**7. Diet-microbiota interactions shape the risk of type 2 diabetes**

Diet represents the main modulator of the composition and metabolism of the gut microbiota. The main macronutrients represented by proteins, carbohydrates and fats have a crucial impact on the microbiome. The role of dietary protein in shaping the microbiota has been described since 1977 when individuals who consumed a diet rich in beef harboured elevated levels of *Bacteroides* and *Clostridia* and low levels of *Bifidobacterium adolescentis* compared to those who had a meatless diet [63]. Several studies have recently used different forms of protein including vegetarian pea protein, whey protein and animal protein (meats, eggs and cheese) and correlated protein consumption with microbial diversity [61]. Conversely, the consumption of animal-based protein positively correlated with the abundance of bile-tolerant anaerobes such as *Alistipes, Bacteroides* and *Bilophila* [64]. Even though it may promote a greater weight loss, a protein-rich diet can also be detrimental. Thus, individuals on a high protein/low carbohydrate diet had a microbiota with diminished levels of *Roseburia* and *Eubacterium rectale* and low levels of butyrate in their feces [65]. Similarly, patients with inflammatory bowel disease (IBD) had a similar microbiota signature, with low levels of *Roseburia* and decreased butyrate levels [66]. In addition, elevated intake of red meat has been linked to elevated levels of the proatherogenic trimethylamine-N-oxide (TMAO) [62]. Animal studies have shown that high protein consumption increases the levels of insulin-like growth factor 1 (IGF-1), which are known to be correlated with a high risk of diabetes and overall mortality. Indeed, proteins of vegetarian origin have been linked to a lower mortality in comparison with animal-derived proteins [67].

Among all the dietary macronutrients, carbohydrates are the most studied. Based on their ability to be degraded enzymatically in the small intestine, carbohydrates are either digestible (i.e., starch and sugars including glucose, lactose, fructose and sucrose) or nondigestible (resistant starch and fibre). Upon degradation, digestible carbohydrates release glucose into the bloodstream and lead to an insulin response [61]. Humans who were fed high levels of glucose, fructose and sucrose in the form of dates had a microbiota enriched in *Bifidobacteria,* and low in *Bacteroides* [72, 73]. Moreover, the addition of lactose to the aforementioned diet replicated the same bacterial shifts but it also decreased the levels of

The Intricate Relationship between Diabetes, Diet and the Gut Microbiota

http://dx.doi.org/10.5772/intechopen.70602

79

Recently, a subject of debate in the field of carbohydrates and their role in shaping the microbiota is represented by the use of artificial sweeteners. Artificial sweeteners such as saccharin, sucralose and aspartame were intended to be a healthier, no-calorie food additive for replacing natural sugar. However, recent work by Suez et al. showed that artificial sweeteners are more prone to induce glucose intolerance than consumption of sucrose or glucose. The effects exhibited by artificial sweeteners were attributed to the induction of microbiota changes characterized by increased abundance of *Bacteroides* and decreased *Lactobacillus reuteri* [75]. Conversely, the use of natural sugars such as fructose, sucrose and glucose promoted microbiota shifts

Unlike digestible carbohydrates, non-indigestible carbohydrates are not digested in the small bowel but rather reach the colon where they undergo fermentation by commensal microbiota leading to SCFAs production such as butyrate, propionate and acetate. Butyrate is an important energy source for intestinal epithelial cells and a modulator of enterocyte differentiation, proliferation and restitution. Loss of microbial producers of SCFA can alter the communication between host epithelium and resident bacteria, thus contributing to the development of colitis. For instance, *F. prausnitz ii* is depleted not only in IBD patients [66]

Dietary fibres are essential for intestinal health and have been designated as prebiotics, that is non-digestible dietary constituents that benefit host health via selective stimulation of the growth and/or activity of certain microorganisms [76]. Prebiotics can originate from a multitude of sources including inulins, unrefined wheat, unrefined barley, raw oats, soybeans and non-digestible oligosaccharides such as fructooligosaccharides (FOS), galactooligosaccharides (GOS), fructans, polydextrose, xylooligosaccharides(XOS) and arabinooligosaccharides (AOS) [77]. A low fibre diet has been associated with a reduced bacterial abundance [78] and high consumption of these non-digestible carbohydrates resulted in an increase in microbiota gene richness in obese patients [79]. Many studies revealed that a diet rich in non-digestible carbohydrates targets the microbiota by increasing probiotic bacteria such as bifidobacteria and lactic acid bacteria. Indeed, diets rich in whole grain and wheat bran led to an increase of intestinal *Bifidobacteria* and *Lactobacilli* [80, 81]. FOS-, polydextroseand AOS-based prebiotics were shown to reduce *Clostridium* and *Enterococcus* species. In addition, resistant starch and whole grain barley increased the abundance of *Ruminococcus*,

exactly opposed the ones induced by the use of artificial sweeteners.

