The intestinal microbiome plays a key role in digestion and absorption of nutrients, regulating energy homeostasis through different mechanisms as energy extraction from food and the modulation of fat storage by the short chain fatty acids (SCFAs) and monosaccharides absorption.

The first information about the role of bacterial flora in the obesity physiopathology was obtained in GF mouse models [124,125,126]. These mice were significantly leaner than controls, despite introducing more calories from food [127]. Moreover, GF mice showed modified plasma fatty metabolic markers and lower amount of leptin and ghrelin, suggesting an energy imbalance [128]. When GF mice were transplanted with gut bacterial flora obtained from conventionally raised mice, they showed an increase in insulin resistance and in body fat without an observed increment in nutrient intake [123]. This evidence has placed the gut microbiome at the center of a completely new research field, concerning the pathophysiology of obesity. Biochemical and metagenomics data analysis suggested that the “obese microbiota” [14] was able to harvest more energy from the diet and this ability was also transferable. Thus, the colonization of GF mice with an obese microbiota (human or murine) induced an increase in total body fat higher than that one obtained through colonization with a lean microbiota [129]. In addition, when eutrophic GF mice received fecal microbiota from obese women, metabolic complications associated to obesity have been observed [130]. This evidence indicates how rapid, transmissible and flexible can be the relation between food and commensal microorganisms in obesity and metabolic syndrome.

Animal obesity models and obese humans present a similar microbial phylum taxonomic rank dysbiosis. In particular, humans and mice share two main phylum: Firmicutes and Bacteroidetes; an alteration of Firmicutes/Bacteroidetes ratio was observed in several obesity studies in both mice [131] and humans [14]. Indeed, the Firmicutes could break down indigestible carbohydrates and converting them into absorbable energy products [132,133,134]. However, in a meta-analysis study the observed alteration in the ratio Firmicutes/Bacteroidetes seemed to be unrelated to weight differences [135]. Also, the reduction in microbial diversity and alteration of particular microbial families or species have been observed in obesity conditions [114], such as the increase of Proteobacteria [136].

The complex interplay between host genetics, gut microbiome and environmental factors is crucial for the obesity pathophysiology (for instance, monozygotic twins showed a more similar GM profile than did dizygotic twins) [137]. Dietary pattern could also affect the bacterial structure, for example, westernized diets increase the abundance of Clostridia (Firmicutes phylum) populations that could extract more energy from the diet, consenting higher energy utilization [138]. The unused extra energy is then accumulated as fat deposits.

While different processes, by which an ‘‘obese microbiota’’ can affect body weight balance [127,139,140] have been indicated, the increased energy harvest via colonic fermentation and SCFAs’ production is the most direct [14]. Bacterial enzymes (specific glycoside hydrolases) metabolize otherwise not digested by humans food components, like vegetable fibers (such as resistant starch, cellulose, and inulin) that cannot be metabolized by human enzymes. The final product of this process are energy-rich substrates, such as SCFAs [141]. SCFAs can provide ≤10% of total daily caloric intake [142]. Obese individuals show significantly increased levels of SCFAs such as acetate, propionate, and butyrate [133,143]. Most of the bacterial SCFAs (in particular butyrate) are derived from the fermentation process of Clostridia cluster [144]. SCFAs not only operate as energy substrates for host tissues and bacteria but also act as signaling molecules in the host metabolism, showing a relevant role in mediation of gut motility, regulation of fat storage and appetite [105]. Indeed, dysbiosis induced by the type of diet has been correlated with an acetate increase that promotes hyperinsulinemia [145]. Furthermore, SCFAs can influence other obesity-associated conditions such as insulin resistance and hyperglycaemia [146].

Among the SCFAs, the propionate can be utilized locally through conversion into glucose by intestinal gluconeogenesis or diffuse into the portal vein to be utilized as a substrate for hepatic gluconeogenesis, preventing high SCFAs concentrations in blood [147]. In addition, propionate decreases human lipogenesis and serum cholesterol (in hepatic and non hepatic tissues) [148], and also reduce the fasting blood glucose and hepatic cholesterol in obese rats [149].

