Open access peer-reviewed chapter

The Microbiome and the Epigenetics of Diabetes Mellitus

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Lissé Angarita Dávila, Valmore Bermúdez Pirela, Waldo Díaz, Nadia Reyna Villasmil, Silvana Cisternas León, Ma Cristina Escobar Contreras, Kristian Buhring Bonacich, Samuel Durán Agüero, Paula Carrasco Vergara, Rodrigo Buhring Bonacich, Constanza Bugman, Virginia Céspedes, Marcell Gatica, Marion Guerrero Wyss, Jorge González Casanova and Francisco Valdebenito

Submitted: July 14th, 2017Reviewed: March 5th, 2018Published: July 11th, 2018

DOI: 10.5772/intechopen.76201

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Abstract

Gut microbiota (GM) in the epigenetic mechanisms of diabetes mellitus and the reprogramming of the cells is a novel and emerging concept. The purpose of this chapter is to describe the modification of the GM and its relation with DM2. The increased risk of this disease is associated with changes in the amount of Bacteroides/Clostridium in the Firmicutes/Bacteroidetes ratio of people having DM. A dysbiosis state associated generates low-grade inflammation with similar characteristics that occur under metabolic syndrome, whose pattern is recognized by Toll-like receptor that recognizes important patterns of immunity. The synthesis of butyrate generated by intestinal microorganisms inhibits the metabolic pathway of histone deacetylase, promoting cellular differentiation, proliferation, and insulin resistance. On the other hand, the direct relationship between the neuroendocrine system and the GM has been demonstrated through the production of serotonin by enterochromaffin cells, whose action could influence the etiopathogenic factors of DM2.

Keywords

  • diabetic
  • epigenetics
  • diet
  • microbiome

1. Introduction

Diabetes mellitustype 2 (DM2) is a global pandemic; although genetic factors can predispose subjects to suffer from it, external factors such as socioeconomic changes and cultural and eating habit changes have more contributions to increasing world prevalence [1], where overweight and obesity are considered as the main mediators of the disease. The number of cases of DM2 according to the International Diabetes Federation is 415 million adults by 2015. The risk death of subjects with DM is significantly higher than those without the disease, doubling it when we refer to cardiovascular death reason [2]. It has been determined that the gut microbiota (GM) is altered in subjects with type 2 diabetes, so studying its role in the development of pathology is essential to determine new approaches to treatment; it permits the identification of those bacteria beneficial to humans, from the bacterial genome recognition. The so-called microbiome correspond to the entire GM genome; it exceeds the size of the human genome, having about 500 times more genes that complement our coding; this bacterial ecosystem has evolved in a symbiotic relationship with human [3]; GM exerts nutritional, metabolic, and immunological functions that affect the human being. During the last decade, several studies have been reported on the effect of the GM on glycemic control [4]. In this context, GM in the epigenetic mechanisms of diabetes mellitus and the reprogramming of the cells is a novel and emerging concept. It is known that products derived from diet along with intestinal bacteria can change the epigenome of the host with favorable metabolic effects [5]. These microorganisms are essential for the biosynthesis of vitamins and hormones, as well as for the degradation of nondigestible dietary fibers and mucin in simple sugars and short-chain fatty acids [6]. Changes in the composition and function of the predominant GM are associated with an increased risk of DM2 and are linked to an increase in the number of Bacteroides[7] and Clostridium[8]. Specifically, the increase of Firmicutes/Bacteroidetesratio in the distal bowel, as well as the number of opportunistic pathogens, and in the production of endotoxins of Gram-negative bacteria is capable of modifying intestinal permeability. The metabolic syndrome is associated with changes in the framework of the GM that lead to low-grade inflammations, since the increased permeability of the intestinal membrane damaged by bacteria induces inflammation, through the epigenetic alteration of inflammatory molecules such as Toll-like receptors [9]. Mucus and glycocalyx layer mainly produced by Bacteroides thetaiotaomicron, Akkermansia muciniphila, and Escherichia colicause chronic low-level inflammation, insulin resistance, and, lastly, DM2 [10]. Evidence demonstrates the link between diabetes and histone deacetylase (HDA), because the microorganisms producing butyrate, an HDA inhibitory molecule that promotes differentiation and cellular proliferation and insulin resistance [11], are decreased in diabetics [5]. On the other hand, it has been recognized that the microbiome has a direct effect on the immune and neuroendocrine system, constituting a new brain gut axis [12], in which the circadian rhythm plays a fundamental role [13]. The production of colonic serotonin [14, 15] by the microbiome, through the effect of short-chain fatty acids on enterochromaffin cells [13, 16, 17], would allow to relate this neurotransmitter to the metabolic processes as one of the possible etiopathogenic factors of DM2. The next challenges are focused on integrating the transcriptomic, epigenetic, proteomic, and metabolic information of the human genome and the microbiome into the nutritional treatment [2].

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2. Microbiome, epigenetics, and diabetes interactions (metabolic pathways)

The human intestinal microbiota (HIM) is composed of a complex community of microorganisms; more than 1000 species have been identified, where only a few are cultivable [18]. The gut microbiome corresponds to a total set of genes present in the HIM (about 3 million genes), approximately 150-fold human genome [19]. This microorganism participates as a counterpart of gut enzymatic activities by a diverse metabolic repertoire becoming an important contributor to the metabolism of the host [20]. Exploratory studies have been shown that play an important role in the etiology and development of many diseases, being considered as markers of the course of the disease. Some chronic illnesses in which HIM has been regarded are the inflammatory bowel disease (IBD), the irritable bowel syndrome (IBS), diarrhea, obesity, diabetes, and inclusive cancer. The recent role attributed to the microbiome and health has promoted the research to study the microorganism characteristics and the design of strategies to restore damage microbiome to a normal “state” by using a microbe inoculation strategy or by using dietary modification to feed specific species and help their development or otherwise consume foods or other substances that induce the extinguishment of some species in the intestine. The abundance and diversity of the intestinal bacteria are located mainly in the large intestine where it exerts its principal metabolic role. Bacteria are capable of hydrolyzing carbohydrates, lipids, and proteins principally; saccharolyticbacterial fermentation produces generally beneficial metabolites such as short-chain fatty acids (SCFAs) and gases. The three most abundant SCFAs detected in feces are acetate, propionate, and butyrate, in molar ratios of 3:1:1 to 10:2:1 [21]. Butyrate is recognized as the most important SCFA for human health and is absorbed by the epithelial cell of the colon in the proximal colon via passive diffusion and by active transport mechanisms. Some properties have been attributed to butyrate, for instance, being able to be used by colonocytes as energy source, the potential anticancer activity inducing apoptosis of colon cancer cells, its ability to regulate gene expression in host by inhibiting histone deacetylases [22], and the beneficial effects in glucose regulation by activation of gluconeogenesis in the gut via cAMP-dependent manner [23].On the other hand, propionate exerts a dual action in intestine and liver regulation of gluconeogenesis and is considered an important molecule for satiety signaling because of an interaction with G protein-coupled receptors GPR 41, GPR 43 receptors, and fatty acid receptors FFAR2 and FFAR3. The net effect of the conversion of propionate to glucose is the decrease of gluconeogenesis in the liver; this generates a reduction in the production of adiposity [23]. Acetate is the most abundant SCFA and is considered as essential metabolite for bacteria growth. Faecalibacterium prausnitziiwill not grow in pure culture in the absence of acetate [24]. Acetate participates in the cholesterol metabolism and lipogenesis in the host [25].

