**2. The gut microbiota-evolution, composition and functions**

The gut microbiota is a dynamic system composed of tens of trillions of microorganisms, which carry out essential functions for the human host. The first composition of the microbiota is acquired at birth when microorganisms from the mother and the environment rapidly colonize the neonatal gastrointestinal tract. Thus, the delivery mode is a keystone factor which determines whether the newborn is colonized by *Lactobacillus*, *Prevotella* or *Sneathia* spp. from the birth canal or by *Staphylococcus* sp. and *Propionibacterium* spp. coming from the skin of the mother and other participants in the caesarean section [15].

Subsequently birth, diet becomes the main modulator of the microbiota composition. In line with this, breastfeeding babies harbour a distinct microbiota from formula-fed babies. While breastfeeding enhances the prevalence of lactic acid bacteria, infant formulas promote the enrichments of species like *Staphylococcus aureus* and *Bacteroides* spp. Until 3 years of age, the microbiota is highly influenced by diet and disease and, in time, its composition becomes very similar to one of the adults [16]. At around 7 years old, 90% of the microbiota is composed of bacteria from the phyla Bacteroidetes and Firmicutes, while the remaining 10% is made of Proteobacteria, Tenericutes and Cyanobacteria [17]. A study by Arumugam et al. proposed the existence of three gut enterotypes for the entire world population: *Bacteroides*, *Rumincoccus* and *Prevotella* [18]. Furthermore, these enterotypes were linked to dietary patterns [19]. For instance, the *Prevotella* enterotype was found to be more prevalent in case of individuals that had a diet rich in fibre and low in fat, whereas the *Bacteroides* enterotype was characteristic for people eating a diet dominated by animal fat and protein. In addition, recent studies have investigated school-age children from different regions of the world and highlighted the role of age, diet, geographical localization and traditions in shaping the microbiota. Children from Mexico, Indonesia, Thailand and Malawi have a diet with a low level of animal protein and fat and a high content of plant polysaccharides and fibre, which translate into a microbiota rich in *Prevotella*. Conversely, children from Japan, the United States, Italy and China have a Western diet rich in fat, animal protein and low in fibre and thus have a microbiota dominated by *Bacteroides* [17]. However, the enterotype hypothesis was recently challenged by Knights et al. who showed that enterotypes can vary widely and continuously over time within an individual [20].

populations studied most obese individuals do not have T2D [1]. Cross-sectional studies have failed to determine a causal relationship between T2D and obesity or a common factor triggering both diseases, but prospective and longitudinal studies have provided some evidence of the direct role of obesity in T2D pathogenesis. Prospective studies on the populations of Japan, Sweden and the Pima Indians show that the central distribution of body adiposity is a major risk factor for the emergence of T2D, regardless of the degree of obesity [11]. However, these studies only suggest that insulin synthesis or deficiency obesity and defects predispose to T2D but offer little data on the duration of these anomalies or their interaction [1]. There is increasing evidence that adipose tissue has a limited capacity to store the energy surplus [12] and that overstressed adipocytes suffer a process of apoptosis or necrosis, precipitating an inflammatory response which contribute to the development of insulin resistance [13].

The specificity of obesity in T2D is also the infiltration of adipose tissue with monocytes and activated macrophages leading to the synthesis of pro-inflammatory cytokines (IL-6 and TNF-α). Because of changes induced in the adipose tissue (lipolysis and lipids products), hepatic lipid synthesis (especially of very low-density lipoproteins-VLDL and triglycerides) occurs. Due to the changes in lipid metabolism, T2D is also characterized by dyslipidemia (elevated triglyc-

The gut microbiota is a dynamic system composed of tens of trillions of microorganisms, which carry out essential functions for the human host. The first composition of the microbiota is acquired at birth when microorganisms from the mother and the environment rapidly colonize the neonatal gastrointestinal tract. Thus, the delivery mode is a keystone factor which determines whether the newborn is colonized by *Lactobacillus*, *Prevotella* or *Sneathia* spp. from the birth canal or by *Staphylococcus* sp. and *Propionibacterium* spp. coming from the

Subsequently birth, diet becomes the main modulator of the microbiota composition. In line with this, breastfeeding babies harbour a distinct microbiota from formula-fed babies. While breastfeeding enhances the prevalence of lactic acid bacteria, infant formulas promote the enrichments of species like *Staphylococcus aureus* and *Bacteroides* spp. Until 3 years of age, the microbiota is highly influenced by diet and disease and, in time, its composition becomes very similar to one of the adults [16]. At around 7 years old, 90% of the microbiota is composed of bacteria from the phyla Bacteroidetes and Firmicutes, while the remaining 10% is made of Proteobacteria, Tenericutes and Cyanobacteria [17]. A study by Arumugam et al. proposed the existence of three gut enterotypes for the entire world population: *Bacteroides*, *Rumincoccus* and *Prevotella* [18]. Furthermore, these enterotypes were linked to dietary patterns [19]. For instance, the *Prevotella* enterotype was found to be more prevalent in case of individuals that had a diet rich in fibre and low in fat, whereas the *Bacteroides* enterotype was characteristic for people eating a diet dominated by animal fat and protein. In addition, recent studies have investigated school-age children from different regions of the world and highlighted the role of age, diet, geographical localization and traditions in shaping the microbiota. Children from Mexico,

**2. The gut microbiota-evolution, composition and functions**

skin of the mother and other participants in the caesarean section [15].

erides, LDL-C levels and low HDLc) [14].

72 Pathophysiology - Altered Physiological States

The gastrointestinal (GI) tract of a healthy host is home to 102 microbial cells within the stomach into the duodenum and jejunum, whereas the distal ileum harbours around 108 microbial cells. However, the highest microbial level (around 1012 cells) resides in the highly anaerobic environment of the colon. Since most of these microbes are not cultivatable, the advent of culture-independent sequencing has provided a valuable insight into the composition of the microbiota in health and disease conditions. Despite the large volume of data generated by sequencing technologies, our understanding of the functional properties of these microorganisms comes from germfree animals. Thus, animals, which were born and reared under sterile conditions, have provided strong evidence regarding the role of microbiota in shaping immunity, host metabolism and even social development. Unlike animals reared under specific pathogen-free (SPF) conditions, germfree animals were shown to have a defective development of the immune system with impaired development of the gut-associated lymphoid tissue, with fewer and smaller Peyer's patches [21].
