CRP were significantly different between the two groups (− 777.57 for the probiotic group vs. + 878.72 ng/ml for the placebo group, P = 0.02). Probiotic supplementation led to a significant increase in plasma GSH levels compared to those with the placebo (240.63 vs. − 33.46 µmol/l, P = 0.03). The results of this study indicated that multispecies probiotic supplementation for 8 weeks in diabetic patients prevented a rise in FPG and resulted in a decrease in serum hs-CRP and an increase in plasma total glutathione, r-glutamyl cysteinyl + glycine (GSH) compared with placebo [56].

Probiotic yogurt supplementation controlled glycemic level (reduced fasting blood glucose and glycated hemoglobin) in type 2 diabetic patients. After consuming probiotic yogurt (L. acidophilus La5 and Bifidobacterium lactis Bb12) for 6 weeks at the dose of 300 g/day, T2D patients experienced a decrease in fasting blood glucose and HbA1. Additionally, probiotics could promote antioxidation in T2DM patients. An increase in erythrocyte superoxide dismutase, glutathione peroxidase activities, and total antioxidants could be detected in the group supplemented with probiotic yogurt [57].

Sasaki et al. showed that type 2 diabetic patients treated with transglucosidase (which generates prebiotic fibers, including oligosaccharides, from dietary starch in the human GI tract) experienced reduced levels of hyperglycemia and body weight gain. These effects were mediated by increased gut production of oligosaccharides and alteration of the gut microbiota composition (increased Bacteroidetes-to-Firmicutes ratio) [58].

The effect on modulating serum lipids

Ann and Spoerry observed the hypocholesterolemic activity of fermented milk in a Maasai tribe located in Kenya. Animal and human models have since been used to evaluate the effects of probiotic microorganisms on serum lipid levels, and probiotic benefits have been emphasized over the last 40 years. Accumulating studies have shown that well-established probiotics, prebiotics and synbiotics possess hypocholesterolemic effects and other effects that modulate serum lipids in humans and animals.

It was reported that probiotic administration could modulate lipid metabolism in animal models, such as in diet-induced obese mice, hypocholesterolemic mice, and hypercholesterolemic rats. Kumar et al. suggested that the indigenous Lactobacillus plantarum Lp91 strain had the potential to be explored as a probiotic in the management of hypercholesterolemia by reporting the hypocholesterolemic effect of L. plantarum in rats fed a hypocholesterolemic diet [59]. In addition, Mohania et al. observed that the supplementation of probiotic dahi prepared by L. plantarum Lp9 might have the therapeutic potential to decrease plasma, hepatic, and aortic lipid profiles and attenuate diet-induced hypercholesterolemia in rats fed a hypercholesterolemic basal diet [60]. Nguyen et al. demonstrated that total serum cholesterol and triglycerides were significantly reduced (by 7 and 10%, respectively) in hypocholesterolemic mice that ingested L. plantarum PH04 for 14 days [61]. The administration of probiotic strain Lactobacillus curvatus HY7601(CU), combined or not combined with L. plantarum KY1032(PL), reduced plasma cholesterol levels and hepatic lipid content (TGs and cholesterol) in mice fed a high-fat high-cholesterol diet (HFCD) [62].

Another focus of the research community was the role of prebiotics in the prevention of cardiovascular disease (CVD) in animal models. Studies by Rault-Nania et al. on apo E-deficient mice demonstrated that the addition of long-chain inulin in the diet of mice inhibited the formation of atherosclerotic plaques; this effect is probably related to changes in lipid metabolism. Both long-chain inulin and an oligofructose-enriched inulin significantly lowered hepatic cholesterol concentrations compared with the control diet (P < 0.05) [63]. The addition of inulin in the diet of rats induced higher excretions of fecal lipids and cholesterol compared to the excretions of rats in the control group. This increased level of excretion was attributed primarily to reduced cholesterol [64]. The administration of a synbiotic food containing L. acidophilus ATCC 4962, fructooligosaccharide, inulin and mannitol in hypercholesterolemic pigs for 8 weeks resulted in reductions in serum triglycerides and total- and low density lipoprotein (LDL)-cholesterol levels as well as an increased HDL-cholesterol concentration [65].