2.1. Microbiota metabolism

A cross-feeding effect has recently been described, for instance, Bifidobacterium longumgrowing in fructooligosaccharides (FOS) produces a conversion into lactate and promotes the growth of Eubacterium halliithat could not grow in the presence of FOS alone and converts it to butyrate [26]. Another example of cross feeding occurs when Roseburia intestinalisincreases its growth in co-cultures with—the acetate contributor—B. longum[27, 28]. Two main routes of butyrate production [29] and three pathways for propionate production have been identified in bacteria; noteworthy peptide and amino acid can be used to form propionate and butyrate from some species of Bacteroidetesand Firmicutes. The main sources of propionate are aspartate, alanine, threonine and methionine, instead glutamate, lysine, histidine, cysteine, serine and methionine for butyrate production [30]. Sequencing targeted gene instead of 16S rRNA genes indicates that most bacteria had the capability to produce exclusively propionate or butyrate but not both. Conversely, bacteria change their fermentation depending on growth conditions and produce different SCFAs. Roseburia inulinivoransproduces butyrate normally, but it can change its gene expression pattern in the presence of fucose producing propionate and propanol [31]. Ruminococcus obeumproduces acetate, formate, and lactate on glucose growth and also produces propionate in the presence of fucose. Bacteroides thetaiotaomicronin the presence of fucose also increases fucosylated glycan to be used in absence of nutrients; it has been described that it is also important in early colonization of the infant gut [32]. By decreasing the carbohydrate content of the diet significantly reduced both fecal butyrate concentrations and numbers of the Roseburia/E. rectalegroup [33]; wheat bran has >70% arabinoxylan oligosaccharides (AXOS) that increase the SCFA content [34]. Unfortunately, the increased SCFA content causes reduced transit time and thus a decreased colonic absorption of SCFA. Excluding those vegetables rich in short fermentable carbohydrates such as oligosaccharides, monosaccharides, and polyol (FODMAP diet) reduces bacterial fermentation, showing a decrease in the total numbers of bacteria, and the fecal concentration of different SCFAs is similar to the control diet [35].

2.2. Gas production and the microbiome

HIM generates hydrogen, carbon dioxide, and methane, all of them odorless gases; odoriferous gases constitute less than 1% of total flatus and include NH3, hydrogen sulfide, indole, skatole, and volatile amines. There are many bacteria that do not produce gas [36] such as lactobacilli and bifidobacteria, so they can be used as probiotic able to reduce the gas content in colon. Gases can be excreted by flatus (several liters per day in a healthy human) [37]. Hydrogen is produced by Bacteroidesand Clostridium[38] and produces a high energy yield, and it can be used by other bacteria from the gut to produce lactate, succinate, and ethanol and sulfate-reducing bacteria (SRB), where Desulfovibriois the principal [39]. In the methanogenesis CO2 is converted to CH4, and in the acetogenesis dioxide and hydrogen are converted into acetate both use hydrogen [38]. Carbon dioxide is between 5 and 50% of the total flatus volume, and it is produced by acidification of bicarbonate in the upper gastrointestinal tract, and bacterial metabolism [40], C. sporogenes, C. butyricum, and C. perfringens, produces hydrogen and CO2.

2.3. Proteins

HIM has an important role converting protein metabolism, enzymes, mucin in short peptides, fatty acids and gases (H2, NH4, CO2 and H2S), Clostridia, Streptococci, Staphylococci, Bacillusand species of Bacteroidesand Propionibacteriumas the predominant proteolytic characteristics in fecal samples [41]. A preference for amino acid fermentation at higher ranges of colonic pH and a reduction in quantity when fermentable carbohydrate was available are observed [42]. The proximal colon was predominantly saccharolytic by nature; whereas protein fermentation increased distally, the fermentation was associated with the presence of phenol, indole, ammonia, and branched-chain fatty acids [21]. Aromatic amino acids phenylalanine, tyrosine, and tryptophan can be fermented to phenylpropanoid, phenylacetic acid, and 4-hydroxyphenyl-acetic acid by Bacteroides, Eubacterium hallii, and Clostridium bartlettii[43].

2.4. Vitamin synthesis and the microbiome

Gut microbiome can synthesize certain vitamins, such as vitamin K, biotin, cobalamin, folates, nicotinic acid, pantothenic acid, pyridoxine, riboflavin, and thiamine of B group [44]. For instance, subjects having low vitamin K diet showed an important decrease in plasma prothrombin when treated with broad-spectrum antibiotic [45]. Explored genomes in gut showed presence of eight vitamin B synthesis pathways. The most represented were riboflavin [46] and niacin with 162 genomes. Bacteroidetesis the phylum with larger B predicted vitamin generators. In the same line, bacteria can complement the biosynthesis of vitamins. In sum, GM can contribute with 25% of total dietary vitamin intake [47].

2.5. Bile acids and the microbiome

Gut microbiota can modify the structure of bile acid in the colon, because bile acids have antimicrobial activity causing membranes and DNA damage [48]. Deoxycholic acid produced by microorganisms is tenfold greater than cholic acid producing a feedback to control bacteria population [49]. Bile salt hydrolase enzyme has been recognized in Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, and Listeria[50]. It can deconjugate bile acids reducing its toxicity [51]. Microbial dehydroxylation by Clostridium and Eubacteriumtransforms chenodeoxycholic acid and cholic acid into lithocholic acid and deoxycholic acid, it can produce a cytotoxic effect on enterocytes, and it can be associated with colon cancer. On the other hand, bile acids are also a ligand for nuclear receptor farnesoid X receptor (FXR) and plasma membrane-bound GPR TGR [52] that regulates their synthesis and affects the lipid and glucose metabolism [53]. Bacteria deconjugate bile acids reducing the efficacy of lipid emulsification showing a downstream effect in metabolic processes.

