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Gut-mirobiota and immune system




Series of studies summarized in recently published reviews indicate a critical role of intestinal commensally microbiota in the development of autoimmune diseases including inflammatory bowel diseases, rheumatoid arthritis and multiple sclerosis [103,104]. The vertebrate GI tract contains an exceptionally complex and dense microbial environment, with bacterial constituents that affect the immune responses of populations of reactive host cells [105], and stimulate a rich matrix of effector mechanisms involved in innate and adaptive immune responses [32].

More recent studies substantiate these assertions with demonstrations that commensally flora recognition by toll-like receptors (TLRs) is necessary to induce increased epithelial cell proliferation thus accelerating repair of the epithelial surface following injury and to inhibit inflammation [106]. TLR signaling is vitally important not only for protection from pathogenic infection, but also for inducing tolerant responses to commensalism. The activation of the TLR2 signaling pathway directly enhances intestinal epithelial integrity through translocation of the tight junction protein zonula occludens-1 (ZO-1) [107,108]. The basic mechanism of the mucosal immune system is innate immunity and its characteristic ability to distinguish potentially pathogenic microbes from harmless antigens is achieved through pattern recognition receptors. TLRs are present on cells of the innate immune system and recognize characteristic molecules called pathogen associated molecular patterns [109]. Pathogen recognition by a particular TLR results in a cascade of events starting with the activation of the NF-κB signaling system and resulting in increased cytokine production and T cell activation [110]. A mechanistic perspective has been provided by a number of studies which found a persistent elevation in rectal mucosal enteroendocrine cells, T-lymphocytes and gut permeability following the infectious insult in subjects who went on to develop IBS [111,112]. Microbiota’s inflammation-suppressing fractions may simultaneously counteract with inflammation-aggravating bacteria, improve the barrier effect of the GI mucosa and more directly interact with inflammation-driving components of the immune system [113]. Multiple studies are regarded as important indicators of a link between alterations in the microbiota and mucosal inflammation in IBS [114-116]. Persistent low grade inflammation is a characteristic of post-infectious IBS (PI-IBS) [17] and these patients exhibit greater IL-1β mRNA expression, both during and after the infection, compared with individuals who do not develop PI-IBS [117]. IBS patients with normal histology had increased intraepithelial lymphocytes and CD3+ and CD25+ cells in the lamina propria [118]. Increased CD25+ cells in IBS suggests an antigen challenge and these cells are preventing “a more florid inflammatory response” [65].

It has been hypothesized that changing diets are altering the gut microbiota towards dysbiosis and may thus be driving an increase in the incidence of inflammatory diseases. Dietary factors apparently associated with dysbiosis in animal models include high-fat, high-carbohydrate, and low-fibre diets. These diets are associated with lower levels of short-chain fatty acids (SCFAs), produced by the microbiota, leading to inflammation [119]. Obesity is regarded as a chronic low-grade inflammatory state, and inflammatory cytokines secreted from adipose tissue are associated with rheumatoid arthritis [120]. Increased bacterial lipopolysaccharide (LPS) uptake through the gut lumen to other tissues occurs in obese murine models as a response to fat feeding [121], and enhanced systemic exposure to LPS could increase the risk of such inflammatory disorders as rheumatoid arthritis. Rheumatoid arthritis patients are prone to a higher ratio of fat to muscle mass, so-called sarcopaenic obesity [122], but debate continues about whether sarcopaenia is a cause or an effect of rheumatoid arthritis.

