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"All diseases begin in the gut” (Hippocrates): A focus on Microbiome and Obesity

Romeo AC1, Kattoyon K2

1Pediatric Unit, University of  Messina, Messina, Italy

2University of California

Introduction
Obesity is the most prevalent nutritional disorder among children and adolescents in the United States and many other resource-rich countries and transitional economies [1]. Childhood obesity has more than doubled in children and quadrupled in adolescents in the past 30 years [2] The percentage of children aged 6–11 years in the U.S. who were obese increased from 7 % in 1980 to nearly 18 % in 2012. Similarly, the percentage of adolescents aged 12–19 years who were obese increased from 5 % to nearly 21 % over the same period [2, 3]. In this country main factors contributing to the weight gain are widespread net of fast food restaurants and hypodynamic habits.  
In Europe last surveys exstimate up to 27 % of 13-year-olds and 33 % of 11-year olds are overweight. Among 11-year-old boys and girls, the prevalence of overweight was highest in Greece (33 %), Portugal (32 %), Ireland (30 %) and Spain (30 %) and lowest in the Netherlands (13 %) and Switzerland (11 %) [4]. Obesity is associated with multiorgan (namely pancreatic, adipose, hepatic, cardiac and muscle tissue) chronic metabolic and inflammatory alterations that together are termed ‘metabolic syndrome’. Childhood obesity predisposes to insulin resistance and type 2 diabetes, hypertension, hyperlipidemia, liver and renal disease, and reproductive dysfunction. This condition also increases the risk of adult-onset obesity and cardiovascular disease. Unequivocal experimental and clinical evidence causally link IL-1β and IL-18 to the development of these metabolic pathologies and their complications.
During nutritional surplus, in addition to adipocyte hypertrophy owing to increased lipid storage, adipose tissue is infiltrated by classically activated, M1, macrophages that secrete pro-inflammatory cytokines. NLRP3, ASC and caspase-1 are preferentially expressed in adipose-tissue-infiltrating macrophages, in which the saturated fatty acid palmitate and lipotoxic ceramides trigger NLRP3 inflammasome activation through a mechanism that involves defective autophagy and the accumulation of mitochondrial ROS.
Chronic hyperglycaemia as a result of peripheral insulin resistance is compensated for by increased insulin output by pancreatic β cells. Local inflammatory processes coupled with the toxic effects of glucose lead to accelerated mass loss of β cells and decreased insulin secretion over time, which prompts the progression from obesity and insulin resistance to overt T2DM. IL-1β, preferentially expressed by pancreatic infiltrating macrophages and to a smaller extent by β cells, has been implicated as a critical driver of β-cell death in conditions of chronic exposure to elevated concentrations of glucose [5].
No single definition of obesity in childhood and adolescence has gained universal approval. Some investigators have used the terms overweight, obese, and morbidly obese to refer to children and adolescents whose weights exceed those expected for heights by 20%, 50%, and 80-100%, respectively. The body mass index (BMI) has not been consistently used or validated in children younger than 2 years.  Many factors, including genetics, environment, metabolism, lifestyle, and eating habits, are believed to play a role in the development of obesity. However, more than 90% of cases are idiopathic; less than 10% are associated with hormonal or genetic causes. Recently, the gut microbiota has emerged as an important contributor to the development of obesity and metabolic disorders, through its interactions with environmental (e.g. diet) and genetic factors. Human intestinal microflora represents a complex ecosystem consisting of trillions of microorganisms and thousands of bacterial species that are deeply involved in different functions of host metabolism, modulation of inflammation, and body weight homeostasis.
 Nutrition is a driving factor in shaping gut microbiota composition and its functional maturation from the early stages of life. The gut microbiota acquired in early life have long term implications for host metabolism and gastrointestinal (GI), immune and neurological function [6]. Reduced diversity or dysbiosis are linked to childhood and later life disorders, including necrotizing enterocolitis [7], eczema [8], asthma[9], inflammatory bowel diseases [10], irritable bowel syndrome [11], obesity [12], diabetes [13] and autism [14].

 