2.6. Gut microbiota and diabetes type 2

Diet plays an important role in obesity. There are preliminary studies suggesting that the consumption of probiotic bacteria found in yogurt and other fermented milk products can beneficially alter the composition of the gut microbiome. Yogurt, a fermented dairy product containing a variety of probiotic bacteria, is found to be associated with a reduction in inflammation markers and weight loss [54]. Yogurt consumption is involved in energy balance and/or energy homeostasis, which in turn controls body weight and reduces the risk of the development of DM2 [55]. One of the causes of dysbiosis is diet, and studies have shown that diet may change the gut microbiota and contribute to obesity and diabetes [56]. Obesity and DM2 are characterized by an altered gut microbiota, inflammation, and gut barrier disruption [57]. Studies in germ-free animals have shown that shifts in the composition of the gut microbiome may play an important role in disease development, specifically obesity and diabetes [58]. There is evidence demonstrating that the composition of the gut microbiota also influences metabolism and can affect energy balance [59], gut permeability [60], and inflammation [61], all of which are associated with obesity and associated disorders, including DM2 [62]. The evidence for the role of the HIM in metabolism of dietary components and the impact on health has been obtained from comparative studies in germ-free animals, by using conventional microbiome, or by animals with human microbiome-associated, and from in vitrostudies using human fecal incubations. In this sense, gastric bypass surgery leads to a substantial shift in the gut microbiota, which may contribute to weight loss in part by HIM modifications [63]. One of the most important situations is that the immune system faces microbiome continuously and it affects the host immunity and inflammation control. In this line, GM can affect the immune system by metabolites like SCFAs [64] and toxin production, such as LPS [61], modifying the adipogenesis and influence in the insulin resistance. LPS induces generation of pro-inflammatory cytokines by the immune system and adipocytes. Acetate, butyrate, and propionate (SCFA) modulate the gene expression in host, modifying the infant microbiome and stimulating white blood cells [65]. Some studies suggested that infants born by cesarean section are at greater risk of developing obesity and/or diabetes than those born vaginally [66]. Other studies with preschool children showed overweight or obesity in children born by cesarean [67], while in other showed the opposite [68]. On the other hand, infant feeding is also important to develop GM because mother milk is not sterile and is the first bacteria to colonize the gut [69]. Breast milk is a source of probiotics and other bacteria [71] containing more than 700 species [70]. The median bacterial load is 106 bacterial cells/Ml [71]. Streptococciand Staphylococciare predominant bacterial genera in human milk [69]. Weissella, Leuconostoc, Staphylococcus, Streptococcus, and Lactococcusare predominant in colostrum and are thought to modify the lactation to increase Veillonella, Leptotrichia, and Prevotellafor over 6 months [71]. In this line, milk from obese mothers contains less-diverse bacteria than normal-weight mothers and has pro-inflammatory properties [72, 73, 74]. Another import issue is the infection of virus or bacteria pathogens. For instance, Clostridium difficilepatients and asymptomatic carriers with the use of 16S ribosomal RNA gene pyrosequencing found that both had reduced microbial richness, diversity, and dysbiosis state compared with healthy subjects [75]. Gut microbiota transplants can help to increase the richness and diversity of GM [76]. For example, clearance of hepatitis B virus infection requires the reestablishment of the gut microbiota. Drugs also affect the microbiome including the drugs used to treat DM2 [77]. But also in the opposite direction. Broad-spectrum antibiotics reduce bacterial diversity and provoke the augmentation of some species like opportunistic pathogens [78], predisposing to inflammatory bowel disease [79]. Clindamycinproduces a prolonged effect of modifying the microbiome in infants [80]. Studies in both mice and humans have found that the use of antibiotics early in life could promote obesity later in life, mediated by the alteration of the gut microbiota [81]. In the same line, antibiotics can reduce body weight and increase insulin sensitivity [82]. Berberineis recognized for its antidiabetic effect by modulating the gut microbiota and diminishing glucose and insulin resistance [83]. Metformin increases the insulin sensitivity in fat cells and hepatocytes and also reduces the overproduction of glucose in hepatocytes. Recent studies showed that metformin alters the GM [84, 85]. In obese mice, metformin caused the increase of mucin-degrading Akkermansia[85]. In human GM, altered gut microbiota can be the cause of common metformin side effects and could have a role in drug efficacy. There is a link between high-calorie diets contributing to obesity and DM2 and GM [55]. Dietary changes can result in substantial and rapid changes in the GM [86]. High-fat diet reduces the α diversity in GM. For instance, A. muciniphiladecreased in obese mice and DM2, and it can be normalized by prebiotic consumption [62]. Treatments with A. muciniphilareduced fat mass, inflammation, and insulin resistance induced/caused by high-fat diet [62]. An enterotype is a classification of living organisms based on their bacteriological ecosystem in the gut microbiome. Changes in GM enterotypes were strongly associated with long-term diets, Bacteroideswith protein and animal fat, and Prevotellawith carbohydrates; gut microbiota composition depends on diseases and long-term dietary interventions. GM alterations can be observed within 24 h after high-fat and low-fiber or low-fat and high-fiber diet [87]. Type 1 is characterized by high levels of Bacteroides, type 2 has few Bacteroidesbut Prevotellaare common, and type 3 has high levels of Ruminococcus[18].

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3. Metagenomic, metatranscriptomic, metaproteomic, and metabolomic approaches to mimic the gut ecosystem

Metagenomics is used to study differences in microbiome composition having diseases and compared with healthy people. Recently a technique was developed (Ecemble; enzyme classification using ensemble approach) to predict enzymes from protein sequences in gut microbiome from metagenomic samples and study the role of GM in metabolism; 48 pathways having at least one bacteria-encoded enzyme were found [88]. The carbohydrate active enzymes are important due to their role in dietary fiber and non-absorbed carbohydrate metabolism; 81 families of glycoside hydrolases have been identified. On the other hand, single-cell genomics uses isolated colonies to shotgun sequencing and put in phylogenetic context to complement metagenomic analysis. Is important to note that the presence of a gene does not mean it amounts to their expression; in this sense, metatranscriptomics, metaproteomics, and metabonomics are needed. Metatranscriptomics involves the generation of cDNA by reverse transcription and permits to identify noncoding RNAs and small RNAs that control quorum sensing and stress response [89]. Metatranscriptomics of fecal microbiome analysis of the 16S rRNA transcripts showed Firmicutes(49%) and Bacteroidetes(31%) are the main source of RNA and smaller proportion of Proteobacteria(3.7%), Actinobacteria(0.4%), and Lentisphaerae(0.2%) and Lachnospiraceaeand Ruminococcaceaeare the major proportion of Firmicutes, whereas Bacteroidaceae, Prevotellaceae,and Rikenellaceaefor Bacteroidetes phylum[90]. Other transcripts were compared with COG database to obtain a functional distribution. Results showed similar behavior for carbohydrate transport, energy production, and synthesis of cellular components. Nevertheless acid and lipid metabolism, motibily, and secondary metabolite biosynthesis were underregulated. Unfortunately, short half time of bacteria RNA makes the detection of all RNAs in fecal samples difficult. Metaproteomics permits to determine gene translation and post-transductional modifications and permits to classify microorganism to a specific catalytic function [91, 92]. Temporal stability of the fecal metaproteome was assessed, and it was determined that glutamate dehydrogenase showed high level of redundancy in Lachnospiraceae, Bacteroidaceae, Ruminococcaceae, and Bifidobacteriaceae. Ten percent of total proteome is involved to ABC sugar transport and glycolytic enzymes; the main functional categories were metabolism of carbohydrates, nucleotides, energy, amino acids, and cofactors and vitamins (especially B12 and folic acid) [87]. Finally, metabolomic approach allows to determine low-molecular-weight compounds in fecal sample and can be influenced by environmental inputs and metabolic interactions between host and environment. For example, SCFA content in the gut can be modified by diet; after that, absorption from the gut initiates the metabolism of the host and results in downstream metabolic perturbations and the generation of microbial-host co-metabolites [93]. For instance, intake of choline (meat and eggs) can form trimethylamine and dimethylamine by GM, trimethylamine is toxic and should be converted to trimethylamine-N-oxide (TMAO), and the latter is an electron acceptor for anaerobic metabolism of E. coliand is implicated in cardiovascular disease (CVD) [94, 95, 96, 97, 98]. Genomic analyses of the GM of subjects suffering from DM2 allowed to identify bacterial genes that are differentially expressed in those subjects; these changes in the gene expression of microbiome are related to the metabolic dysfunction and inflammation that these patients suffer from [99]. Bacterial genes including Clostridialessp. SS3/4, Faecalibacterium prausnitzii, Roseburia intestinalis, and Roseburia inulinivoransare decreased in patients with DM2, whereas genes corresponding to Bacteroidessp., Clostridium hathewayi, Clostridium ramosum, Clostridium symbiosum, and Eggerthella lenta, are increased in these subjects [100]. Functional analyses suggest enriched genes in samples of DM2 patients are involved in plasmatic membrane sugar transport, branched-chain amino acids transport, methane metabolism, xenobiotic degradation and metabolism, biosynthesis of hydrogen sulfide, and oxidative stress. In contrast, decreased genes are related to functions such as chemotaxis, flagellum assembly, butyrate biosynthesis, and the metabolism of cofactors and vitamins [100]. The depletion of bacterial strains producing butyrate in patients with DM2 may be related to the ability of this fatty acid to increase secretion of peptide similar to glucagon type 1 (GLP1) and peptide YY, whose function is to promote intestinal gluconeogenesis, which leads to a better control of glucose homeostasis and cellular energy (Figure 1) [101, 102].