Ataie-Jafari et al. evaluated a group of people with mild to moderate hypercholesterolemia and reported that after consumption of probiotic yogurt (fermented with a starter composed of L. acidophilus and Bifidobacterium lactis in addition to the bacteria in ordinary yogurt) for 6 weeks, blood cholesterol rates were significantly lowered, whereas other blood lipid indices did not show any significant differences compared with those of the group that consumed traditional yogurt [66]. Similarly, Jones et al. demonstrated that the consumption of a yogurt containing microencapsulated bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242, which was taken twice per day during a 6-week period, was effective at reducing LDL-cholesterol, total cholesterol and non-HDL cholesterol in hypercholesterolemia adults; this treatment appeared to be superior to traditional probiotic therapy [67]. Anderson et al. utilized a probiotic called L. acidophilus L1 and showed that daily consumption of 200 g of fermented milk (FM) containing L. acidophilus L1 for 3 weeks was accompanied by a 2.4% (P < 0.05) reduction of serum cholesterol concentration compared to that of the placebo group [68]. Fukushima et al. indicated that a mixture of organisms (a probiotic mixture) comprised of Bacillus, Lactobacillus, Streptococcus, Clostridium, Saccharomyces, and Candida effectively reduced total cholesterol and liver cholesterol compared to individual bacteria strains. The supplied mixed-bacteria and L. acidophilus groups exhibited a 23–57% decrease in cholesterol concentrations in the liver. Additionally, the serum total cholesterol in the supplied mixed-bacteria group was reduced by 15–33% compared with that in the single-bacteria supplemented groups [69].

Consumption of prebiotics was shown to improve lipid metabolism in healthy volunteers. Brighenti et al. showed that inulin seemed to have a lipid lowering potential in normolipidemic men. When normolipidemic individuals consumed cereal containing 18% inulin on a daily basis without any other dietary restrictions, total plasma cholesterol and triacylglycerols decreased by 7.9 ± 5.4% (P < 0.05) and 21.2 ± 7.8% (P < 0.005), respectively [70]. Recently, Russo et al. concluded that an intake of 11% inulin-enriched pasta in healthy young male volunteers for 5 weeks improved HDL cholesterol and the total cholesterol/HDL-cholesterol ratio [71].

A significant reduction in serum total- and LDL-cholesterol levels was also seen with intake of a synbiotic containing L. gasseri and inulin among hypercholesterolemic patients after 12 weeks. Schaafsma et al. found that consumption of milk (fermented by yogurt starters and L. acidophilus and containing 2.5% fructooligosaccharides) by adult male volunteers for 3 weeks significantly lowered values of serum total cholesterol (P < 0.001), LDL-cholesterol (P < 0.005), and the LDL/HDL-ratio (P < 0.05) by 4.4, 5.4 and 5.3%, respectively [72].

Some researchers have investigated the effects of prebiotics on cholesterol levels, but the results have not been consistent. Balcázar-Muñoz et al. reported that the oral consumption of inulin (7 g/day) for 4 weeks by dyslipidemic obese subjects led to a significant reduction of total cholesterol (248.7 ± 30.5 and 194.3 ± 39.8 mg/dl; P = 0.028), LDL, cholesterol (136.0 ± 27.8 and 113.0 ± 36.2 mg/dl; P = 0.028), very low density lipoproteins (VLDL) (45.9 ± 18.5 and 31.6 ± 7.2 mg/dl; P = 0.046) and triglyceride concentrations (235.5 ± 85.9 and 171.1 ± 37.9 mg/dl; P = 0.046) [73]. Other prebiotics, such as oligodextrans, lactose, resistant starches and their derivatives, lactoferrin-derived peptides, and N-acetyl chitooligosaccharides have also been identified as having the ability to maintain hypocholesterolemic effects in people with T2DM who are at high risk of developing CVD [74]. On the other hand, Giacco et al. reported that daily intake of 10.6 g of short-chain-fructooligosaccharides (sc-FOS) for 2 months by mild hypocholesterolemic individuals had no major effects on lipid metabolism compared with placebo groups (maltodextrin plus aspartame, 15 g/day) [75]. However, Kellow et al. emphasized that the results of these studies were limited because they evaluated relatively short-term prebiotic intervention periods and that large-scale trials of longer duration would be required to draw stronger conclusions [76].