Definition
The microbiome refers to the entire habitat, including the microorganisms (bacteria, archaea, lower and higher eurkaryotes, and viruses), their genomes (i.e., genes), and the surrounding environmental conditions. The microbiome is characterized by the application of one or combinations of metagenomics, metabonomics, metatranscriptomics, and metaproteomics combined with clinical or environmental metadata. Different parts of the body have different microbiomes, for example, the skin microbiome is different to the gut microbiome, but they are all part of the human microbiome [15].
The microbiota, includes all the microorganisms present in a defined environment identified using molecular methods relying predominantly on the analysis of 16S rRNA genes, 18S rRNA genes, or other marker genes and genomic regions, amplified and sequenced from given biological samples.
The normal gut microbiome comprises 100 trillion diverse microbes, whose collective genomes contain at least 100 times as many genes as our own eukaryote genome, mostly bacteria, encompassing over 1100 prevalent species, with at least 160 species in each individual (e.g., about up to 1.5 kg of bacteria in the human gut) with Firmicutes (35–80%) and Bacteriodetes (17–60%)  and Actinobacteria constituting the dominant phyla. Generally, Firmicutes and Bacteroidetes are most abundant, followed by Proteobacteria and Actinobacteria with minor contributors like Verrucomicrobia and Fusobacteria .
It is believed that the ratio of potentially pathogenic to beneficial commensal microbes, rather than the presence of a specific organism or a group, is more crucial for disease development.
Faecalibacterium prausnitzii (F. prausnitzii) is the most abundant bacterium in the human intestinal microbiota of healthy adults. It represents more than 5% of the total bacterial population and it is a major representative of Firmicutes phylum, Clostridium class, Ruminococcaceae family [16].  
While the Bacteroidetes phylum mainly produces acetate and propionate, the Firmicutes phylum has butyrate as its primary metabolic end product.
The intestinal flora could be grouped in 3 main distinct enterotypes (Bacteroides, Prevotella or Ruminococcus) that are influenced by dietary intake:  Bacteroides enterotype is associated with a “western” protein rich diet as opposed to the Prevotella enterotype which was associated with a carbohydrate rich diet [17] (Fig. 1).

Fig.1 Taxonomic of microrganisms. (Taylor K. Soderborg & Sarah J. Borengasser & Linda A. Barbour & Jacob E. Friedman;  Microbial transmission from mothers with obesity or diabetes to infants: an innovative opportunity to interrupt a vicious cycle; Diabetologia (2016) 59:895–906 DOI 10.1007/s00125-016-3880-0).

 

Gut microbiome development
The intestinal flora of the human body is established in infancy and gradually stabilizes with age. By approximately 2 years of age, it is similar to the adult intestinal flora (Fig. 2).  Host genetics and environmental factors such as gestational age, delivery mode, diet, pre- and probiotics, antibiotics, maternal weight and stress influence the process. Several factors, such as diet and genetic background of the host and immune status, affect the composition of the microbiota (Fig. 3). Antibiotic use in human infancy, before age 6 months, was significantly associated with obesity development [18]. In contrast, perinatal administration of a Lactobacillus rhamnosus GG-based probiotic decreased excessive weight gain during childhood [19].
Caesarian section instead of vaginal delivery is an obvious example of the potential impact of medical practice on microbiota composition, with substantial differences in founding population, that may persist for months. Immediately after vaginal delivery, founding microbial populations in the baby closely resemble that of their mother’s vagina and mother’s milk, with lactobacilli predominating. [20, 21].
Early life nutrition with breast or formula feeding of newborns impact differently on the gut microbiome composition in the early stages of life. Bacterial composition and alpha-diversity differ between breastfed (BF) and formula-fed (FF) infants, and solid food introduction has been associated with rapid and sustained alterations in the fecal microbiota.  Initially after birth, the newborn fecal microbiota is composed primarily of facultative anaerobes, such as Staphylococcus, Streptococcus, Lactobacillus, and Enterobacteriaceae, which are thought to consume oxygen and prime the GI tract for colonization with obligate anaerobes such as Bifidobacterium, Bacteroides, and Clostridium [22]. From the first week of life, different colonization patterns are present in BF and FF infants. The fecal microbiota of BF infants is more stable over time, and characterized by a lower alpha-diversity compared to FF infants. Bifidobacteria have been shown to account for 70% of the sequences of exclusively breastfed (EBF) infants and appear earlier in the feces of EBF than in FF infants. For example, B. longum and B. breve are the dominant species in BF infants, whereas FF infants also harbor adult associated bifidobacterial species, such as B. adolescentis. The FF infant microbiome was enriched in functions characteristic of a more mature microbiota (e.g. more similar to that of an adult) such as bile acid synthesis, methanogenesis, and the phosphotransferase system, while the fecal microbiome of BF infants was enriched in patterns associated with synthesis of B vitamins and oxidative phosphorylation. A greater prevalence and higher proportion and total counts  of C. difficile in FF compared to BF infants, as well as, significantly more Peptostreptococcaceae, Akkermansia, Veillonella, and Enterococcus have been described. Escherichia abundance was also higher in FF than BF infants [23].  
Breastfeeding may compensate for factors shown to negatively impact the infant’s GI microbiota. Certain strains of bacteria previously isolated from HM produce bacteriocins and others prevent growth of various GI-associated pathogens, which could contribute to the decreased prevalence of illness and other health problems observed in BF vs. FF infants.
 For example, infants delivered by Cesarean section (CS) had different fecal microbiota depending on if they had been breast- or formula-fed. The BF infants achieved numbers of B. bifidum comparable to those of vaginally-delivered (VD) infants earlier than FF or MF infants. Moreover it seems that feeding likely moderates the effects of intrapartum antibiotic prophylaxis (IAP) exposure on microbial colonization. Regardless of feeding mode, IAP-exposed infants, delivered by emergency CS, presented with dybiosis at 3 months. Compared to infants who were not exposed to IAP, these infants had a lower abundance of Bacteroidetes and increased abundance of Firmicutes. These differences, between IAP exposed and non-exposed, remained at 1 yr, but only in infants who were not exclusively breastfed at 3 mos. Moreover, available data suggest that early antibiotic administration is strongly associated with later overweight or obesity. In particular, a significant risk of increased body mass index (BMI) was shown in a large number of children who were prescribed antibiotics in the first 6 months of life or were given these drugs repeatedly during the first 2 years of life. Interestingly, several experimental studies have shown that although animal exposure to antibiotics was limited to infancy, weight gain could emerge later, even in adult age and the metabolic perturbation initially induced by microbiota alteration persisted after the cessation of antibiotic administration, despite the microbiota [24, 25, 26].
These findings further support the notion that breastfeeding may help to reconcile imbalances in an infant’s microbial composition resulting from adverse life events. Differences in the colonization patterns and microbial composition in BF vs. FF infants are proposed to be guided by complex sugars present in HM of each mother, known as human milk oligosaccharides (HMO). These sugars are the third largest component of HM and have been identified in over 200 distinct forms. Abundance of HMOs decreases throughout lactation and maternal genetic differences determine both the composition and orientations of the 5 monosaccharides known to comprise these glycans – Lfucose, D-glucose, D-galactose, N-acetylglucosamine, and N-acetylneuraminic acid. Being resistant to enzymatic hydrolysis, the HMOs pass intact through the infant stomach and upper GI tract to the distal small intestine and colon. HMOs exert prebiotic effects and inhibit the binding of pathogenic bacteria, thereby modulating the infant immune system and shaping the composition of the resident GI microbes. Of particular interest to researchers is the ability of Bifidobacterium to metabolize HMOs. Certain HMO show bifidogenic effects in vitro, selectively stimulating the growth of certain commensal bacteria often identified in BF infants, such as B. infantis, B. bifidum, B. breve and B. longum [27].
Additional studies investigating the long-term impacts of early feeding regimes on GI profiles beyond infancy are also necessary, as existing evidence has demonstrated that infants who were fed with HM for at least 50% of feedings during the first 3 months of life maintained a different fecal microbial composition between 12 and 24 mos than those who had received less than 50% of feedings from HM. The transition toward a more adult-like microbiota is observed during the introduction of solids foods; however, more recent studies suggest that this shift toward a more mature microbiota is more likely attributed to the cessation of breastfeeding, rather than the introduction of complementary foods. For example, continued breastfeeding during the introduction of solid foods seems to support consistent levels of Lactobacillus spp. and Bifidobacterium spp [28].