In addition, several studies shows acetate benefits on metabolism. Acetate could bind to the receptor GPR43 in several target organs. In adipose tissue, the GPR43 activation inhibits insulin signaling and suppresses fat accumulation, while systemically, it improves insulin sensitivity [150]. Mice deficient in the acetate receptor GPR43 become obese when fed a normal diet, whereas mice who overexpress GPR43 remain lean even when fed an obesogenic diet [150]. In the liver, acetate reduces lipid accumulation and improves liver function and mitochondrial efficiency. In adipose tissue, acetate inhibits fat breakdown but induces the browning of white adipose tissue and metabolic improvements, leading to a reduction in body fat [151]. Finally, prebiotics such as inulin, increased acetate production that crosses the blood–brain barrier of rats and results in reduced grehlin production and so, inducing a decrease of body weight, food intake, and fat mass [152]. Moreover prebiotic fructooligosaccharides increase acetate production, reducing body weight and fat mass because it favors a lower food intake in mice [153].

Microbial metabolites can also regulate the composition of bile acid species. A reduced bile acid amount in the intestine has been associated with inflammation and microbiota overgrowth [154]. Some intestinal bacteria are able to extract energy from the metabolization of bile acids, inducing the activation of bile acid receptors farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). These two receptors maintain insulin sensitivity and glucose tolerance in both liver and intestine [29,30]. In addition, other mechanisms have been proposed to account for the increased microbiota capacity to extract energy from the diet intake [155]:

• GM influences energy homeostasis by regulating gene expression via complex mechanisms started by SCFAs and monosaccharides [156]. In particular, the commensal microorganisms stimulate monosaccharide cellular uptake [157] and induce lipogenesis by activating the transcription factors carbohydrate response element binding protein (ChREBP) and sterol response element binding protein (SREBP) [155]. Triacylglycerols, produced trought hepatic lipogenesis, are thus sent from the liver to the blood in the form of very low-density lipoprotein and chylomicrons.
• HF diet triggers an increased absorption of bacterial lipopolysaccharide (LPS) (an endotoxin in the cell wall of Gram-negative bacteria) from the gut lumen to the bloodstream inducing low-grade inflammation, by activating B cells or dendritic cells activating and cytokine production [158]. The inflammation could also be stimulated by endotoxemia condition [157]; moreover, also the damaged gut barrier might contribute to this metabolic endotoxaemia [159].
• GM induces a suppression of angiopoietin-like protein 4 (ANGPTL4) in the intestinal epithelium. ANGPTL4 is a circulating enzyme produced by liver, gut and adipose tissue that inhibits LPL; its suppression provokes an increase of triacylglycerol storage in the adipose tissue [127].

Of note, relevant evidence suggests that both the consumption of fermentable carbohydrates and the supplementation of SCFAs result in positive effects on host physiology and energy homeostasis. The resistant starch (RS) is a fermentable dietary fiber used as a carbohydrate source in food. Obanda and colleagues used obesity-prone and obesity-resistant rats to examine how weight gain and fat accretion relate to fermentation levels and GM after feeding RS [160]. Obese-prone rats fed with RS at 20% of the weight of the diet did not gain more body fat than the same type of rats fed the same diet except without the RS [160]. It could be possible that fermentation of prebiotics increased energy expenditure but with contemporary greater energy absorption, and so without net gain in weight and body fat. The authors hypothesized that dietary RS decreases body fat accumulation through stimulating endogenous GLP-1 and PYY production [161]. However, the majority of these recent researches have investigated the effect of SCFAs on animal models or in particular tissue or metabolic process. Since SCFAs have different and parallel metabolic processes that affect energy homeostasis, more studies are needed to bring these effects together in order to elucidate the real impact of SCFAs [139].

