An essential role of gut microbiota is the fermentation of dietary polysaccharides that the host cannot otherwise digest. Dietary fibers constitute the indigestible portion of plant foods containing insoluble and soluble fibers. These soluble fibers are digested by enzymes derived from the gut microbiota into short-chain fatty acids (SCFAs). SCFAs (butyrate, acetate, and propionate) are absorbed in the intestines and used as energy by the host. In addition to their role as energy substrates, SCFAs function as regulators of food or energy intake [10] and inflammation [11]. It is well known that SCFAs are associated with increased satiety and reduced food intake [10]. SCFAs bind to G protein-coupled receptors, (GPCRs) such as GPR41 and GPR43, which are expressed in the enteroendocrine cells [12]. This action leads to the secretion of certain peptide hormones, such as peptide YY (PYY), that are released basolaterally into the systemic circulation, enabling a form of communication between the gut milieu and the host. Reduced food intake is, in part, due to the increases in the gut hormones, such as glucagon-like peptide (GLP)-1 and PYY [13] which decrease appetite and energy intake, and due to the decreased release of the gut peptide ghrelin, which increases food intake through effects on the hypothalamic and brainstem reward-related circuits (Fig. 1) [14]. SCFAs-mediated activation of GPR43 resulted in suppression of insulin signaling in the adipose tissue subsequently preventing fat accumulation [15]. Recent study reported that dietary soluble fibers exert their antiobesity and antidiabetic effects via the induction of intestinal gluconeogenesis (IGN), which is contrary to the general idea that gluconeogenesis impairs glucose tolerance [16]. Butyrate activates IGN gene expression through a cAMP-dependent mechanism, while propionate, itself a substrate of IGN, activates IGN gene expression via a gut-brain neural circuit [16]. Glucose released by IGN is detected by a portal vein glucose sensor that signals to the brain through the peripheral nervous system, thus exerting beneficial effects on food intake and improving glucose tolerance (Fig. 1)[16,17].

Several recent studies have suggested that disruption of the gut barrier function and the gut microbiota-derived endotoxemia could contribute to the pathogenesis of obesity and T2DM [18,19]. A HFD dramatically increased gut permeability and reduced the expression of tight junction protein, such as zonula occludens-1 and occludin, in the intestinal epithelial cells of mice (Fig. 2) [20]. Disruption of the gut barrier in genetically or HFD-induced obese mice increased gut permeability, resulting in the leakage of lipopolysaccharide into the portal blood circulation (Fig. 2) [21,22,23]. Consistent with this concept, the modulation of the gut microbiota composition with antibiotics or prebiotics improved gut permeability, reduced metabolic endotoxemia, lowered inflammation, and alleviated glucose intolerance [24].

Prebiotics are non-digestible but fermentable polysaccharides, such as inulin, fructo-, oligosaccharides, galato-oligosaccharides, or lactulose. Foods artificially enriched with these fibers are defined as prebiotics, which promote SCFA production and the growth of beneficial bacteria, especially Bifidobacterium and Lactobacillus [25]. Studies in healthy humans and rodents have demonstrated that prebiotic consumption reduces hunger and enhances satiety [26]. As discussed above, this modulation of ingestive behavior is mediated, in part, by SCFA-induced changes in gut peptide secretion. Additionally, by promoting Bifidobacterium populations, prebiotics improve gut barrier function [27].

Probiotics are defined as live microorganisms that confer a beneficial health effect on the host when administered in proper amounts. Some probiotic strains, especially those of the genera Lactobacillus and Bifidobacterium, have been shown to ameliorate obesity and metabolic disorders. The suggested mechanisms include inhibition of the pathogen adhesion to gut mucosa, stabilization of the microbial community, or improvement of the mucosal integrity and barrier function [27,28,29,30,31]. The improvements of gut barrier function may reflect the actions of the SCFA products of bacterial fermentation. A recent study reported the direct beneficial actions of Lactobacilli on the epithelial cells and on the enteric nervous system regulating gut contractility [32].

A recent study showed that metformin, widely used for treatment of T2DM, is able to slow aging in Caenorhabditis elegans by metabolically altering Escherichia coli with which it is cocultured [33]. This effect was found to be due to the alteration of folate and the methionine metabolism of E. coli by metformin. Metformin decreased the methionine cycle and increased the levels of both S-adenosylmethionine (SAMe) and S-adenosylhomocystein. SAMe acts a co-repressor of methionine synthesis genes and also inhibits the folate cycle, resulting in decelerated aging in the worm [33].

Metformin can also affect the intestinal microbiota of mammals. We have demonstrated that metformin is able to affect the mouse microbiota and increase the abundance of Akkermansia muciniphila, a mucin-degrading G (-) anaerobes, in the gut of experimental mice fed a HFD (Fig. 2) [34]. We also observed that the administration of A. muciniphila had similar beneficial metabolic effects to that of metformin administration: (1) increased the number of mucin-producing goblet cells was similarly found after the administration of metformin or A. muciniphila; (2) diminished regulatory T (Treg) cell numbers and elevated interleukin 1β (IL-1β) or IL-6 mRNA expression in the visceral adipose tissue of mice fed a HFD were similarly reversed after the administration of metformin or A. muciniphila. Mucin has recently been shown to enhance delivery of tolerogenic immunoregulatory signal to the intestinal epithelium by forming galectin-3-dectin-1-FcγRIIB complex besides its classical role as a physical barrier [35] This study therefore underscores that drugs, such as metformin, might exert therapeutic effects, at least in part by modulating the gut micriobiota.

Recently, articles in the literature regarding fecal microbiota transplantation (FMT) have aroused strong interest. FMT is reported to be a highly successful therapy for recurrent Clostridium difficile infection [36]. These results also suggested a potential therapeutic effect of FMT in metabolic syndrome or T2DM. A recent study showed that FMT via a gastroduodenal tube from lean donors into obese subjects with metabolic syndrome induced a significant improvement of insulin sensitivity in the recipients [37]. FMT resulted in an increase of the microbial diversity and a 2.5-fold increase in the proportion of butyrate producer Roseburia intestinalis after 6 weeks of treatment, whereas, fecal SCFA levels were decreased. Despite this first evidence that such as approach could be attractive, more information is needed with larger, well-designed studies to prove whether such approaches are overall beneficial for patients with metabolic syndrome or T2DM.