Fig.2 Sketch of the development of the microbiota from the first inoculum as an infant through continued change, modified by diet, genetics and the environment, throughout life.  (Dominguez-Bello; Development of the Human Gastrointestinal Microbiota and Insights From High-Throughput Sequencing; Gastroenterology 2011;140:1713–1719).

Fig.3 Proposed pathways for the transgenerational cycle of obesity. GWG, pre-pregnancy BMI, development of GDM and/or HFD/WSD can result in maternal gut dysbiosis. This dysbiosis may be directly transmitted to the infant and may cause dysbiosis in the infant gut by causing alterations to SCFA metabolite production, a proinflammatory state, epigenetic alterations and increased energy extraction from ingested nutrients. External influences such as early-life nutrition (breastfeeding vs formula-feeding), mode of delivery and antibiotic treatment may additionally influence the composition of the infant gut microbiome. These changes in gut microbiome function may result in infants born large for gestational age and with excess adiposity, both of which place the child at increased risk of obesity, immune dysfunction and NAFLD later in life. Adulthood obesity during childbearing years then perpetuates the cycle of obesity. DM, type 1 or 2 diabetes. (Taylor K. Soderborg & Sarah J. Borengasser & Linda A. Barbour & Jacob E. Friedman;  Microbial transmission from mothers with obesity or diabetes to infants: an innovative opportunity to interrupt a vicious cycle; Diabetologia (2016) 59:895–906 DOI 10.1007/s00125-016-3880-0).