Microbial infections were thought to trigger multiple sclerosis (MS). Although there is no clear epidemiological evidence, which suggests that commensal bacteria contribute to MS pathogenesis, the effects of diet on MS development provide some indirect evidence [123]. Recently a review by Berer and Krishnamoorthy, clearly summarized the role of commensal gut flora and brain autoimmunity [124]. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, suggests that the gut flora contribute to the development of this disease and therapeutic administration of probiotics (live beneficial bacteria) or prebiotics (compounds that stimulate the growth of beneficial bacteria) have been studied in various autoimmune disease models including MS [125,126]. EAE is typically induced in experimental animals via immunization with myelin antigens in combination with a strong adjuvant. In contrast, sterilization of the gut by treatment with a mixture of antibiotics reduced the severity of EAE [127,128]. The reduced severity of demyelinating disease is thought to be due to the attenuation of pro-inflammatory TH1/TH17 responses. Lee and colleagues showed that disease protection in germ free mice coincided with reduced levels of the pro-inflammatory cytokines IL-17 and IFN-c and increased numbers of Forkhead box P3+ (Foxp3+) regulatory T (TReg) cells in peripheral lymphoid tissues and the CNS [129]. Moreover, IL-10-producing, Foxp3+ TReg cells accumulated in the cervical LNs (cLNs) of antibiotic-treated mice and were able to protect naive recipients against the transfer of EAE [127].

Stress and gut microbiota

The core neuroendocrine pathway in human is the hypothalamic-pituitary-adrenal (HPA) axis and activation of this axis takes place in response to a variety of physical and psychological stressors [130]. After much initial speculation, an elegant study by Sudo et al. provided some insight into the role of the intestinal microbiota in the development of the HPA axis [67].

Signaling molecules released into the gut lumen from cells in the lamina propria that are under the control of the CNS can result in changes in gastrointestinal motility and secretion as well as intestinal permeability, thus altering the GIT environment in which the bacteria reside [2].

Stress affects our Brain and GI tract both ways:
(a) from up to down, when our CNS triggers response through hypothalamic-pituatary-adrenal pathway and the autonomic nervous system (ANS) resulting in increase of cortisol, adrenaline and noradrenaline secretion, and corticotropin-releasing-factor (CRF) as well, increases anxiety-like behavior, abdominal pain, colon secretions, muscle contractions (motility) and increased permeability within the lining of the bowel.
(b) from down to up, when under the stress GI inflammation triggers intense firing of the gut’s sensory neurons, culminating in a kind of sensory hyperactivity.

Stress also induces permeability of the gut allowing bacteria and bacterial antigens to cross the epithelial barrier and this can activate a mucosal immune response which in turn alters the composition of the microbiome [131]. Acute stress was shown to cause an increase in colonic paracellular permeability which involved mast cells and overproduction of IFN-γ with decreased expression of ZO-2 and occludin mRNA [132].

Recently, some studies indicate a positive effect of probiotics on stress related pathology in upper GI tract, however the effects need to be further evaluated [133]. There is also evidence that stress may have a profound effect on bacterial flora leading to increased adhesion and translocation of bacteria due to increased barrier permeability. Chronic stress disrupts the intestinal barrier, making it leaky and increasing the circulating levels of immune modulator bacterial cell wall components such as lipopolysaccharide [134]. Stress may be an important factor leading to the activation of the immune system resulting in the exacerbation or induction of acute colitis [135,136]. The modulator role of stress-related brain-gut interactions in the IBS pathophysiology, in particular neuroimmune modulation associated with psychological factors and emotional state [6,8,137] has been confirmed by the encouraging outcome of non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception [138-140]. Recent developments showing the critical interdependence between the composition and stability of the microbiota and GI sensory-motor function indicate a novel approach to IBS treatment with a use of probiotics, prebiotics and antibiotics [2,141]. Specific modulation of the enteric microbiota in the context of neuroimmune interactions within the brain-gut axis opens a new promising strategy for stress-related disorders, particularly in the aspects of comorbidity in functional GI disorders such as IBS [1,142]. Experimental findings suggest that minor irritation of the gut in neonatal animals leading to features of depression and anxiety that persist into adulthood [143].

An early study conducted in a gastroenterology clinic reported a very high lifetime prevalence of generalized anxiety disorder of 34% in newly referred IBS patients [144]. Talley et al. reported that dyspepsia patients who present for investigation were more likely to be neurotic, anxious, and depressed than non-dyspepsia controls [145]. Using the gold standard diagnostic method with psychiatrist-conducted structured Clinical Interview for Diagnostic Statistical Manual of Mental Disorders-IV Axis I Disorders, reported that anxiety disorders are diagnosed in 38% of patients with functional dyspepsia compared with 4% in the general population [146]. It has been shown that stress or bacterial-mediated disruption of epithelial barrier function in IBS result in malfunctioning of inflammation tuning-down mechanisms may lead to longstanding increase of gut permeability and hypersensitivity [147].

