10 Gut Microbiota - “Lost in Immune Tolerance” Serena Schippa and Valerio Iebba Public Health and Infectious Diseases dept., ‘Sapienza’ University of Rome, Italy 1. Introduction “There are a number of immune-mediated diseases known to be increased in Inflammatory Bowel Diseases (IBD)”, says Charles N. Bernstein, MD, from University of Manitoba, Canada. “The finding of an increased association of chronic inflammatory diseases with either form of IBD could suggest a common genetic predisposition, common causative triggers, or possibly the triggering of one inflammatory condition secondary to the treatment of a primary inflammatory condition” (Snook et al., 1989). IBD could be classified as auto-inflammatory disorders characterized by recurrent episodes of systemic inflammation, often manifested by fever, as well as inflammation of specific tissues, such as joints, skin, gut, and eyes. These disorders are caused by primary dysfunction of the innate immune system, without evidence of adaptive immune dysregulation. (Galeazzi et al., 2006). In order to find out common causative triggers, in autoimmune disorder and/or auto-inflammatory disorders we would think about the important role of the gut microbiota in human health. IBD spectrum, including Crohn’s disease (CD) and Ulcerative colitis (UC) as the main phenotypes, is a multi-factorial pathology where auto-inflammatory background, genetic susceptibility, environmental factors and intestinal bacteria are the main proposed etiological triggers, and the intestinal tissue injury is principally caused by the immune tolerance loss against the intestinal microbiota. The most numerous bacterial populations are in the gastrointestinal tract with a surprisingly total bacterial weight of 1.5 Kg. Although these populations are highly stable, they are still prone to perturbations by environmental insults (Sullivan et al., 2001), with important consequences for our physiology and, consequently, our health. In the evolution of human diseases some, that were once rare, have become common, while others have disappeared and new varieties have emerged. The hypothesis proposed by Martin J. Blaser to explain it postulates how changes in human ecology result in changes in the microbes that populate our bodies (Blaser & Falkow, 2009). In the past century, the human condition, especially in developed countries, has undergone dramatic changes that affect the transmission and maintenance of the indigenous microbiota. Partly responsible for an increased prevalence of allergic and autoimmune disorders in later years (Strachan, 1989; Cookson & Moffatt, 1997) could be the hygiene hypothesis, that is a diminished exposure of humans to parasites and pathogens. The lack of such exposition may cause the immune system to shift its immunological response away from a balance between type 1 and type 2 T-helper cells (Prescott et al., 1999). Studies on intestinal bacteria composition in IBD patients have reported an altered balance of beneficial versus aggressive microbial species (dysbiosis): this

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could lead to a pro-inflammatory luminal milieu driving chronic intestinal inflammation in a susceptible host. Many other autoimmune pathologies are being associated to an altered intestinal microflora. To date, several evidences on the role of the gut microbiota in shaping intestinal immune responses during health and disease have been collected. Immunological de-regulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. It has recently been proposed that the total information encoded by the mammalian genome is not sufficient to carry out all functions that are required to maintain health and that products of our microbiome are a crucial protection from various diseases. It is possible that alterations in the development or composition of the microbiota (dysbiosis) disturb the partnership between the microbiota and the human immune system, ultimately leading to altered immune responses that may underlie various human inflammatory and immune disorders. According to numerous recent studies there is a vast, intricate and unexpected level of interdependence between beneficial bacteria and the immune system. Recent studies have shown that, at least for experimental IBD, the disease spontaneously occurs when immune suppression is defective; thus, inflammation seems to be a default immunological state in the absence of regulation. In this chapter, after a description of the structure and function of the gut microbiota organ and his cross-talk with the human host, we shall give a description of the forces that contribute to the intestinal ecosystem stability. We shall report findings indicating how the host immune system responds to bacterial colonization of the gastrointestinal tract, indicating that disturbances in the bacterial microbiota will result in the deregulation of adaptive immune cells, which may underlie autoimmune disorders. “This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms is, in fact, itself controlled by microorganisms” (Round & Mazmanian, 2009). In conclusion, it seems conceivable that alterations in both structure and function of intestinal microbiota could be one of the “common causative triggers” of autoimmune and/or auto-inflammatory disorders.