 

The impact of diet on gut microbiome
Dietary habits are considered one of the main factors contributing to the diversity of human gut microbiota (Fig.4).  Long-term and short-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut. Gary D. Wu [29] proved that on 10 subjects, the microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study.  
Lawrence A . David [30] showed that the short-term consumption of diets composed entirely of animal or plant products, alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii).
Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. The increase in the abundance and activity of Bilophila Wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles [31].
Due to overwhelming material abundance, high fat, high sugar and high protein diets are common. Numerous studies have determined that diet and its impact on gut microbiota are closely related to obesity and metabolic diseases. Different dietary components affect gut microbiota, thus impacting gastrointestinal disease occurrence and development.
We do not yet completely understand how the different environments and wide range of diets that modern humans around the world experience has affected the microbial ecology of the human gut, but several recent reviews provide a comprehensive treatment of the subject.
De Filippo et al. [32] analyzed  the fecal microbiota of European children (EU) and that of children from a rural African village of Burkina Faso (BF) where the diet, is rich in fiber (10.0 g/d in 1- to 2-y-old children and 14.2 g/d in 2- to 6-y-old children) , carbohydrate, and nonanimal protein and includes mostly cereals (millet grain, sorghum), legumes (black-eyed peas, called Niébé), and vegetables. Burkina Faso children showed a significant enrichment in Bacteroidetes and depletion in Firmicutes, with a unique abundance of bacteria from the genus Prevotella and Xylanibacter, known to contain a set of bacterial genes for cellulose and xylan hydrolysis, completely lacking in the EU children.  In addition, short-chain fatty acids (P < 0.001) in BF were more abundant than in EU children.  Also, Enterobacteriaceae (Shigella and Escherichia) were significantly underrepresented in BF than in EU children (P < 0.05).  This study enlighted the hypothesis that gut microbiota coevolved with the polysaccharide-rich diet of BF individuals, allowing them to maximize energy intake from fibers while also protecting them from inflammations and noninfectious colonic diseases.
A recent study [33] compared the omnivore diet to the Mediterranean diet, that includes high-level consumption of cereals, fruit, vegetables and legumes. It was detected significant associations between consumption of vegetable-based diets and increased levels of faecal short-chain fatty acids, Prevotella and some fibre-degrading Firmicutes, whose role in human gut warrants further research.  
Conversely, they detected higher urinary trimethylamine oxide levels, risk factor for promoting atherosclerosis in individuals with lower adherence to the MD.  High-level consumption of plant foodstuffs consistent with a Mediterranean diet is associated with beneficial microbiome-related metabolomic profiles [34]. It has been demonstrated that a diet high in saturated fatty acids led to an increased proportion of intestinal Firmicutes and decreased intestinal flora diversity [35]. One study found that converting a low sugar, low fat diet to a high sugar, high fat diet caused a rapid decline in the number of Bacteroidetes in the intestines. Another study also suggested that the number of Bacillus bifidus was reduced in mice fed a high fa diet [36].
In summary, gut microbiota may be an important intermediate link, causing gastrointestinal diseases under the influence of changes in diet and genetic predisposition. A diet that is high in fat, especially high in saturated and transfat, is closely related to obesity, metabolic syndrome and gastrointestinal diseases.


Fig.4 Interaction between diet and gut microbiota affects host metabolism. Dietary manipulation with probiotics and prebiotics alters the composition and metabolic capacity of gut microbiota. Dietary  anipulation in obesity with prebiotics and probiotics changes gut microbiota by favouring bacteria beneficial to the host and enhances the production of short chain fatty acids (SCFAs) – acetate, propionate and butyrate. These result in decreased lipogenesis, reduced inflammation and oxidative stress in liver;decreased adipogenesis, and reduced adipocyte size and number in adipose tissue; increased production of gut hormones and intestinal transit in the large intestine; reduced appetite in the brain. GLP-1: Glucagon like peptide-1, PYY: Peptide YY. (Petia Kovatcheva-Datchary, Tulika Arora;  Nutrition, the gut microbiome and the metabolic syndrome;  Best Practice & Research Clinical Gastroenterology 27 (2013) 59–72).

 