The anti-inflammatory effect

Gut permeability can be modified by an unbalanced intestinal microbiota, and bacteria and/or bacterial fragments, such as lipopolysaccharides (LPS), passing through the gut into the blood can lead to metabolic endotoxemia [77, 78]. LPS then binds to the cytokine receptors located in hepatocytes and adipocytes, thereby inducing pro-inflammatory cytokine release and insulin resistance. These molecules induce macrophage infiltration and result in the synthesis of inflammatory cytokines [77, 79], and induced cytokine signaling can then inhibit protein synthesis in order to enhance catabolism [79, 80]. Probiotics and prebiotics can enhance intestinal barrier functions, thus promoting the proliferation rate of beneficial or commensal gut microbes and impeding the progression of several gram-negative pathogens. In addition, probiotics and prebiotics can reduce LPS leakage and decrease pro-inflammatory cytokine production in adipose tissues. In total, we have acknowledged the need for future studies to evaluate whether this probiotic/synbiotic treatment can lead to a reduced pro-inflammatory state.

Moreover, gut microbiota composition can be mediated through probiotic supplementation by restoring glucose transporter-4 (GLUT4), PPAR-γ and lipogenic genes and pro-inflammatory marker (IL-6, TNF-α) expression in high-fructose fed rats. In mouse models, prebiotic supplementation can reduce low-grade inflammation caused by altered gut microbiota composition (decreased number of Firmicutes and increased abundance of Bacteroidetes) [40, 81]. Laminarin or fucoidan supplementation reduced Enterobacteriaceae population and abundance, which were clarified as attaching and effacing E. coli strains. Further studies confirmed that prebiotic supplementation could improve gut barrier functions in pigs. These prebiotics also markedly down-regulated the colonic mRNA expression of pro-inflammatory cytokines [82]. Increased expression levels of circulating GLP-1 and GLP-2 were observed in mouse models developed by diet control [44]. Prebiotic intake might also regulate enteroendocrine L-cell differentiation and the GLP-1 response [83, 84]. Increased GLP-2 production following a prebiotic diet was associated with an increased number of beneficial gut bacteria, improved integrity of the intestinal barrier, and lowered metabolic inflammation and endotoxemia. However, these effects have not been unraveled in humans [44, 83, 85,86,87,88,89]. Several studies have suggested that the gut microbiota can mediate the low-grade inflammation classically associated with metabolic disorders related to obesity by exerting an interesting “anti-inflammatory” effect [84, 90, 91].

Increased pro-inflammatory cytokine production was associated with aging [92], and the low-grade inflammation that is usually found in older people influenced the incidence of several age-associated diseases [22, 93]. Probiotics can modulate the immune system through phagocytosis, TH1 responses and pro-inflammatory cytokine production utilizing interleukin-10 (IL-10) [94]. Decreased IL-6 production can be detected in peripheral blood mononuclear cell (PBMC) in older people. In addition, a related prebiotic galacto-oligosaccharide mixture was shown to decrease Tumor Necrosis Factor-α (TNF-α), IL-1β and IL-6 and increase the production of IL-10 and natural killer cells [95]. An increase in serum CRP, which has been shown to correlate with circulating IL-6, can be evidence of systemic inflammation [96]. Several studies confirmed that the production of IL-6 was down-regulated and that the number of apoptotic T cells was increased in the lamina propria by the interaction of probiotics with inflamed intestinal tissues. A number of probiotic strains passing through the gastrointestinal tract can also induce anti-inflammatory cytokine production. The study advocated that this probiotic strain or its symbiotic combination can be beneficial by preventing lifestyle-associated, inflammation-associated, or gut microbiome-associated metabolic disorders through the amelioration of inflammatory status and gut microbial populations.