2. Structure of the gut microbiota organ The human body is colonized by a vast number of bacteria, archaea, viruses, and unicellular eukaryotes. This enormous number of microorganisms form complex communities, or microbiota, at various sites within the human body. In fact, humans have been proposed to be “meta-organisms” consisting of 10-fold greater numbers of bacterial than animal cells that are metabolically and immunologically integrated. Human gut ‘microbiota’ The gastrointestinal tract harbors the largest and most complex bacterial ecosystem in the human body (Hattori & Taylor, 2009; Neish, 2009). The majority of the gut microbiota is composed of strict anaerobes, which dominate the facultative anaerobes and aerobes by two to three orders of magnitude (Gordon & Dubos, 1970; Harris et al., 1976). An increasing gradient in bacterial concentration characterizes the human gastrointestinal tract, from stomach, to jejunum, ileum and colon, where the concentration peaks to 1011-1012 bacterial cells per gram of stool (Ley et al., 2006; Leser & Molbak, 2009). The human intestinal microbial community is complex and is composed of at least 1,000 distinct bacterial species. For long times, our understanding of the composition of intestinal microbial communities

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was based on the enumeration and characterization of cultivable organisms. However, this approach left substantial gaps in the catalogue of intestinal bacterial species, as most gut organisms are resistant to culture by available methods. The recent development of molecular profiling methods allowed unprecedented knowledge into the intestinal microbial communities, leading to the identification of new bacterial species (Eckburg et al., 2005). Molecular profiling of the human intestinal microbiota has revealed a high level of variability between individuals at the bacterial species level. Although there have been over 50 bacterial phyla described to date (Schloss & Handelsman, 2004), the human gut microbiota is dominated only by Bacteroidetes and Firmicutes, whereas Proteobacteria, Verrucomicrobia, Actinobacteria, Fusobacteria, and Cyanobacteria are present in minor proportions (Eckburg et al., 2005). The intestinal Firmicutes are Gram-positive bacteria, dominated by species belonging to the Clostridia class, but also include Enterococcaceae and Lactobacillaceae families and Lactococcus spp. Intestinal Bacteroidetes are Gram-negative bacteria comprised of several Bacteroides species, including Bacteroides thetaiotaomicron, Bacteroides fragilis and Bacteroides ovatus. The remaining intestinal bacteria, accounting for less than 10% of the total population, belong to the Proteobacteria, Fusobacteria, Actinobacteria, Verrucomicrobia and Spirochaetes phyla and a bacterial group that is closely related to Cyanobacteria (Eckburg et al., 2005). The mucosal immune system must be able to flexibly and rapidly adapt to microbiota, the composition of which may change in unpredictable ways as a function of host diet or other interactions with the external environment. The adult-like structure of the gut microbiota is established after the two years of life, during which the gut ecosystem progresses from sterility to extremely dense colonization (Palmer et al., 2007). Through healthy adulthood, the bacterial density and diversity in the gut remains relatively stable over time, in spite of the continuous flow of intestinal content, reflecting the ability to maintain a high degree of homeostasis (Vanhoutte et al., 2004; Leser & Molbak, 2009). The adult microbiota shows an astonishing individual variability, and it is considered as unique as a fingerprint in terms of species and strains composition (Zoetendal et al., 1998; Eckburg et al., 2005; Ley et al., 2006). Age, sex, diet, lifestyle, and geographic origins influence the composition of the gut microbiota, but studies involving human adults with different relatedness, from genetically unrelated people to monozygotic twins, demonstrated that the impact of genotype may also be significant in shaping the gut bacterial ecosystem (Vaughan et al., 2000; Ley et al., 2005; Mueller et al., 2006; Khachatryan et al., 2008; Li et al., 2008). For example, European children with a fat-rich western-life diet, and Burkina Faso ones, with a fiber-rich dietary content, showed marked differences in fecal microbiota composition (De Filippo et al., 2010). Shaped by millennia of co-evolution, host and bacteria have developed beneficial relationships, creating a suitable environment for mutualism. Human gut ‘microbiome’ Despite the remarkable host specificity in the gut community membership, a high degree of conservation in its expressed functions and metabolites has been reported (Mahowald et al., 2009). This suggests that the gut microbiota may be characterized by a marked “functional redundancy” to ensure that the key functions of the microbial community remain unaffected by the individual variability in terms of species composition (Gill et al., 2006). The existence of a “human core gut microbiome”, defined as those genes which are common to the gut microbiomes of all or the majority of humans, has been hypothesized to be responsible for the functional stability of the gut microbiota (Turnbaugh & Gordon, 2009). On the contrary,