The role of the gut microbiome
There are broadly three enterotypes, namely: Enterotype 1, which has a high abundance of Bacteroides; Enterotype 2, which has high abundance of Prevotella; and Enterotype 3 which has high abundance of Ruminococcus. The bacteria belonging to Enterotype 1 have a wide saccharolytic potential, as evidenced by the presence of genes that code for enzymes such as proteases, hexoaminidases and galactosidases. In view of these set of enzymatic potential, it appears likely that these organisms derive energy from dietary carbohydrates and proteins. Enterotype 2 behave predominantly as a degrader of the mucin glycoproteins that line the gut mucosal layer. Enterotype 3 also is associated with mucin degradation, in addition to membrane transport of sugars. The enterotypes also possess other specific metabolic functions. For instance, biotin, riboflavin, pantothenate and ascorbate synthesis are more abundantly seen in enterotype 1 while thiamine and folate synthesis are more predominant in enterotype 2 [37, 38].
Nutrients metabolism : The gut microbiota functions as a metabolically active organ and digests dietary components that are indigestible for human cells which can then be absorbed and metabolized by the human body. The interaction between microbiome and the host can be realized by the production of short chain fatty acids (SCFAs) (acetate, propionate and butyrate), hydrogen and methane. Short-chain fatty acids (SCFAs) are derived from the microbial fermentation of undigested dietary fibers in the colon (polysaccharides and oligosaccharides), proteins, peptides, and glycoprotein precursors by the microbiota in the colon and distal small intestine [39].
The SCFAs absorbed through the gut epithelial cells, have strong effects on the energy regulation and the immune system of the host.  The relative absorption of SCFAs by the colon varies between 60–90%, and oxidization of SCFAs can provide energy for colonic mucosa and may contribute up to 5–10% of the total energy in a healthy body. Butyrate and propionate can regulate intestinal physiology and immune function, while acetate acts as a substrate for lipogenesis and gluconeogenesis. As carbohydrate becomes depleted as digesta moves distally, the gut microbiota switches to other substrates, notably  protein or amino acids. Fermentation of amino acids, besides liberating beneficial SCFAs, produces a range of potentially harmful compounds, like ammonia, phenols, p-cresol, certain amines and hydrogen sulfide, play important roles in the initiation or progression of a leaky gut, inflammation, DNA damage and cancer progression [40].
Synthesis of vitamin K and several components of vitamin B is another major metabolic function of the gut microbiota. Members of genus Bacteroides have been shown to synthesize conjugated linoleic acid (CLA) that is known to be antidiabetic, antiatherogenic, antiobesogenic, hypolipidemic and have immunomodulatory properties. The gut microbiota, especially Bacteroides intestinalis, and to a certain extent Bacteroides fragilis and E. coli, also has the capacity to deconjugate and dehydrate the primary bile acids and convert them into the secondary bile acids deoxycholic and lithocolic acids in the human colon [41, 42].
Recent studies have shown that human gut microbiota is also involved in breakdown of various polyphenols (phenolic compounds) that are consumed in the diet, found in a variety of plants, fruits and plant derived products (tea, cocoa, wine). Polyphenols exist as glycosylated derivatives bounded with sugars such as glucose, galactose, rhamnose, ribulose, arabinopyrinose and arabinofuranose and the can’t be adsorbed unless they are biotransformed to active compounds after removal of the sugar moiety by the gut microbiota [43, 44].
The gut microbiota could promote storage of triglyceride in adipocytes through suppression of intestinal expression of a circulating lipoprotein lipase (LPL) inhibitor, the angiopoietin-like 4. Another potential mechanism by which probiotics can counteract the negative effect of obesogenic diet is by interaction with commensal bacteria and altering expressions of microbial enzymes, especially those involved in carbohydrate metabolism or butyrate synthesis pathways [45].
Antimicrobial  function and immunomodulation : The gut microbiota, via its structural components and metabolites, has been shown to induce synthesis of antimicrobial proteins (AMP) such as cathelicidins, C-type lectins, and (pro) defensins by the host Paneth cells. Bacteroides thetaiotaomicron and Lactobacillus innocua appear to be among the key individual species that drive this production. The organism Bacteroides thetaiotaomicron has also been shown to induce expression of the matrix metalloproteinase matrilysin from the Paneth cells, which subsequently cleaves prodefensin to form active defensin. Another example of microbiota-host interaction in providing antimicrobial protection is the capability of Lactobacillus sp. to produce lactic acid, which can augment the antimicrobial activity of host lysozyme by disrupting the outer membrane of the bacterial cell wall [46, 47].The gut microbiota is also involved in the stimulation of the immune system and in providing resistance to pathogens. The gut microbiota, especially Gram-negative organisms like Bacteroides are shown to activate intestinal dendritic cells (DCs), which induces plasma cells in the intestinal mucosa to express secretory IgA (sIgA).  The sIgA that coats the microbiota are predominantly of sIgA2 subclass, which is more resistant to degradation by bacterial proteases. These mechanisms restrict the translocation of the microbiota from the intestinal lumen to the circulation, thereby preventing a systemic immune response. Intestinal microbiota is also essential for the normal development and function of Foxp3+ T regulatory (Treg) cells. Mucosal plasma cells produce secretory IgA upon induction by DCs [48, 49, 50, 51].
Integrity of the gut barrier and structure of the gastrointestinal tract:
The gut microbiota contributes to structural development of the gut mucosa by inducing the transcription factor angiogenin-3, which has been implicated in the development of intestinal microvasculature [52, 53].
Bacteroides thetaiotaomicron is reported to induce expression of the small proline-rich protein 2A (sprr2A), which is required for maintenance of desmosomes at the epithelial villus. Another mechanism that maintains the tight junctions is by TLR2 mediated signaling that is stimulated by the microbial cell wall peptidoglycan. Furthermore, the Lactobacillus rhamnosus GG strain produces two soluble proteins namely p40 and p75 that can prevent cytokine induced apoptosis of the intestinal epithelial cells in an epithelial growth factor receptor (EGFR) and protein kinase C (PKC) pathway dependent manner [54, 55].
The endocannabinoid system is yet another entity that regulates gut microbiota mediated maintenance of the gut barrier function. E.g., the Gram negative bacteria Akkermansia muciniphilia can increase the levels of endocannabinoids that control gut barrier functions by decreasing metabolic endotoxemia [56].
Recent studies have suggested a bacterial role in the development of autoimmune disorders including type 1 diabetes  (T1D). Metagenomics analysis realized on stool sample showed that autoimmune subjects have a functionally aberrant microbiome and altrered gut.  Those data suggest that a consortium of lactate- and butyrate-producing bacteria in a healthy gut induce a sufficient amount of mucin synthesis to maintain gut integrity. In contrast, non-butyrate-producing lactate-utilizing bacteria prevent optimal mucin synthesis, as identified in autoimmune subjects [57].