Figure 1.

Changes in the composition of the gut microbiome are associated with an increased risk of DM2: In patients with DM2, the intestinal dysbiosis causes a decrease of short-chain fatty acid content, molecules that stimulate the secretion of peptide similar to glucagon type 1 (GLP1) and YY peptide by intestinal cells, proteins that control glucose homeostasis and regulate the intake of nutrients in intestinal cells.

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4. Nutrigenomics and the microbiome

In most chronic pathologies, environmental and genetic factors are involved because of a polygenic behavior. Recent research investigate the mechanisms involved in the dysfunction of a healthy phenotype to another with chronic dysfunction, explaining how gene expression and dietary components regulate genetic information. Nutrigenomics involves understanding how diet components affect gene expression, meaning which genes are induced and which are repressed against a particular nutrient [103]. Chronic diseases, such as obesity, DM2, and cancer, are expressed from complex polygenic reactions with the environment. The most influential environmental interaction in the development of these diseases is given by the consumed nutrients. Evidence of gene-nutrient interaction is substantially demonstrated, estimating that a balanced healthy nutrition reduces the overall incidence of cancer by 35%. On the other hand, polymorphisms that predispose to certain diseases have been identified under unhealthy diet; this is the case of DM2, osteoporosis, vascular disease, and others, which can be prevented by modifying the diet [104]. The regulation of gene expression is performed through specific proteins that interact with DNA through posttranscriptional or posttranslational modifications. Regulation can occur at the level of mRNA during splicing; it would result from the interaction of certain molecules with specific nutrients, whose result could be potentially preventive [104]. The diet and the GM composition have also been associated with different characteristics of the metabolic syndrome (MS) (obesity, DM2, cardiovascular diseases, and nonalcoholic steatohepatitis). Increasing evidence suggests that the GM contributes to the onset of its characteristic low-grade inflammation, through mechanisms associated with intestinal barrier dysfunction [105]. The GM of an obese person in comparison with a normal-weight person presents a greater percentage of Firmicutesand smaller percentage of Bacteroidetes, causing dysbiosis in most of the obese and/or diabetic patients (Figure 2). Due to its physiological impact, GM is now recognized as an organ and can be transplanted from one individual to another [106]. Recent evidence suggests that the intestinal microbiome affects nutrient acquisition, energy storage, and metabolic pathways of the host [10]. Bacteroideteshave been shown to easily assimilate dietary carbohydrates. In a study in mice lacking Toll-like receptors (TLRs), which are receptors that recognize important patterns of inflammation and immunity, it is shown that these mice present hyperphagia and obesity and develop metabolic syndrome, when intestinal microbiome of these mice is transplanted to germ-free mice with the TLR5 gene intact; they also developed the Bifidobacteriumstrain similar to the metabolic syndrome, suggesting that the GM was the determinant factor of this disease phenotype [107]. Another study showed that mice deficient in TLR2 presented greater amount of Firmicutesand Actinobacteriaand smaller amount of the genus Bifidobacterium[10, 107]. Administration of an antibiotic cocktail eliminated many of the Firmicutesand resulted in improved insulin action and increased glucose tolerance [107].

Figure 2.

The GM of an obese person in comparison with a normal-weight person presents a greater percentage ofFirmicutesand smaller percentage ofBacteroidetes, causing dysbiosis in most of the obese and/or diabetic patients.

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5. New brain gut axis, serotonin production, and its relationship with DM

Some studies have shown the clear connection between immune system and neuroendocrine system highlighting the effect of the GM, which allows a new focus for research on the so-called brain gut axis [12]. The mechanisms of enteric neuroprotection were recently been described; enteric neurons have one of their own signaling molecules to this propose. In the adult intestine, serotonin acts like a paracrine signal hormone and neurotransmitter [108]. However, it is also a neuronal growth factor during development and a major promoter of mucosal epithelium growth by stimulating submucosal cholinergic neurons [109]. This neurotransmitter may even stimulate neurogenesis in the growing enteric nervous system, and in adults, this hormone promotes neurogenesis and neuroprotection through the activation of 5-HT4 receptors. It is interesting to mention that mucosal serotonin is not a direct neuroprotective agent to enteric neurons. Mucosal serotonin behaves as a pro-inflammatory factor, and this ability constitutes a threat to neuronal survival [110]. According to these facts, this hormone has received the name of “sword and shield” of the intestine. Mucosal serotonin is the pro-inflammatory “sword,” while neuronal serotonin is the anti-inflammatory “shield” [111]. It has been demonstrate that DM1 is related with an excess of pro-inflammatory cytokines close to B pancreatic cells, while DM2 is caused due to an excess of pro-inflammatory cytokines in systemic circulation, which could be related to intestinal serotonin secretion. Gershon et al. have established that neurodegenerative/neuroprotective actions of 5-HT4 receptor complex may be vital for the normal enteric nervous system’s maintenance [12]. Bianco et al. show the mechanisms through the 5-HT4 agonist participate in protection of enteric neurons against oxidation [112]. This sentence is relevant because the enteric neurons lost during inflammation strongly depend on the released forces throughout oxidative stress (Figure 3) [113, 114]. Bhattarai et al. suggest that the “sword” function is manipulated by the microbiome [115]. The intestine has a variety of regulatory mechanisms that contrast the actions of 5-HT for transport maintenance; conversely, Chang and Rao incorporate the GM as a homeostasis influence factor evading the alteration of 5-HT during diarrhea and intestine inflammatory diseases. Recently, observations have been made about the possible mechanisms by which dysbiosis of the microbiome alters the function of 5-HT [14]. The HIM plays a key role in enhancing the serotonin biosynthesis in enterochromaffin cells. This increased serotonin content stimulates the intrinsic projections of the primary afferent neurons and in turn activates interneurons, which activate the peristaltic reflex promoting intestinal motility and besides accelerate the gastric emptying, which is augmented when 5-HT receptor is antagonized [111]. The intestinal speedup promotes the production of several gastrointestinal hormone secretions that mediate glucose metabolism, unleashing insulin synthesis such as β-cell proliferation or glucagon release [116]. On the other hand, it has been shown that serotonin participates during lactate signaling cascade to stimulate β-cell proliferation [117]. Under this premise, there is a hypothesis of a possible relation between the alteration of the GM by serotonin and the metabolic pathway that generates insulin resistance, and it could be considered as one of the possible etiopathogenic factors of DM2.