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a “human core gut microbiota”, defined as a number of species which are common to all humans, could hardly be defined, since different combinations of species could fulfill the same functional roles (Tschop et al., 2009; Turnbaugh et al., 2009). A recent study from the MetaHIT consortium (Arumugam et al., 2011) identified three fecal enterotypes geographicand ethnicity-independent, showing a limited number of equilibrated host-microbial relationships, that could respond differently to environmental endeavors. Aside to the core, the set of genes, present in smaller subsets of human, represents the “human variable microbiome”. This wide variation from the core is the result of a combination of hostspecific factors, such as genotype, physiological status, host pathologies, lifestyle, diet, environment, and the presence of transient populations of microorganisms that cannot persistently colonize the human gut. In return, core and variable components of the human microbiome influence different aspects of the human health, including nutrient responsiveness and immunity (Turnbaugh et al., 2007).

3. Function of the gut microbiota organ It was given emphasis to the importance of an ecologic view of our relationships with microbes, where the mutual survival of harbored microbiota and human host is interdependent (Ley et al., 2006; Chow et al., 2010). The cross talk between environmental microbiologists and human microbiota researchers should be improved in order to better understand the relationships between human and his microbiota. Not much is known yet about the possible roles of microbes in human-associated communities outside the intestinal tract, but it becomes increasingly clear that the gut microbiota exerts many beneficial effects on the human body system. Our intestinal symbionts play many important roles in: nutrient digestion and synthesis; energy metabolism; vitamin synthesis; epithelial development, immune responses (Tappenden & Deutsch, 2007; Flint et al., 2007). In addition, host-microbe interactions are essential for the host’s defense against pathogenic infections. Trophic functions Collectively, the flora has a metabolic activity equal to a virtual organ within an organ (Scheline, 1973; Sousa et al., 2008). In return, the intestinal microorganisms are provided with steady growth conditions and a constant stream of nutrients (Savage, 1977). The presence of an intestinal microbiota is not essential for survival of the host, but germ-free (GF) mice require 30% more energy in their diet (Wostmann, 1981), showing the rule of the indigenous microbiota in energy scavenging from food. This energy utilization by the gut microbiota works on different levels. Specialized intestinal bacteria synthesize enzymes that human cells lack for the digestion of plant polysaccharides. The intestinal microbial community is well equipped to degrade these biomolecules (Hooper et al., 2002; Robert & Bernalier-Donadille, 2003). Microbial fermentation generates butyrate and other short-chain fatty acids that the host can use as energy sources and that help maintain the integrity of the intestinal epithelium (Tappenden & Deutsch, 2007; Flint et al., 2007; Pryde et al., 2002). In addition to its direct role in increasing caloric uptake from diet, the presence of a gut microbiota regulates fat storage in the host (Greiner & Bäckhed, 2011), promoting the absorption of monosaccharides from the gut lumen (Bäckhed et al., 2004). Host’s defense development The intestinal symbionts provide an important barrier to colonization by potential pathogens, called “colonization resistance,” by competing for the same nutrients and

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attachment sites as intruding microorganisms. (Dethlefsen et al., 2007; Tappenden & Deutsch, 2007; van der Waaij et al., 1971; Stecher & Hardt, 2008). Furthermore, the presence of a microbiota stimulates the development of the mucosal immune system. Without the interaction host-microbiota, the intestinal surface is more sensitive to injury, and less capable of inducing repair of the damaged surface. The host epithelium and its immune cells do not simply tolerate commensal bacteria, but depend on them to maintain the architectural integrity (Rakoff-Nahoum et al., 2004).