As previously reported, the gut microbiome affects the host’s CNS functions (as cognitive and vegetative activities) through the MGB axis. CNS functions, vice versa, may influence the structure of the microbiota that inhabits the intestinal lumen [112]. Several studies suggest that this mutual interplay has a pivotal role in the occurrence of metabolic disorders, such as diabetes and obesity [162], but also in the development of eating and stress-related neuropsychiatric disorders, including [163] anxiety and depression.

Currently, researchers are focusing on whether the microbiome can have effects on the CNS process and on the hedonic and homeostatic control of dietary intake [164] (Figure 1).

As previously described, the SCFAs produced by the microbiota have systemic effects, but they can also directly signal to the (enteral and central) nervous system, via stimulation of the vagus nerve, or indirectly through immune-neuroendocrine processes [158].

The role of the vagus nerve is important in the MGB axis because it connects the 100 million neurons of the enteric nervous system to the “nucleus tractus solitaries” [112]. The information inserted in this communication axis is then delivered to the hypothalamus, which modulates energy balance, appetite and dietary intake [20]. This information also includes signals from commensal microorganisms, linking the cognitive and emotional nucleus of the CNS with peripheral gut activity, finally leading to host eating control. Experiments showed that transection or blockade of the vagus nerve could induce a dramatic weight loss [165]. On the other hand, vagus nerve functions appear to drive extreme eating behavior in satiated animals when they are treated with norepinephrine [166]. The parasympathetic vagal activity was linked with weight loss also in anorexia nervosa [167], indicating that vagal signaling, involved in the modulation of body weight, can lead to pathological anorexia, and other CNS disorders as anxiety-depressive behaviors and autism [168,169].

The vagus nerve could be stimulated by enteroendocrine cell hormones as gut peptide YY (PYY) and glucagon-like peptide 1 (GLP-1). The satiety hormone PYY inhibits gut motility, increases gut transit time, and reduces appetite [170], while GLP1 decreases appetite and improves insulin sensitivity [171]. The bacterial SCFAs could alter the release of those hormones into systemic circulation binding to their specific enteroendocrine G-protein coupled receptors (GPRs) [172,173]. Through the GPRs activation, SCFAs induce leptin expression, which produces the suppression of the appetite and GLP-1 production [174]. The increased plasma GLP-1 and PYY levels inhibit ghrelin secretion [174] and regulate appetite by releasing it into the blood stream [175]. Acetate, the main SFCA produced by the microbiome, has a direct effect in the suppressing of appetite via central hypothalamic process [152]. The increased acetate production, due to an altered gut microbiome, induces the stimulation of the parasympathetic nervous system with improved secretion of ghrelin, obesity and hyperphagia [145]. Lactate, another bacterial metabolite produced by Enterobacteriaceae, Lactobacilli and Bifidobacteria, is the favorite substrate for neuronal cells and could prolong the postprandial satiety [176].

Furthermore, the microbiome can affect the central control of appetite by producing neuroactive metabolites as tryptophan, serotonin, gamma-aminobutyric acid, endocannabinoid ligands, and ghrelin. These bacterial metabolites are the exact analogs of the mammalian hormones implicated in behavior and mood signaling [177]. More than half of the dopamine and the majority of the body’s serotonin are produced at gut level [178]. Indeed, components of bacterial flora, as Bacillus cereus, Escherichia coli [179], B. subtilis, B. mycoides, Serratia marcescens, Proteus vulgaris, and Staphylococcus aureus [180] can produce dopamine. The probiotic B. infantis 35624 improves blood levels of tryptophan [181], a precursor of serotonin that mediates appetite-suppressant function by the regulation of melanocorting neurons, which control body weight homeostasis [182,183]. Moreover, the lactic acid producing bacteria could secrete the neurochemicals histamine [184] and GABA [185] that is involved in the regulation of feeding and energy balance [186,187]. Interestingly, GABA stimulates the same neuroreceptors that are targeted by anti-anxiety drugs (benzodiazepines).