Childhood Obesity: A Role for Gut Microbiota?
Besides the well known and established causes of obesity like genetic predisposition, excessive intake of high calorigenic diet (fatty food) and lack of exercise which favours storage of calories in the form of fat in adipocytes, recently researchers in the field have shown the contribution and involvement of several other factors like hormonal imbalance; inflammatory cytokines of adipocyte and nonadipocyte origin; adipocytokines like adiponectin, leptin, and resistin, etc., toll-like receptors (TLR) and many others in the genesis of obesity [58]. Several metabolic studies have suggested that imbalances in the intestinal bacterial population may result in obesity, systemic inflammation and metabolic dysfunction (Fig. 5). Gut microflora are involved in obesity through some of their constitutive structural materials and through some of their metabolic end products (SCFAs; butyrate, acetate and propionate) that have been shown to be definitely related with obesity. It is important to say at the beginning that none of the most important enterotypes is purely obesogenic or antiobesogenic since they individually they produce more than one SCFA, each of which possessing opposite actions as metabolites, but the crucial factor to take in consideration  is the  the population ratio [59]. It has been demonstrated that obesity is associated with a reduction in the relative abundance of Bacteroidetes, and that the obese microflora has lower bacterial diversity than lean microflora [60]. Moreover, a high-fat diet increases the intestinal gram-negative to gram-positive bacterial ratio and thus the plasma lipopolysaccharide concentration, which sets the tone for metabolic endotoxemia and thus triggers the low-grade inflammatory state affecting insulin sensitivity. In overweight/obese humans, low faecal bacterial gene richness is associated with more marked overall adiposity and dyslipidaemia, impaired glucose homeostasis and higher low-grade inflammation [61, 62, 63].
High fat diet, both in animals and humans, has been found to alter the gut microbiota composition (more in favour of Gram negative phylum), which in turn increases the production and intestinal permeability of LPS, resulting in its high plasma concentration and development of “metabolic endotoxemia”. Recent observations show that obese person’s microbiota are rich in Prevotellaceae (a subgroup of Bacteroidetes), which is a good source of LPS [64, 65]. Chronic low-grade inflammation found in endotoxemia has been demonstrated to be due to activation of TLR-4 by LPS and dietary saturated fatty acids. TLR-4 activation induces upregulation of common intracellular inflammatory pathways like c-Jun N-terminal kinase and nuclear factor-kappa B in adipocytes and macrophages resulting in development of insulin resistance and increased adiposity [66].
SCFA act in this scenario in different ways. Some important actions of these three SCFAs have been found to be mediated through activation of endogenous free fatty acid receptor (FFAR) like FFAR2 and FFAR3, both these receptors has been demonstrated in adipocytes, epithelial cells and enteroendocrine cells. Activation of these two receptors leads to an increase in expression of satiety hormone polypeptide YY (PYY) and increase in intestinal motility. In addition to the above effect, their activation also increases the expression of leptin in adipocytes. SCFAs, like butyrate and propionate, increase the formation of the gut hormone glucagon-like peptide-1 (GLP-1). It reduces food intake by decreasing appetite. Maximal induction of GLP-1 requires activation of Gpr41, but is not essential [67, 68].
Butyrate has been shown to possess some mixed metabolic effects which include an increase in mitochondrial activity, prevention of metabolic endotoxemia and activation of intestinal gluconeogenesis. These actions are mediated through gene expression and regulation of hormonal activity. Some studies have indicated the antiinflammatory potential of butyrate which may contribute towards a decrease in obesity-associated metabolic complication, because of its capability to increase intestinal barrier function. For instance, F. prausnitzii, a butyrate producer from Clostridium cluster IV, was increased in the nonobese subjects. Butyrate and other short chain fatty acids are known to inhibit inflammation by limiting immune cell migration, adhesion, and cytokine production . In line with this, F. prausnitzii has been found to negatively correlate with inflammatory markers in obese subjects , suggesting that this microbe belonging to the Firmicutes may protect non-obese subjects from inflammation [69, 70].
Butyrate and propionate (beneficial SCFAs) cause weight regulation at least partially by controlling food intake; the action appears to be mediated through their stimulatory effect on the anorexigenic gut hormones. Like butyrate, propionate also possesses favourable some effects in obesity [71, 72]. They are as follows: (1) The SCFA has been found to reduce food intake and regulate body weight, similar to butyrate; (2) It decreases cholesterol synthesis by inhibiting the activity of the enzyme acetyl-CoA synthetase (the enzyme converts acetate to acetyl-CoA), thereby antagonizing the cholesterol increasing action of acetate; (3)  Moreover, propionate has been found to be a precursor for gluconeogenesis in the live [73, 74].
This may decrease the hepatic synthesis of cholesterol because fatty acids necessary for cholesterol synthesis are diverted towards synthesis of glucose (gluconeogenesis; (4) It has been shown that like butyrate, propionate also stimulates the formation of the anorexigenic hormone leptin. Of all the three SCFAs, acetate seems to be more obesogenic than butyrate and propionate [75, 76 , 77].