*Clostridia* species [74].

but also in diabetics.

*E. rectale* and *Roseburia* [61].

In addition to high protein content, animal-based diets are also high in fat. The well-known Western diet, which is nowadays the main culprit for obesity and diabetes development, is high in saturated and trans fats and low in mono and polyunsaturated fats [61]. While consumption of high saturated and trans fat diets increases cholesterol levels and is associated with a risk of cardiovascular disease, mono and polyunsaturated fats decrease the risk of chronic disease [68]. Human studies have revealed that a high-fat diet increases the abundance of total anaerobic microorganisms and the levels of *Bacteroides* as well [19, 57]. The consumption of different types of fat has different effects on the microbiome. Consumption of a low fat diet promotes the overabundance of *Bifidobacterium* and leads to a reduction of fasting glucose and total cholesterol. Conversely, a high saturated fat diet determined the establishment of a microbiota enriched in *Faecalibacterium prausnitzii*, and a diet high in monounsaturated fat was correlated to a reduced total bacterial load and reduced cholesterol [69].

Animal studies revealed that a high fat diet promotes a microbiota with less *Lactobacillus intestinalis* and with more *Clostridiales, Bacteroides* and *Enterobacteriales.* In addition, the abundance of *L. intestinalis* was negatively correlated with fat mass and body weight [70]. Studies in mice compared the effects of different type of lipids on the microbiota. Thus, lard-fed mice harboured elevated *Bacteroides* and *Bilophila* whereas mice fed with fish oil had increased lactic acid bacteria (*Lactobacillus* and *Streptococcus*), increased *Verrucomicrobia* (*A. muciniphila*) and *Actinobacteria* (*Bifidobacterium* and *Adlercreutzia*). In addition, lard-fed mice had white adipose tissue inflammation and impaired insulin sensitivity compared to fish oil-fed mice [71].

Among all the dietary macronutrients, carbohydrates are the most studied. Based on their ability to be degraded enzymatically in the small intestine, carbohydrates are either digestible (i.e., starch and sugars including glucose, lactose, fructose and sucrose) or nondigestible (resistant starch and fibre). Upon degradation, digestible carbohydrates release glucose into the bloodstream and lead to an insulin response [61]. Humans who were fed high levels of glucose, fructose and sucrose in the form of dates had a microbiota enriched in *Bifidobacteria,* and low in *Bacteroides* [72, 73]. Moreover, the addition of lactose to the aforementioned diet replicated the same bacterial shifts but it also decreased the levels of *Clostridia* species [74].

crucial impact on the microbiome. The role of dietary protein in shaping the microbiota has been described since 1977 when individuals who consumed a diet rich in beef harboured elevated levels of *Bacteroides* and *Clostridia* and low levels of *Bifidobacterium adolescentis* compared to those who had a meatless diet [63]. Several studies have recently used different forms of protein including vegetarian pea protein, whey protein and animal protein (meats, eggs and cheese) and correlated protein consumption with microbial diversity [61]. Conversely, the consumption of animal-based protein positively correlated with the abundance of bile-tolerant anaerobes such as *Alistipes, Bacteroides* and *Bilophila* [64]. Even though it may promote a greater weight loss, a protein-rich diet can also be detrimental. Thus, individuals on a high protein/low carbohydrate diet had a microbiota with diminished levels of *Roseburia* and *Eubacterium rectale* and low levels of butyrate in their feces [65]. Similarly, patients with inflammatory bowel disease (IBD) had a similar microbiota signature, with low levels of *Roseburia* and decreased butyrate levels [66]. In addition, elevated intake of red meat has been linked to elevated levels of the proatherogenic trimethylamine-N-oxide (TMAO) [62]. Animal studies have shown that high protein consumption increases the levels of insulin-like growth factor 1 (IGF-1), which are known to be correlated with a high risk of diabetes and overall mortality. Indeed, proteins of vegetarian origin have been linked to a lower mortality in comparison with animal-derived