4. Host immune system and gut microbiota organ Macpherson & Harris report the intrinsic potential of the microbiota to stimulate both proand anti-inflammatory responses. The composition of the bacterial communities in the gut may linked to the correct functioning of the immune system (Macpherson & Harris, 2004). Recently it has been proposed that the mammalian genome information is not sufficient to achieve all functions required to maintain health, and that products of our microbiome are essential in protecting from different diseases (Zaneveld et al., 2008). It is possible that alterations in the development or composition of the microbiota could affect the cross-talk between microbiota and human immune system, in the end leading to altered immune responses that may trigger various human inflammatory disorders. Germ-free animals show a defective development of gut-associated lymphoid tissues (Macpherson & Harris, 2004; Falk et al., 1998), of antibody production, and have fewer and smaller Peyer’s patches and mesenteric lymph nodes (Bouskra et al., 2008; Abrams et al., 1963). These structures could be collectedly called “inducible structures”, due to their exnovo formation following the introduction of gut bacteria. This observable fact suggests a dynamic relationship between the immune system and the microbiota. Furthermore, gut bacteria have been shown to direct the glycosylation of surface proteins exposed in the lumen (Bry et al., 1996). The observations of developmental defects in germ-free mice at the tissue, cellular and molecular levels suggest that normal immune function may be impaired in the absence of the gut microbiota. An evolutionary alliance has been forged between mammals and beneficial bacteria that is crucial for maintaining the long-term survival of both. In other words our well-being seems to be dependent to the microorganisms we harbor. The evidence described above implicates microbiota ability in shaping immune responses during health and disease. Physiological inflammation The concept of ‘physiological inflammation’ was introduced as a normal response to colonizing flora. When the capacity to develop or maintain physiological intestinal inflammation is lost, pathological inflammation takes over, resulting in disease (Fiocchi, 2008). Recently it has been reported (Rescigno et al., 2008) the interplay between dendritic cells (DCs), intestinal epithelial cells (IECs) and luminal bacteria. It was demonstrated how a specific protein produced by IECs give instructions to DCs in order to give a mitigated response (physiological inflammation). Moreover, the NALP3 (NACHT domain-, leucinerich repeat-, and PYD-containing protein 3) large cytoplasmic complex, called inflammasome, links the sensing of microbial products and metabolic stress to the activation of the proinflammatory cytokynes IL-1 (Interleukyne-1 ) and IL-18 (Interleukyne-18). Inflammasome has been associated with several auto-inflammatory conditions (Martinon et

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al., 2009). An altered microbiota could exert its function on underlying mucosal immune system both directly, trough bacterial PAMPs (Pathogen-Associated Molecular Patterns), and indirectly, through bacterial products. Bacterial role in maintaining bowel health Several bacterial species have ability in control the inflammatory response. On this base, in the early 1900s, Ilya Mechnikov was the first to propose the use of live microorganisms to maintain bowel health and prolong life. Now, the term probiotic is used to describe dietary microorganisms that are beneficial to the health of the host (Sartor, 2004). Bacterial species can act on several cell types (epithelial cells, DCs and T cells), but recent evidence suggests that the induction of regulatory T cells (TReg) by these microorganisms is crucial to their ability to limit inflammation and/or auto-inflammatory disease. Moreover, it has been recently evaluated the potential role of Faecalibacterium prausnitzii on intestinal inflammation using cellular and animal models (Sokol et al., 2008). The authors found that stimulation by F.prausnitzii led to significantly lower IL-12 (Interleukyne-12) and IFN- (Interferon- ) production levels and higher secretion of IL-10 (Interleukyne-10). Another gram negative bacterium linked to human innate immunity is Bacteroides thetaiotaomicron, able to elicit the over production of the small proline-rich protein-2 (sprr2a), an epithelial barrier fortifier, and the decay-accelerating factor (DAF), an apical epithelial inhibitor of complementmediated cytolysis (Hooper et al., 2001). Moreover current evidence supports the idea that certain beneficial bacteria have evolved molecules (known as symbiosis factors) that induce protective intestinal immune responses. One of these is the polysaccharide A (PSA) produced by Bacteroides fragilis, which induces an immunoregulatory response that provides protection from inflammation induced by Helicobacter hepaticus. In particular, PSA suppresses pro-inflammatory interleukin-17 production by intestinal immune cells and protects from inflammatory disease through a functional requirement for interleukin-10producing CD41 T cells (Mazmanian et al., 2008). Gut bacteria could also interact with the underlying immune system in an indirect fashion, through their metabolic products. It was reported (Segain et al., 2000) how short-chain fatty acids (SCAFs), and particularly n-butyric acid, could promote epigenetic changes in pro-inflammatory genes. A better knowledge of the complex microbial networks existing in the intestinal human ecosystem will be an important step to assess their interplay with sub-mucosal immune system (Gill et al., 2006). Development of the intestinal microbiota Recent papers (Palmer et al., 2007; Cucchiara et al., 2009) on development of the intestinal microbiota in infants revealed that in the first few days/weeks of life, the microbiota of newborns is highly variable and subject to waves of temporal fluctuations to coordinately assemble a stable microbiota. The first years of life are also a time of great post-natal development of the immune system. As the microbiota has marked influences on the immune system, deviations from the normal development of the microbiota (through modern strategies such as caesarean section, formula-based diet, hygiene, vaccination and use of antimicrobials in infants) may alter the outcome of immune development and potentially predispose individuals to various inflammatory diseases later in life. On the basis of clinical, epidemiological and immunological evidence, it seems possible that changes in the intestinal microbiota may be an essential factor in the incidence of numerous inflammatory disorders.

