**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; *saccharolytic* bacterial 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 prausnitzii* will 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**

**1. Introduction**

12 Diabetes Food Plan

the microbiome into the nutritional treatment [2].

Diabetes *mellitus* type 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/ Bacteroidetes* ratio 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 coli* cause 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

A cross-feeding effect has recently been described, for instance, *Bifidobacterium longum* growing in fructooligosaccharides (FOS) produces a conversion into lactate and promotes the growth of *Eubacterium hallii* that could not grow in the presence of FOS alone and converts it to butyrate [26]. Another example of cross feeding occurs when *Roseburia intestinalis* increases 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 *Bacteroidetes* and *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 inulinivorans* produces butyrate normally, but it can change its gene expression pattern in the presence of fucose producing propionate and propanol [31]. *Ruminococcus obeum* produces acetate, formate, and lactate on glucose growth and also produces propionate in the presence of fucose. *Bacteroides thetaiotaomicron* in 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. rectale* group [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].

and tryptophan can be fermented to phenylpropanoid, phenylacetic acid, and 4-hydroxyphe-

The Microbiome and the Epigenetics of Diabetes Mellitus

http://dx.doi.org/10.5772/intechopen.76201

15

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. *Bacteroidetes* is the phylum with larger B predicted vitamin generators. In the same line, bacteria can complement the biosynthesis of vitamins. In sum, GM

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 Eubacterium* transforms 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 membranebound 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

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

nyl-acetic acid by *Bacteroides*, *Eubacterium hallii*, *and Clostridium bartlettii* [43].

**2.4. Vitamin synthesis and the microbiome**

**2.5. Bile acids and the microbiome**

a downstream effect in metabolic processes.

**2.6. Gut microbiota and diabetes type 2**

can contribute with 25% of total dietary vitamin intake [47].

#### **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 NH<sup>3</sup> , 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 *Bacteroides* and *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 sulfatereducing bacteria (SRB), where *Desulfovibrio* is 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 H2 S), Clostridia, Streptococci, Staphylococci, *Bacillus* and species of *Bacteroides* and *Propionibacterium* as 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].