Figure 3.

The hypothesis of the alteration of the GM by serotonin and the metabolic pathway that generates insulin resistance it could be considered as one of the possible etiopathogenic factors of DM2.

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6. Conclusions

The interaction of the diet in the modification of HIM, in addition to its potential effect on the microbiome and the development of DM, has been positively affected by the evolution of nutrigenomics as a science discipline. Diets rich in carbohydrates and fats, favor the development of bacteria capable of causing intestinal dysbiosis of low degree of inflammation; affecting the permeability of the intestinal mucosa. It has been shown that intestinal production of serotonin by enterochromaffin cells participates in the cascade of stimulation of the proliferation of pancreatic β cells, via the lactate pathway, suggesting the hypothesis of a possible link between serotonin, insulin resistance, and DM2. Finally, the advances reflected in this chapter demonstrate a small part of the future projection around nutrigenomics and its effect on the composition of the microbiome in diabetic subjects; it would be interesting to carry out more specific studies of this area, associating it with the effect of satiety and the alteration of the microbiome in patients with obesity and/or metabolic syndrome, as an integral part in the prevention of DM2.

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Acknowledgments

This work team is composed of Carrera de Nutrición y Dietética, Universidad Andres Bello, Concepción, Chile; Centro de Investigaciones Endocrino - Metabólicas. Facultad de Medicina, Universidad del Zulia. Maracaibo - Venezuela. Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla, Colombia. Facultad de Ciencias para el Cuidado de la Salud, Escuela de Nutrición y Dietética, Universidad San Sebastián, Santiago, Chile; Departamento de Salud Pública, Universidad Católica de la Santísima Concepción, Concepción, Chile; and Hospital 12 de Octubre, Madrid, España.