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Equilibrium imbalance in gut microbiota It is conceivable that the absence of beneficial microorganisms (owing to dysbiosis) that promote the appropriate development of the immune system leads to the induction of inflammatory responses and immune-mediated disease. We could asses that both autoimmune diseases and auto-inflammatory diseases, dysfunction of the innate immune system, without evidence of adaptive immune dysregulation, may be influenced by deviances from well-established microbial equilibria. Literature data established that specific aspects of the adaptive immune system are influenced by intestinal commensal bacteria (Lee & Mazmanian, 2010). Elevated systemic antibodies towards commensal gut microbiota were found in auto-inflammatory condition as reported by a study conducted on Familiar Mediterranean Fever (FMF), an auto-inflammatory diseases. It has been shown that FMF is characterized by increased systemic reactivity against commensal gut microbiota. This is probably the consequence of hypersensitivity of the inflammasome in FMF that triggers the inflammation and contributes to the excessive translocation of bacteria and bacterial antigens through the gut barrier (Manukyan GP et al., 2008).Understanding the molecular mechanisms mediating host-microbiota symbiosis could redefine our vision of the evolution of adaptive immunity and, consequently, our approach in the treatment of numerous immunologic disorders.

5. The potential impacts of a disturbance on microbial gut composition and/or ecosystem processes It is predictable that social and medical progress that affects the composition of the microbiota will also have consequences for our physiology and health. The microbial composition is generally sensitive to disturbance. Perturbations on microbial composition might have different results, depending on the resistance or resilience phenotype of the gut microbiota. Finally, a community whose composition is sensitive and not resilient might produce process rates similar to the original community if the members of the community are functionally redundant. Generally adult are more resistant, whilst children are more resilient, due to their developing microbiota till age of 7, when a ‘climax’ is reached (Cucchiara et al., 2009). It has been proposed that improved hygiene, is at the origin of increased incidence of allergic and autoimmune diseases (Strachan, 1989; Bach, 2002). Some bacterial agents – notably those that co-evolved with us – are able to protect against a large spectrum of immune-related disorders. In 1998, about one in five children in industrialized countries suffered from allergic diseases such as asthma, allergic rhinitis or atopic dermatitis (International Study of Asthma and Allergies in Childhood, ISAAC committee, 1998). This proportion has tended to increase over the last 10 years, asthma becoming an ‘epidemic’ phenomenon (Masoli et al., 2004). As human health and longevity have improved in developed countries, new diseases have arisen without obvious explanation. Beginning in the nineteenth century and accelerating in the twentieth century, there have been dramatic changes in human ecology, including cleaner water, smaller families, an increase in the number of Caesarian sections, increased use of pre-term antibiotics, lower rates of breastfeeding and more than 60 years of widespread antibiotic use, particularly in young children, representing a deep microbiota perturbation (Dethlefsen & Relman, 2011). The ‘hygiene hypothesis’ has postulated that our decreased sampling of the microorganisms in