As widely discussed over the review, the immune system plays a crucial role in the gut–brain axis communications since immune mediators are important messengers of this complex dialogue and, consequently, it mechanistically links the function’s impairments in both brain and gut, as shown by the association between chronic gut inflammation and psychological morbidity [211,212,213,214]. The immune system plays a key role in obesity and correlated pathologies, such as in the colorectal cancer [215]. In obese patients, a chronic low-grade inflammatory state is maintained [216,217] and the peripheral inflammation, with the activation of innate immune components (like TLRs) and the loss of intestinal barrier integrity, can lead to neuro-inflammation. Interestingly, recent studies have demonstrated that dysbiosis and inflammation may concur to the development of various diseases, including obesity and depression disorders [218]. In addition, numerous studies have now clearly confirmed that the gut microbiome can, qualitatively and quantitatively, shape the host immune responses, both in the gut and in systemic tissues. In this way, the GM influences the concentration and profile of cytokines present in any given individual and, in turn, differentially affects the brain function. For example, GF mice show numerous immune abnormalities, including impaired antibody responses, diminished numbers of T and B lymphocytes and a defective production of cytokines (such as IL-10, TNF-alfa, IL-6 and IL-1) [219,220]. Moreover, selective GM constituents shape specific aspects of adaptive and innate immunity, including the differentiation of particular effector T-cell lineages [221,222,223]. The obesity-associated dysbiosis is characterized by a remarkable inflammatory potential of microbiota [224,225], which is able to activate innate and adaptive immunity in the gut and beyond, increasing the inflammatory tone by TLRs activation and production of pro-inflammatory cytokines [226]. Sen and colleagues have demonstrated that a dysbiotic microbiota (high sugar diet-associated) alters the vagal gut–brain communication [208], producing an inflammatory state that increases gut permeability. The result is the passage of LPS and pro-inflammatory cytokines from the lumen to the lamina propria (triggering an inflammatory response) and so, microglia activation in the nodose ganglion and finally leading to vagal remodeling [224]. Moreover, a microbiota with enhanced pro-inflammatory activity has been demonstrated to be able to promote intestinal inflammation, inducing colitis and metabolic syndrome [14,226]. The loss of intestinal barrier integrity, seems to be a crucial step in the obesity pathogenesis and related diseases, including neurological disorders [219,227] (Figure 2). In fact, the leaky gut allows the translocation of Gram-negative bacteria’s components into the mesenteric lymph nodes and the circulation, boosting the release of pro-inflammatory cytokines (especially TNF-alpha), via TLR2/4 direct or indirect activation [227,228,229,230], and increasing the production of IgA and IgM [231,232]. In general the gut permeability can be considered the direct consequence of the dysbiotic microbiota-driven local gastrointestinal inflammation [233,234], and notably, in obese mice, the prebiotics’ supplementation can improve the gut integrity, reducing the weight gain [235]. The leaky gut and the associated-inflammation lead to peripheral insulin resistance and hyperglycemia, supporting the obesity establishment; moreover, the increased inflammatory cytokines in the peripheral system can affect the BBB integrity, contributing to the development of mood disorders [234]. Bruce-Keller and colleagues have linked obesity, microbiome, and neurologic dysfunction, demonstrating the ability of HF diet-dysbiotic microbiota to increase inflammatory gene expression in the medial prefrontal cortex associated with anxiety and memory impairment [236]. Moreover, the inflammation generated by HF diet-dysbiotic microbiota can activate the microglia [237], a process observed in various neurological disorders [237,238,239,240] and associated with weight gain and bacteria-driven hyperphagia [241].

Finally, expanding the knowledge of the mechanisms underlying the triggers of such inflammatory responses in obesity could offer unique opportunities for intervention strategies reducing the risk of related neurological conditions and supporting personalized treatments [242].