References

  1. 1.Unnikrishnan R, Pradeepa R, Joshi SR, Mohan V. Type 2 diabetes: Demystifying the global epidemic. Diabetes. 2017;66(6):1432-1442. DOI: 10.2337/db16-0766
  2. 2.The 7th Edition of the Diabetes Atlas. International Diabetes Foundation; International Diabetes Federation (IDF) 2015. Available from: idf@idf.org/www.idf.org[Accessed: September 29, 2017]
  3. 3.Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011;140(6):1729-1737. DOI: 10.1053/j.gastro.2011.02.012
  4. 4.Florez JC. The pharmacogenetics of metformin. Diabetologia. 2017 [Epub ahead of print]. DOI: 10.1007/s00125-017-4335-y
  5. 5.Khan S, Jena G. The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: Experimental evidence for therapeutic intervention. Epigenomics. 2015;7(4):669-680. DOI: 10.2217/epi.15.20
  6. 6.Brunkwall L, Orho-Melander M. The gut microbiome as a target for prevention and treatment of hyperglycaemia in type 2 diabetes: From current human evidence to future possibilities. Diabetologia. 2017;60(6):943-951. DOI: 10.1007/s00125-017-4278-3
  7. 7.Chen Y, Li Z, Hu S, Zhang J, Wu J, Shao N, Bo X, Ni M, Ying X. Gut metagenomes of type 2 diabetic patients have characteristic single-nucleotide polymorphism distribution in Bacteroides coprocola. Microbiome. 2017;5(1):15. DOI: 10.1186/s40168-017-0232-3
  8. 8.De Groot F, de Clercq N. Fecal microbiome transplantation in metabolic syndrome: History, present and future. Gut Microbes. 2017;8(3):253-267. DOI: 10.1080/19490976.2017.1293224
  9. 9.Devaraj S, Hemarajata P, Versalovic J. La microbiome intestinal humana y el metabolismo corporal: Implicaciones con la obesidad y la diabetes. Acta Bioquímica Clínica Latino-americana. 2013;47(2):421-434. Available from:www.scielo.org.ar/scielo.php?script=sci_arttext&pid=S0325-29572013000200019&lng=es[Accessed August 28, 2017]
  10. 10.Remely M, Aumueller E, Jahn D, Hippe B, Brath H, Haslberger AG. Microbiome and epigenetic regulation of inflammatory mediators in type 2 diabetes and obesity. Beneficial Microbes. 2014;5(1):33-43. DOI: 10.3920/BM2013.006
  11. 11.Berni CR, Di Costanzo M, Leone L. The epigenetic effects of butyrate: Potential therapeutic implications for clinical practice. Clinical Epigenetics. 2012;4:4. DOI: 10.1186/1868-7083-4-4
  12. 12.Gershon MD. 5-HT4-mediated neuroprotection: A new therapeutic modality on the way? American Journal of Physiology. Gastrointestinal and Liver Physiology. 2016;310:G766-G767. DOI: 10.1152/ajpgi.00120.2016
  13. 13.Singhal M, Manzella C, Soni V, Alrefai WA, Saksena S, Hecht GA, Dudeja PK, Gill RK. Role of SHP2 protein tyrosine phosphatase in SERT inhibition by enteropathogenicE. coli. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2017;312(5):G443-G449. DOI: 10.1152/ajpgi.00011.2017
  14. 14.Chang EB, Rao MC. A new role for microbiome? Dulling the thrust of serotonin and 5HT3 signaling cascade. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2017;313(1):G14-G15. DOI: 10.1152/ajpgi.00166.2017
  15. 15.Woo V, Alenghat T. Host-microbiome interactions: Epigenomic regulation. Current Opinion in Immunology. 2017;16(44):52-60. DOI: 10.1016/j.coi.2016.12.001
  16. 16.Malcomson FC, Willis ND, McCallum I, Xie L, et al. Effects of supplementation with nondigestible carbohydrates on fecal calprotectin and on epigenetic regulation of SFRP1 expression in the large-bowel mucosa of healthy individuals. The American Journal of Clinical Nutrition. 2017;105:400-410. DOI: 10.3945/ajcn.116.135657
  17. 17.Jayamuthunagai J, Srisowmeya G, Chakravarthy M, Gautam P. D-Tagatose production by permeabilized and immobilized lactobacillus plantarum using whey permeate. Bioresource Technology. 2017;235:250-255. DOI: 10.1016/j.biortech.2017.03.123
  18. 18.Rajilić-Stojanović M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiome. FEMS Microbiology Reviews. 2014;38(5):996-1047. DOI: 10.1111/1574-6976.12075
  19. 19.Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104-107. DOI: 10.1038/nature08780
  20. 20.Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, et al. Host-gut microbiota metabolic interactions. Science. 2012;336(6086):1262-1267. DOI: 10.1126/science.1223813
  21. 21.Macfarlane GT, Gibson GR, Cummings JH. Comparison of fermentation reactions in different regions of the human colon. The Journal of Applied Bacteriology. 1992;72(1):57-64
  22. 22.Steliou K, Boosalis MS, Perrine SP, Sangerman J, Faller DV. Butyrate histone deacetylase inhibitors. Bioresources. 2012;1(4):192-198. DOI: 10.1089/biores.2012.0223
  23. 23.De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, et al. Microbiome-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014;156(1-2):84-96. DOI: 10.1016/j.cell.2013.12.016
  24. 24.Duncan SH, Holtrop G, Lobley GE, Calder AG, Stewart CS, Flint HJ. Contribution of acetate to butyrate formation by human faecal bacteria. The British Journal of Nutrition. 2004;91(6):915
  25. 25.Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nature Communications. 2014;5. DOI: 10.1038/ncomms4611
  26. 26.Belenguer A, Duncan SH, Calder AG, Holtrop G, Louis P, Lobley GE, et al. Two routes of metabolic cross-feeding between Bifidobacterium adolescentis and butyrate-producing anaerobes from the human gut. Applied and Environmental Microbiology. 2006;72(5):3593-3599. DOI: 10.1128/AEM.72.5.3593-3599.2006
  27. 27.Falony G, Vlachou A, Verbrugghe K, De Vuyst L. Cross-feeding between Bifidobacterium longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on oligofructose. Applied and Environmental Microbiology. 2006;72(12):7835-7841. DOI: 10.1128/AEM.01296-06
  28. 28.Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. MBio. 2014;5(2). DOI: 10.1128/mBio.00889-14
  29. 29.Louis P, Duncan SH, McCrae SI, Millar J, Jackson MS, Flint HJ. Restricted distribution of the butyrate kinase pathway among butyrate-producing bacteria from the human Colon. Journal of Bacteriology. 2004;186(7):2099-2106
  30. 30.Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiome. Environmental Microbiology. 2017;19:29-41. DOI: 10.1111/1462-2920.13589
  31. 31.Scott KP, Martin JC, Campbell G, Mayer CD, Flint HJ. Whole-genome transcription profiling reveals genes up-regulated by growth on fucose in the human gut bacterium “Roseburia inulinivorans”. Journal of Bacteriology. 2006;188(12):4340-4349. DOI: 10.1128/JB.00137-06
  32. 32.Hooper LV, Xu J, Falk PG, Midtvedt T, Gordon JI. A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proceedings of the National Academy of Sciences. 1999;96(17):9833-9838
  33. 33.Duncan SH, Belenguer A, Holtrop G, Johnstone AM, Flint HJ, Lobley GE. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Applied and Environmental Microbiology. 2007;73(4):1073-1078. DOI: 10.1128/AEM.02340-06
  34. 34.François IEJA, Lescroart O, Veraverbeke WS, Marzorati M, Possemiers S, Evenepoel P, et al. Effects of a wheat bran extract containing arabinoxylan oligosaccharides on gastrointestinal health parameters in healthy adult human volunteers: A double-blind, randomised, placebo-controlled, cross-over trial. The British Journal of Nutrition. 2012;108(12):2229-2242. DOI: 10.1017/S0007114512000372
  35. 35.Halmos EP, Christophersen CT, Bird AR, Shepherd SJ, Gibson PR, Muir JG. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut. 2015;64(1):93-100. DOI: 10.1136/gutjnl-2014-307264
  36. 36.Cummings JH, Macfarlane GT. The control and consequences of bacterial fermentation in the human colon. Journal of Applied Bacteriology. 1991;70:443-459
  37. 37.Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology. 1992;102(4 Pt 1):1269-1277
  38. 38.Gibson GR. Physiology and ecology of the sulphate-reducing bacteria. The Journal of Applied Bacteriology. 1990;69(6):769-797
  39. 39.Suarez F, Furne J, Springfield J, Levitt M. Insights into human colonic physiology obtained from the study of flatus composition. The American Journal of Physiology. 1997;272(5 Pt 1):G1028-G1033