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food, air, water or soil is an important factor in modern allergic and metabolic diseases (Blaser, 2006). Our decreased sampling of the microorganisms could reflect the loss of our ancestral microorganisms. As the representation of particular species diminishes in one generation, the vertical transmission to the next generation (Nahar et al., 2009) will decrease. Several specific examples illustrate the concept that the loss of an indigenous microorganism will have consequences for the host. For example, as H. pylori is disappearing from human populations, reflecting both diminishing transmission and increasing antibiotic treatment , both ‘idiopathic’ peptic ulcer disease and gastric cancer rates are diminishing, which is clearly salutary. However, oesophageal reflux, barrett’s oesophagus and adenocarcinoma are increasing, which is clearly deleterious (Pohl & Welch, 2005; el-Serag & Sonnenberg, 1998). We believe that the “hygiene” and the “disappearing” hypotheses , reported as alternatives, could instead coexist. In fact the changing in the in human macro ecology, improved by our decreased sampling of the microorganisms, could progressively affect the composition of our indigenous microbiota, which in turn influence human physiology and, ultimately, disease risk.

6. Intestinal microbiota and autoimmune disorders The recent identification of symbiotic bacteria with potent anti-inflammatory properties, and their correlative absence during disease, suggests that certain aspects of human health may depend on the status of the microbiota. The medical and social reconsideration of the microbial world may have profound consequences for the health of our future generations. If improvements in hygiene and health care have altered the process by which a healthy microbiota is assembled and maintained, then patients with autoimmune and/or autoinflammatory disorder should display signs of dysbiosis. This indeed seems to be the case, at least according to a growing number of studies that are now linking these diseases to alterations in the microbiota. The bacterial composition of the intestines of adult patients with IBD is known to differ from that of healthy controls (Frank et al., 2007). This is reported in IBD pediatric patients too (Conte et al., 2006). No infectious organisms have been conclusively shown to be the causative agents of IBD. This raises the possibility that the targets of inflammation in IBD are not pathogens and instead are pathobionts that are overrepresented during dysbiosis. In IBD a breakdown in immune tolerance to gut bacteria also exists (De Winter et al., 1999; Elson et al., 2007; Elson et al., 2000). The cause of this increase in immune stimulation is of great interest, and several lines of evidence indicate a fundamental role for commensal bacteria in the progression of disease (Sartor, 1997). Patients with IBD respond favorably to antibiotic treatment and fecal diversion, and have higher antibody titers against indigenous bacteria than unaffected individuals (Elson, 2000; Tannock, 2002). In addition, inflammatory lesions are more pronounced in areas of the intestine that contain the highest number of bacteria. It has been shown an increased expression of antimicrobial peptides (Cash et al., 2006), higher levels of antibodies towards mucosal bacteria (Furrie et al., 2004) and an exaggerated mucosal immune response particularly in active CD but also in UC directed against bacterial cytoplasmic proteins (Macpherson et al., 1996). Similar results were found in Celiac Disease, a multi-factorial disease where genetic factor together with environmental factors (gluten) participate to the pathology. Our group carried out a study on the characterization of the intestinal microbiota in pediatric Celiac patients before and after gluten-free diet (GFD). Our results showed a

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peculiar dominant microbiota associable to CD, significantly different before and after the GFD diet and to the control group (Schippa et al., 2010). Furthermore, the gastric ulcer due to Helicobacter pilory seems to be related to an enhanced level of auto-antibodies against gastric epithelial proteins (Ayada et al., 2009; Bergman et al., 2005; Sorrentino et al., 1998). In active Systemic Lupus Erythematosus (SLE) patients the quality of the colonization resistance (CR) of the intestinal micro flora is lower than in healthy individuals. A lower CR results in translocation of more species of foreign bacteria. Some of these bacteria may serve as antigen for the production of anti-bacterial antibodies cross reacting with DNA (Apperloo-Renkema et al., 1995). Among patients with Ankylosing Spondylitis (AS) it has been shown an over-expression of Toll-Like Receptor 4 (TLR4) and TLR5 genes in peripheral blood cells (PBC), providing further support for the importance of TLR subtypes responsive to Gram-negative bacteria in the pathogenesis of AS (Assassi et al., 2010). In the autoimmune arthritis disorder the causative etiologies of inflammation are: a genetic predisposition, life style, feeding, and allergy against foods and microorganisms. It has been reported (Mielants et al., 1996; Rodríguez-Reyna et al., 2009) an abnormal intestinal transepithelial permeability in these patients that allows a direct passage of undigested food particles and bacterial components in the blood stream, leading to an immune reaction around joints. This altered permeability could be due to the direct interaction existing between adherent intestinal bacteria and the tight junctions of intestinal epithelial cells, as reported in other pathologies (Weflen et al., 2009; Fasano & Nataro, 2004). Epidemiological studies have provided evidence for a link between altered intestinal microbiota to other allergic disorders, such as atopic eczema and rheumatoid arthritis (Penders et al, 2007; Kalliomaki & Isolauri, 2003). In 1999 an investigation of the role of intestinal bacteria in the development of asthma concluded that allergic children from Sweden and Estonia had lower levels of colonization by Bacteroides spp. and higher levels of colonization by aerobic microorganisms than non-allergic children from either region (Bjorksten, 1999). Although it is not clear whether dysbiosis is a cause or an effect of disease, it seems that deviations in the composition of the gut microbiota may be one factor underlying the development of disease in genetically predisposed individuals. The effects of the microbiota on the immune system are thus becoming increasingly evident.