It has also been observed that IBS patients with psychiatric morbidity are characterized by low rectal distension pain thresholds, high rates of healthcare consultations, interpersonal problems and sexual abuse [148]. In a population based study in Hong Kong, the prevalence of generalized anxiety disorder is significantly higher in subjects reporting IBS symptoms compared to those reporting these symptoms (16.5% vs. 3.3%, P<0.001), and IBS is associated with 6-fold increase in the likelihood of having generalized anxiety disorder [149]. Yet, there are cumulating evidence showing that the pathophysiology of functional gastrointestinal disorders (FGID) involves abnormal processing of visceral nociceptive signals in the brain-gut axis, which leads to visceral hypersensitivity and hyperalgesia [150]. Furthermore, FGID patients are also characterized by abnormalities in autonomic, neuroendocrine and immune functions. This neural network involves corticotrophin releasing factor (CRF) containing neuronal projections that activate both the autonomic nervous system and hypothalamus-pituitary-adrenal axis. The alterations in CRF secretion and expression of its receptor, CRF1, involved in the pathophysiology of stress-related, which includes anxiety, depression, and changes in gastrointestinal motility and visceral sensation [147].

The system is involved in a wide spectrum of physiological activities such as arousal, vigilance and pain modulation. Hyperactivity of the neuroendocrine and visceral perceptual response to physiological (e.g. meal) or psychological stimuli may account for the stress-induced flare of bowel symptoms in IBS patients [151,152], and administration of CRF alleviates visceral hyperalgesia and negative affective response to bowel stimulation in IBS patients [153]. Increased β-adrenergic activity is significantly correlated with visceral hypersensitivity and symptoms of hard or lumpy stools in constipation- predominant IBS [153,154]. It has also been reported that anxiety induces gastric sensorimotor dysfunction and postprandial symptoms in patients with functional dyspepsia [155]. Psychological disorders and FGID also share common genetic predispositions particularly the genes that are involved in serotonergic activities. It has been reported that the polymorphism of serotonin reuptake transporter (SERT) genes is associated with the subtypes of IBS [156]. Polymorphisms in the promoter for synthesis of SERT influence response to serotonergic medications in depression as well as colonic transit response to alosetron, a serotonin receptor-3 (5-HT3) antagonist, in patients with diarrhea predominant IBS [157]. Early life adversity, particularly psychological stress, has been speculated to play an important role of pathogenesis of FGID. Other social and environmental factors, such as exposure to war time conditions, infantile and childhood trauma and social learning of illness behavior are predictors of the IBS in adulthood [158,159]. In recent years, a positive association between psychological stress and abnormal immunity has also been implicated in the pathophysiological mechanism of IBS. IBS patients have coexisting hyperactivity of the hypothalamic-pituitary-adrenal axis and increase in pro-inflammatory cytokine levels [130]. Chronic psychological stress leads to maladaptive increase in mucosal permeability and decrease in secretory response of intestinal epithelium to luminal stimuli [160]. It has been shown that the change in intestinal mucosal permeability is mediated by CRF [161,162].

Within the realm of gastrointestinal disorders, inflammatory bowel disease (IBD), which includes the two distinct disease patterns of ulcerative colitis (UC) and Crohn’s disease (CD) has attracted attention as a disorder with an aberrant GIT microbial signature [163-167]. Altered microbiota is also evident in animal models of inflammation relevant to IBD with a dramatic increase in the Proteobacteria classes of bacteria evident [168]. Furthermore, in terms of exogenous microbial threats, the frequency of Clostridium difficile has been shown to be higher in IBD and may trigger relapse where the disease is established but in remission [169]. It is well recognized that psychological stress, a factor which can perturb the microbiota, exacerbates the condition [170,171]. A number of strands of evidence support a role for the microbiota in the pathophysiology of IBS and chief among these is the supporting data for PI-IBS, a term which describes the development of IBS following an episode of bacteriologically confirmed gastroenteritis [115,172].





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