  40. 40.Macfarlane GT, Cummings JH, Allison C. Protein degradation by human intestinal bacteria. Journal of General Microbiology. 1986;132(6):1647-1656
  41. 41.Smith EA, Macfarlane GT. Enumeration of human colonic bacteria producing phenolic and indolic compounds: Effects of pH, carbohydrate availability and retention time on dissimilatory aromatic amino acid metabolism. The Journal of Applied Bacteriology. 1996;81(3):288-302
  42. 42.Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, et al. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Molecular Nutrition & Food Research. 2013;57(3):523-535. DOI: 10.1002/mnfr.201200594
  43. 43.Hill MJ. Intestinal flora and endogenous vitamin synthesis. European Journal of Cancer Prevention. 1997;6(1):S43-S45
  44. 44.Frick PG, Riedler G, Brögli H. Dose response and minimal daily requirement for vitamin K in man. Journal of Applied Physiology. American Physiological Society. 1967;23(3):387-389
  45. 45.Lockyer S, Corona G, Yaqoob P, Spencer JPE, Rowland I. Secoiridoids delivered as olive leaf extract induce acute improvements in human vascular function and reduction of an inflammatory cytokine: A randomised, double-blind, placebo-controlled, cross-over trial. The British Journal of Nutrition. 2015;114(1):75-83. DOI: 10.1017/S0007114515001269
  46. 46.Magnúsdóttir S, Ravcheev D, De Crécy-Lagard V, Thiele I. Systematic genome assessment of B-vitamin biosynthesis suggests cooperation among gut microbes. Frontiers in Genetics. 2015;6:148. DOI: 10.3389/fgene.2015.00148
  47. 47.Kandell RL, Bernstein C. Bile salt/acid induction of DNA damage in bacterial and mammalian cells: Implications for colon cancer. Nutrition and Cancer. 1991;16(3-4):227-238
  48. 48.Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. Journal of Bacteriology. 2006;188(5):1979-1986. DOI: 10.1128/JB.188.5.1979-1986.2006
  49. 49.Jones BV, Begley M, Hill C, Gahan CGM, Marchesi JR. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(36):13580-13585. DOI: 10.1073/pnas.0804437105
  50. 50.Van Eldere J, Celis P, De Pauw G, Lesaffre E, Eyssen H. Tauroconjugation of cholic acid stimulates 7 alpha-dehydroxylation by fecal bacteria. Applied and Environmental Microbiology. 1996;62(2):656-661
  51. 51.Eloranta JJ, Kullak-Ublick G. The role of FXR in disorders of bile acid homeostasis. Physiology (Bethesda, Md.). 2008;23:286-295. DOI: 10.1152/physiol.00020.2008
  52. 52.Hirokane H, Nakahara M, Tachibana S, Shimizu M, Sato R. Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4. The Journal of Biological Chemistry. 2004;279(44):45685-45692. DOI: 10.1074/jbc.M404255200
  53. 53.Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: Food sources and bioavailability. American Journal of Clinical Nutrition. 2004;79:727-747
  54. 54.Duda-Chodak A, Tarko T, Satora P, Sroka P. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiome: A review. European Journal of Nutrition. 2015;54:325-341. DOI: 10.1007/s00394-015-0852-y
  55. 55.Marín L, Miguélez EM, Villar CJ, Lombó F. Bioavailability of dietary polyphenols and gut microbiota metabolism: Antimicrobial properties. BioMed Research International. 2015;905215. DOI: 10.1155/2015/905215
  56. 56.Santiago S, Sayón-Orea C, Babio N, Ruiz-Canela M, Martí A, Corella D, et al. Yogurt consumption and abdominal obesity reversion in the PREDIMED study. Nutrition, Metabolism, and Cardiovascular Diseases. 2016;26(6):468-475. DOI: 10.1016/j.numecd.2015.11.012
  57. 57.Gómez-Ambrosi J, Silva C, Galofré JC, Escalada J, Santos S, Gil MJ, et al. Body adiposity and type 2 diabetes: Increased risk with a high body fat percentage even having a normal BMI. Obesity. 2011;19(7):1439-1444. DOI: 10.1038/oby.2011.36
  58. 58.Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences. 2013;110(22):9066-9071. DOI: 10.1073/pnas.1219451110
  59. 59.Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789-799. DOI: 10.1016/j.cell.2014.09.053
  60. 60.Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027-1031. DOI: 10.1038/nature05414
  61. 61.Wu GD, Chen J, Hoffmann C, Bittinger K, Chen Y-Y, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334(6052):105-108. DOI: 10.1126/science.1208344
  62. 62.Koren O, Goodrich JK, Cullender TC, Spor A, Laitinen K, Kling Bäckhed H, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell. 2012;150(3):470-480. DOI: 10.1016/j.cell.2012.07.008
  63. 63.Cani PD, Possemiers S, Van de Wiele T, Guiot Y, Everard A, Rottier O, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091-1103. DOI: 10.1136/gut.2008.165886
  64. 64.Remely M, Aumueller E, Merold C, Dworzak S, Hippe B, Zanner J, et al. Effects of short chain fatty acid producing bacteria on epigenetic regulation of FFAR3 in type 2 diabetes and obesity. Gene. 2014;537(1):85-92. DOI: 10.1016/j.gene.2013.11.081
  65. 65.Alvarez-Curto E, Milligan G. Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Biochemical Pharmacology. 2016;114:3-13. DOI: 10.1016/j.bcp.2016.03.017
  66. 66.Kulas T, Bursac D, Zegarac Z, Planinic-Rados G, Hrgovic Z. New views on cesarean section, its possible complications and long-term consequences for children’s health. Medical Archives. 2013;67(6):460-463. DOI: 10.5455/medarh.2013.67.460-463
  67. 67.Portela DS, Vieira TO, Matos SM, de Oliveira NF, Vieira GO. Maternal obesity, environmental factors, cesarean delivery and breastfeeding as determinants of overweight and obesity in children: Results from a cohort. BMC Pregnancy and Childbirth. 2015;15:94. DOI: 10.1186/s12884-015-0518-z
  68. 68.Kuhle S, Tong OS, Woolcott CG. Association between caesarean section and childhood obesity: A systematic review and meta-analysis. Obesity Reviews. 2015;16(4):295-303. DOI: 10.1111/obr.12267
  69. 69.Rutayisire E, Wu X, Huang K, Tao S, Chen Y, Tao F. Cesarean section may increase the risk of both overweight and obesity in preschool children. BMC Pregnancy and Child-birth. 2016;16(1):338. DOI: 10.1186/s12884-016-1131-5
  70. 70.Flemming K, Woolcott CG, Allen AC, Veugelers PJ, Kuhle S. The association between caesarean section and childhood obesity revisited: A cohort study. Archives of Disease in Childhood. 2013;98(7):526-532. DOI: 10.1136/archdischild-2012-303459
  71. 71.Brockow I, Zutavern A, Franke K, Schaaf B, von Berg A, Kraemer U, et al. Influences of lifestyle-related factors on the immune system and the development of allergies in childhood (LISA). Design and results to date of a prospective birth cohort study. Monatsschrift Kinderheilkd. 2008;156:249-255. DOI: 10.1007/s00112-007-1527-4
  72. 72.Fitzstevens JL, Smith KC, Hagadorn JI, Caimano MJ, Matson AP, Brownell EA. Systematic review of the human milk microbiome. Nutrition in Clinical Practice. 2016. DOI: 10.1177/0884533616670150
  73. 73.Muegge BD, Kuczynski J, Knights D, Clemente JC, Gonzalez A, Fontana L, et al. Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science. 2011;332(6032):970-974. DOI: 10.1126/science.1198719
  74. 74.Panagos PG, Vishwanathan R, Penfield-Cyr A, Matthan NR, Shivappa N, Wirth MD, et al. Breastmilk from obese mothers has pro-inflammatory properties and decreased neuroprotective factors. Journal of Perinatology. 2016;36(4):284-290. DOI: 10.1038/jp.2015.199
  75. 75.Hanson LA, Ahlstedt S, Andersson B, Cruz JR, Dahlgren U, Fallstrom SP, et al. The immune response of the mammary gland and its significance for the neonate. Annals of Allergy. 1984;53(6 Pt 2):576-582
  76. 76.Seekatz AM, Young VB. Clostridium difficile and the microbiome. Journal of Clinical Investigation. 2014;124(10):4182-4189. DOI: 10.1172/JCI72336
  77. 77.Blanchi J, Goret J, Megraud F. Clostridium difficile infection: A model for disruption of the gut microbiota equilibrium. Digestive Diseases. 2016;34(3):217-220. DOI: 10.1159/000443355
  78. 78.Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiome transplantation for relapsingClostridium difficileinfection. Journal of the American Medical Association. 2014;312(17):1772-1778. DOI: 10.1001/jama.2014.13875