 

Fig.5 The role of inflammasomes in metabolic syndrome. During obesity, the NLRP3 inflammasome is activated by obesity-associated DAMPs in multiple tissues and cell types; the resultant pro-inflammatory-induced state often leads to a deterioration in metabolic functions. In adipose tissue, palmitate and ceramides activate the NLRP3 inflammasome in infiltrating macrophages, which leads to an enhancement of insulin resistance. In addition, caspase-1 activation through an unknown sensor protein regulates adipocyte differentiation and fatty acid oxidation. In the pancreas, IAPP and increased mitochondrial ROS production activate the NLRP3 inflammasome in mmLDL-primed macrophages and β cells, respectively. The increased levels of IL-1β in pancreatic islets result in increased β-cell death and decreased insulin production. Minute cholesterol crystals in early atherosclerotic lesions activate the NLRP3 inflammasome in mmLDL-primed macrophages, promoting inflammatory-cell infiltration and increased atherosclerosis progression. (Till Strowig, Jorge Henao-Mejia, Eran Elinav & Richard Flavell ; Inflammasomes in health and disease;  278; Nature, 481; 2012).


Dietary manipulation in obesity: Probiotics and Prebiotics
Probiotics are defined as the live microorganisms that, when administered in adequate amounts, confer health benefits to the host. Probiotic supplementation results in enrichment of the probiotic species in intestinal contents. It also results in alterations in the composition of gut microbiota and microbial metabolites, like SCFAs, in both murine models and humans [78].
Prebiotics are defined as dietary ingredients that promote ‘the selective stimulation of growth and/or activity (ies) of one or a limited number of microbial genus (era)/species in the gut microbiota that confer (s) health benefits to the host [79, 80]. Dietary fibres are known to exhibit prebiotic effects as they are utilized by specific bacteria, resulting in their proliferation, which are considered beneficial to the host.
Most currently used probiotics belong to bifidobacteria, lactic acid bacteria (LAB), dairy propionibacteria, yeasts (Saccharomyces boulardii), Bacillus, and the gram-negative Escherichia coli strain Nissle 1917. LAB represent a heterogeneous group of microorganisms broadly present in the diet, particularly by the use of non-human strains in the fermentation of dairy products being also normal inhabitants of the gastrointestinal and urogenital tract. Most of them are members of the phylum Firmicutes, while Bifidobacterium, also considered as lactic-producing bacteria, belong to Actinobacteria phylum.
Probiotic administration is frequently associated with important shifts in gut bacterial composition, along with beneficial effects on metabolism and inflammatory tone. Probiotic administration has been shown to stimulate the immune response, improve lactose tolerance, help prevent diarrhea, have an anti-inflammatory effect and even restore obesity-linked gut dysbiosis [81, 82, 83]. Fecal microbiota transplantation showed good results for treating Clostridium difficile infection (CDI), and  the three most relevant studies published in the last years on patients affected by Ulcerative colitis, not responding to conventional therapy,   and treated with retention enema, showed a remission ranging from 3 months to several years [84, 85, 86].
Treatment with VSL#3 in patients with active UC, not responding to mesalamine therapy, was proved to a trend toward a remission/response rate of 77% without presenting any adverse events [87].
Given the relationship between obesity-related disorders and gut homeostasis, probiotics may be of interest to supplement the limited arsenal of therapies against the metabolic syndrome.
In the context of obesity and metabolic disorders, probiotic supplementation may help to reduce hyperphagia [88], improving control of weight gain, fat mass loss and glucose tolerance. On the contrary, such positive effects could also be obtained without modulation of caloric intake, as demonstrated by most of the reported studies [89, 90].
Probiotics have been shown to reduce adipocyte size in different adipose depots, which is considered an important parameter in assessing their anti-obesity potential [91].
The putative mechanisms put forth are increased fecal excretion of neutral sterols and bile acids, decreased lymphatic absorption of triglycerides, phospholipids and cholesterol, or increased lipolysis. VSL#3 was demonstrated to promote the release of the hormone GLP-1, resulting in reduced food intake and improved glucose tolerance. By activating the G-protein-coupled receptors GPR41 and GPR43 on intestinal epithelial cells, SCFAs stimulate peptide YY (PYY) and glucagon-like peptide (GLP)-1 secretion. In turn, these hormones may suppress gut motility and retard intestinal transit, allowing for greater nutrient absorption [92].
Prevention and management of obesity is proposed to begin in childhood when environmental factors exert a long-term effect on the risk for obesity in adulthood. Thus, identifying modifiable factors may help to reduce this risk. With advancing knowledge of how probiotics interact with the gut microbiome, there is an increasing interest in exploring the anti-obesity potential of probiotics [93].  