In addition to high protein content, animal-based diets are also high in fat. The well-known Western diet, which is nowadays the main culprit for obesity and diabetes development, is high in saturated and trans fats and low in mono and polyunsaturated fats [61]. While consumption of high saturated and trans fat diets increases cholesterol levels and is associated with a risk of cardiovascular disease, mono and polyunsaturated fats decrease the risk of chronic disease [68]. Human studies have revealed that a high-fat diet increases the abundance of total anaerobic microorganisms and the levels of *Bacteroides* as well [19, 57]. The consumption of different types of fat has different effects on the microbiome. Consumption of a low fat diet promotes the overabundance of *Bifidobacterium* and leads to a reduction of fasting glucose and total cholesterol. Conversely, a high saturated fat diet determined the establishment of a microbiota enriched in *Faecalibacterium prausnitzii*, and a diet high in monounsaturated fat was correlated to a reduced total bacterial load and reduced choles-

Animal studies revealed that a high fat diet promotes a microbiota with less *Lactobacillus intestinalis* and with more *Clostridiales, Bacteroides* and *Enterobacteriales.* In addition, the abundance of *L. intestinalis* was negatively correlated with fat mass and body weight [70]. Studies in mice compared the effects of different type of lipids on the microbiota. Thus, lard-fed mice harboured elevated *Bacteroides* and *Bilophila* whereas mice fed with fish oil had increased lactic acid bacteria (*Lactobacillus* and *Streptococcus*), increased *Verrucomicrobia* (*A. muciniphila*) and *Actinobacteria* (*Bifidobacterium* and *Adlercreutzia*). In addition, lard-fed mice had white adipose tissue inflammation and impaired insulin sensitivity compared to

proteins [67].

78 Pathophysiology - Altered Physiological States

terol [69].

fish oil-fed mice [71].

Recently, a subject of debate in the field of carbohydrates and their role in shaping the microbiota is represented by the use of artificial sweeteners. Artificial sweeteners such as saccharin, sucralose and aspartame were intended to be a healthier, no-calorie food additive for replacing natural sugar. However, recent work by Suez et al. showed that artificial sweeteners are more prone to induce glucose intolerance than consumption of sucrose or glucose. The effects exhibited by artificial sweeteners were attributed to the induction of microbiota changes characterized by increased abundance of *Bacteroides* and decreased *Lactobacillus reuteri* [75]. Conversely, the use of natural sugars such as fructose, sucrose and glucose promoted microbiota shifts exactly opposed the ones induced by the use of artificial sweeteners.

Unlike digestible carbohydrates, non-indigestible carbohydrates are not digested in the small bowel but rather reach the colon where they undergo fermentation by commensal microbiota leading to SCFAs production such as butyrate, propionate and acetate. Butyrate is an important energy source for intestinal epithelial cells and a modulator of enterocyte differentiation, proliferation and restitution. Loss of microbial producers of SCFA can alter the communication between host epithelium and resident bacteria, thus contributing to the development of colitis. For instance, *F. prausnitz ii* is depleted not only in IBD patients [66] but also in diabetics.

Dietary fibres are essential for intestinal health and have been designated as prebiotics, that is non-digestible dietary constituents that benefit host health via selective stimulation of the growth and/or activity of certain microorganisms [76]. Prebiotics can originate from a multitude of sources including inulins, unrefined wheat, unrefined barley, raw oats, soybeans and non-digestible oligosaccharides such as fructooligosaccharides (FOS), galactooligosaccharides (GOS), fructans, polydextrose, xylooligosaccharides(XOS) and arabinooligosaccharides (AOS) [77]. A low fibre diet has been associated with a reduced bacterial abundance [78] and high consumption of these non-digestible carbohydrates resulted in an increase in microbiota gene richness in obese patients [79]. Many studies revealed that a diet rich in non-digestible carbohydrates targets the microbiota by increasing probiotic bacteria such as bifidobacteria and lactic acid bacteria. Indeed, diets rich in whole grain and wheat bran led to an increase of intestinal *Bifidobacteria* and *Lactobacilli* [80, 81]. FOS-, polydextroseand AOS-based prebiotics were shown to reduce *Clostridium* and *Enterococcus* species. In addition, resistant starch and whole grain barley increased the abundance of *Ruminococcus*, *E. rectale* and *Roseburia* [61].