  79. 79.Bashan A, Gibson TE, Friedman J, Carey VJ, Weiss ST, Hohmann EL, et al. Universality of human microbial dynamics. Nature. 2016;534(7606):259-262. DOI: 10.1038/nature18301
  80. 80.Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. The American Journal of Gastroenterology. 2010;105(12):2687-2692. DOI: 10.1038/ajg.2010.398
  81. 81.Johnson MK, Thomson AJ, Richards AJ, Peterson J, Robinson AE, Ramsay RR, et al. Characterization of the Fe-S cluster in aconitase using low temperature magnetic circular dichroism spectroscopy. The Journal of Biological Chemistry. 1984;259(4):2274-2282
  82. 82.Fujisaka S, Ussar S, Clish C, Devkota S, Dreyfuss JM, Sakaguchi M, et al. Antibiotic effects on gut microbiota and metabolism are host dependent. The Journal of Clinical Investigation. 2016;126(12):4430-4443. DOI: 10.1172/JCI86674
  83. 83.Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. The FASEB Journal. 2008;22(7):2416-2426. DOI: 10.1096/fj.07-102723
  84. 84.Chou C, Membrez M, Blancher F. Gut decontamination with norfloxacin and ampicillin enhances insulin sensitivity in mice. Nestle Nutrition Workshop Series: Pediatric Program. 2008;62:127-137. DOI: 10.1159/000146256. Discussion 137-40
  85. 85.Han J, Lin H, Huang W. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Medical Science Monitor. 2011;17(7):RA164-RA167
  86. 86.Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut microbiota. Pharmacological Research. 2013;69(1):52-60. DOI: 10.1016/j.phrs.2012.10.020
  87. 87.Graf D, Di Cagno R, Fåk F, Flint HJ, Nyman M, Saarela M, et al. Contribution of diet to the composition of the human gut microbiota. Microbial Ecology in Health and Disease. 2015;26:26164. DOI: 10.3402/mehd.v26.26164
  88. 88.Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS, Sonnenburg JL. Diet-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529(7585):212-215. DOI: 10.1038/nature16504
  89. 89.David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-563. DOI: 10.1038/nature12820
  90. 90.Wei X, Yan X, Zou D, Yang Z, Wang X, Liu W, et al. Abnormal fecal microbiome community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach. BMC Gastroenterology. 2013;13(1):175. DOI: 10.1186/1471-230X-13-175
  91. 91.Mohammed A, Guda C. Application of a hierarchical enzyme classification method reveals the role of gut microbiome in human metabolism. BMC Genomics. 2015;16(Suppl 7):S16. DOI: 10.1186/1471-2164-16-S7-S16
  92. 92.Abram F. Systems-based approaches to unravel multi-species microbial community functioning. Computational and Structural Biotechnology Journal. 2015;3(13):24-32. DOI: 10.1016/j.csbj.2014.11.009
  93. 93.Gosalbes MJ, Durbán A, Pignatelli M, Abellan JJ, Jiménez-Hernández N, Pérez-Cobas AE, et al. Metatranscriptomic approach to analyze the functional human gut microbiota. PLoS One. 2011;6(3). DOI: 10.1371/journal.pone.0017447
  94. 94.Young JC, Pan C, Adams RM, Brooks B, Banfield JF, Morowitz MJ, et al. Metaproteomics reveals functional shifts in microbial and human proteins during a preterm infant gut colonization case. Proteomics. 2015;15(20):3463-3473. DOI: 10.1002/pmic.201400563
  95. 95.Lichtman JS, Marcobal A, Sonnenburg JL, Elias JE. Host-centric proteomics of stool: A novel strategy focused on intestinal responses to the gut microbiota. Molecular & Cellular Proteomics. 2013;12:3310-3318
  96. 96.Sharon I, Morowitz MJ, Thomas BC, Costello EK. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Research. 2013;23:111-120
  97. 97.Costello EK, Carlisle EM, Bik EM, Morowitz MJ, Relman DA. Microbiome assembly across multiple body sites in low-birthweight infants. Molecular & Cellular Proteomics. 2013;4:e00782-e00713
  98. 98.Cilieborg MS, Boye M, Sangild PT. Bacterial colonization and gut development in preterm neonates. Early Human Development. 2012;88:S41-S49
  99. 99.Qin J et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60. DOI: 10.1038/nature11450
  100. 100.Zhou J et al. Peptide YY and proglucagon mRNA expression patterns and regulation in the ut. Obesity. 2006;14:683-689. DOI: 10.1038/oby.2006.77
  101. 101.Karlsson FH et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498:99-103. DOI: 10.1038/nature12198
  102. 102.Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nature Reviews. Microbiology. 2014;12:661-672. DOI: 10.1038/nrmicro3344
  103. 103.Pisabarro R. Nutrigenética y nutrigenómica: la revolución Nutrigenética y nutrigenómica: la revoluciónNutrigenética y nutrigenómica: la revolución sanitaria del nuevo milenio. Implicancias clínicas sanitaria del nuevo milenio. Implicancias clínicassanitaria del nuevo. Revista Médica del Uruguay. 2006;22(Revisión):100-107
  104. 104.Sanhueza J, Valenzuela A. Artículos de actualización nutrigenómica: Revelando los aspectos moleculares de una nutrición personalizada nutrigenomics: Revealing molecular aspects of a personalized nutrition. Revista Chilena De Nutricion. 2012;39(1):71-85
  105. 105.Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Practice & Research. Clinical Gastroenterology. 2013;27:73-83. DOI: 10.1016/j.bpg.2013.03.007
  106. 106.Ariza-Andraca R, García-Ronquillo M. El microbioma humano. Su papel en la salud y en algunas enfermedades. Cir Cir. 2016;84(Supl 1):31-35
  107. 107.Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, et al. Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biology. 2011;9(12):e1001212. DOI: 10.1371/journal.pbio.1001212
  108. 108.Gershon MD. 5-Hydroxytryptamine (serotonin) in the gastrointestinal tract. Current Opinion in Endocrinology, Diabetes, and Obesity. 2013;20(1):14-21. DOI: 10.1097/MED.0b013e32835bc703
  109. 109.Li Z, Chalazonitis A, Huang YY, Mann JJ, Margolis KG, Yang QM, Kim DO, Cote F, Mallet J, Gershon MD. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. The Journal of Neuroscience. 2011;31:8998-9009. DOI: 10.1523/JNEUROSCI.6684-10.2011
  110. 110.Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD. Role of serotonin in intestinal inflammation: Knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2009;296(3):G685-G695. DOI: 10.1152/ajpgi.90685.2008
  111. 111.Gershon MD. Serotonin is a sword and a shield of the bowel: Serotonin plays offense and defense. Transactions of the American Clinical and Climatological Association. 2012;123:268-280. Discussion 280
  112. 112.Bianco F, Bonora E, Natarajan D, Vargiolu M, Thapar N, Torresan F, Giancola F, et al. Prucalopride exerts neuroprotection in human enteric neurons. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2016;310(10):15, G768-G775. DOI: 10.1152/ajpgi.00036.2016
  113. 113.Brown IA, McClain JL, Watson RE, Patel BA, Gulbransen BD. Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. Cellular and Molecular Gastroenterology and Hepatology. 2016;2:77-91. DOI: 10.1016/j.jcmgh.2015.08.007
  114. 114.Gulbransen BD, Bashashati M, Hirota SA, Gui X, Roberts JA, MacDonald JA, Muruve DA, et al. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine. 2012;18(4):600-604. DOI: 10.1038/nm.2679
  115. 115.Battarai Y, Schmidt BA, Linden DR, Larson ED, Grover M, Beyder A, Farrugia G, Kashyap PC. Human derived gut microbiota modulates colonic secretion in mice by regulating 5-HT3 receptor expression via acetate production. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2017;313(1):G80-G87. DOI: 10.1152/ajpgi.00448.2016
  116. 116.Uranga-Ocio JA. Enteric neuropathy associated to diabetes mellitus. Revista Española de Enfermedades Digestivas. 2015;107(6):366-373
  117. 117.Georgia S, Bhushan A. Pregnancy hormones boost beta cells via serotonin. Nature Medi-cine. 2010;16(7):756-757. DOI: 10.1038/nm0710-756

Written By

Lissé Angarita Dávila, Valmore Bermúdez Pirela, Waldo Díaz, Nadia Reyna Villasmil, Silvana Cisternas León, Ma Cristina Escobar Contreras, Kristian Buhring Bonacich, Samuel Durán Agüero, Paula Carrasco Vergara, Rodrigo Buhring Bonacich, Constanza Bugman, Virginia Céspedes, Marcell Gatica, Marion Guerrero Wyss, Jorge González Casanova and Francisco Valdebenito

Submitted: July 14th, 2017Reviewed: March 5th, 2018Published: July 11th, 2018