One double-blind study focused on the impact of perinatal probiotic intervention , 4 weeks before expected delivery and 6 months postnatally (Lactobacillus rhamnosus GG ATCC 53103 vs palcebo) in 113 children, observed for 10 years, regards the development of overweight, obesity and child’s BMI. 
The probiotic intervention showed to modify the growth pattern of the child by restraining excessive weight gain during the first years of life [94].
The genus Bifidobacterium, affecting both the quantity and quality of the microbiota during the first year of life, was shown to be higher in number in children who remained normal weight at 7 y than in children developing overweight as reported in the prospective follow up study of Kalliomaki et al. [95, 96].
As regard prebiotics, several in vitro studies have shown that HMOs serve as the primary substrate for the growth of Bifidobacterium and other bacteria. Furthermore, several studies have demonstrated correlations between several bacterial genera present in BF infant feces, with the HMO in their mother’s milk or present in the infant feces. The most studied prebiotic addition to infant formula is a 9:1 mixture of short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS) [97]. Investigators have identified significant clinical impacts of these prebiotics on the immune and metabolic development of infants. Infants who consume formula supplemented with this mixture have a lower fecal pH and exhibit a fecal SCFA profile and stool characteristics comparable to that of BF infants. Findings have also shown that infants exposed to scGOS and lcFOS to require fewer doses of antibiotics and have a decreased incidence of infection likely due to an increased colonization resistance to enteric pathogens. The other prebiotics added to infant formula individually or in combination include, GOS, FOS, oligofructose and inulin, polydextrose (PDX), lactulose (LOS) and acidic oligosaccharides (AOS). Prebiotics are resistant to gastric acidity and enzymatic hydrolysis in the upper gastrointestinal tract and enter the colon intact, where they are metabolized by colonic microbiota. Shortchain prebiotics, such as FOS and GOS, are mainly fermented in the ascending colon, while longer-chain prebiotics, like PDX and inulin, are fermented along the entire colon [98, 99]. Most studies showed that supplementation of prebiotics to infant formula increased the numbers of beneficial bacteria, mainly Bifidobacterium and sometimes Lactobacillus. In the context of obesity, the use of relatively new prebiotics such as arabinoxylan (AX) and rabinoxylan oligo-saccharides (AXOS) may be promising candidates to counteract related metabolic disorders, since AX and AXOS have been linked to adiposity reduction  and lower metabolic endotoxemia  in obese mice, respectively [100].
Another growing concept is to genetically engineer bacterial strains in order to reinforce a pre-existing probiotic capacity or to increase their effectiveness. Duan et al. [101] recently reported the successful application of an engineered probiotic that secretes the inactive full-length form of GLP-1 to reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of type 1 diabetes.
Another interesting potential strategy is the genetic modification of the probiotic E. coli Nissle 1917 to produce N-acylphosphatidylethanolamines, which is converted quickly after meals into potent appetite-suppressing lipids, know as N-acylethanolamines [102].

Conclusions
Diet and lifestyle are crucial factors influencing the development and progression of obesity. Recent insights have examined obesity aetiology with a new perspective and found that our own microbiota might be involved in the development of these disorders. The infant GI microbiota undergoes rapid and profound changes during the first year of life. During this process, diet plays a predominant role over other environmental factors in shaping the microbial composition.
Most of medications for treatment of obesity are taken out the production because of their adverse. One of the potential ideal strategy for obesity treatment may be manipulation with gut microbiota. Probiotics are food supplements that confer beneficial effects under various clinical conditions inclusive of atherogenesis, allergy, and inflammatory bowel diseases. However, the widespread use of probiotics against obesity and
diabetes is lacking , primarily because of insufficient mechanistic insight and a paucity of efficacy data in small animal models. More controlled human and animal studies are necessary to clarify these complex interactions.


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www.thechild.it Four-monthly Journal of Pediatrics edited by Genetics and Pediatric Association (APIG)
Law March 7th, 2001, n. 62 - Press Register Court of Messina n. 4/2012
Director manager: Giuseppe Micali - Scientific manager: Giorgio Ciprandi - Editor in chief: Carmelo Salpietro
Secretariat writing:  Basilia Piraino - Piera Vicchio - Italia Loddo
Editorial staff from Genetics and Pediatric Unit - University of Messina