7. Conclusion Accumulating evidence from various sources suggests that the increase in autoimmune and/or auto-inflammatory diseases observed is partly caused by a decline in infectious diseases and progress in hygiene. In a healthy microbiota we will find a balanced composition of many classes of bacteria: a) symbionts, organisms with known healthpromoting effects; b) commensals, permanent residents of this complex ecosystem, providing no benefits; c) pathobionts, also permanent residents of the microbiota with the potential to induce pathology. In conditions of dysbiosis there is an unnatural shift in the composition of the microbiota, which results in either a reduction in the numbers of symbionts and/or an increase in the numbers of pathobionts. Overall bacterial richness is reduced, but some microbial taxa may benefit from the inflammatory conditions and increase in abundance. The causes for this are not entirely clear, but are likely to include recent societal advances in developed countries. In addition to the classic pathogenic species, we propose that another kind of pathogenicity exists in the gut: one in which the

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whole community is ‘‘pathogenic’’ when its emergent properties contribute to disease. In a ‘‘pathogenic community’’ no single microbe is pathogenic alone. Instead, the community assemblage is an environmental risk factor that contributes to a disease state. A microbial community will be pathogenic within the context of other risk factors, such as host genotype, diet, and behavior. A ‘‘pathogenic community’’ could be formed as results of improvements in hygiene and health care, all factors that have altered the process by which a healthy microbiota is assembled and maintained. Thus, patients with autoimmune and/or auto-inflammatory disorder should display signs of dysbiosis in their intestinal microbiota. Genetic and habitual factors shape the composition of the microbiota, which in turn shapes the immune system of individuals that are predisposed to inflammatory disease. The recent identification of symbiotic bacteria with potent anti-inflammatory properties, and their correlative absence during disease, suggests that certain aspects of human health may depend on the status of the microbiota. We can asses that the disruption of the cross-talk between humans and microbes, the “lost in immune tolerance”, could be one of the factors leading to the development of a diseases status. The millenary human-microbes coevolution led to a complete interdependence between harbored microbiota and human host. Understanding the intricate network existing in this complex ecosystem will be a necessary step, in order to give insights on autoimmune and/or auto-inflammatory diseases.

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Autoimmune Disorders - Pathogenetic Aspects Edited by Dr. Clio Mavragani

ISBN 978-953-307-643-0 Hard cover, 508 pages Publisher InTech

Published online 26, October, 2011

Published in print edition October, 2011 The present edition entitled "Autoimmune disorders - Pathogenetic aspects"​ aims to present the current available evidence of etiopathogenetic insights of both systemic and organ specific autoimmune disorders, the crossover interactions among autoimmunity, cardiovascular morbidity and malignancy as well as novel findings in the exciting fields of osteoimmunology and immunology of pregnancy.

How to reference

In order to correctly reference this scholarly work, feel free to copy and paste the following: Serena Schippa and Valerio Iebba (2011). Gut Microbiota - “Lost in Immune Tolerance”, Autoimmune Disorders - Pathogenetic Aspects, Dr. Clio Mavragani (Ed.), ISBN: 978-953-307-643-0, InTech, Available from: http://www.intechopen.com/books/autoimmune-disorders-pathogenetic-aspects/gut-microbiota-lost-in-immunetolerance-

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