WHAT IS THE CLINICAL SIGNIFICANCE OF THE CHANGES TO THE GUT-BRAIN-AXIS MICROBIOTA IN INFLAMMATORY BOWEL DISEASE?

IBD pathogenesis is only partly understood, and some studies highlight a link with intestinal microbiota. In particular, the bidirectional relationship of the gut-brain axis, seems to be central also in the onset and development of IBD.

Furthermore, as discussed below, a confirmation of the influence of the microbiota on IBD pathogenesis is given by the benefits of using probiotics or prebiotics for these patients. The use of selected probiotics is effective in inducing and maintaining remission in ulcerative colitis (UC) [ 43 ] and in the treatment of pouchitis [ 44 ] , whereas the use of prebiotics has been shown to be successful in reducing inflammation and bringing about remission in UC [ 45 ] . Data are far less impressive in Crohn's disease (CD) [ 46 , 47 ] . Faecal transplantation also appears to produce a modest increase in remission rates in patients with IBD [ 48 ] .

Similar to IBS, there is an alteration of the balance between microbiota and the gastrointestinal tract, with the onset of dysbiosis [ 33 , 34 ] . The dysbiosis present in patients with IBD is characterized by reduced bacterial diversity, reduction of Bacteroidetes and Firmicutes, and an increase in Proteobacteria [ 35 ] , in particular Escherichia coli [ 36 ] . Other species such as Faecalibacterium prausnitzii and Roseburia hominis are selectively reduced in patients with IBD [ 37 , 38 ] . Patients with active IBD have a lower abundance of intestinal flora than patients in remission [ 39 ] . An alteration of intestinal bacterial flora in genetically susceptible individuals can lead to abnormal intestinal immune responses and intestinal imbalance [ 40 ] . Interestingly, antibiotics may have some effect on IBD symptoms [ 41 ] , and it is known that the predisposing genes involved in IBD pathogenesis are those with an important role in recognition of pathogen microbes [ 42 ] or in tolerance of commensals.

There are several murine models of IBD, which include, for example, the use of dextran sodium sulfate (DSS), the colorectal instillation of dinitrobenzenic sulfonic acid and 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) [ 61 - 67 ] , that show an increase in hippocampal, cerebral and hypothalamic pro-inflammatory cytokines. Indeed, the disruption of the blood-brain barrier and the leukocyte infiltration of the brain following colic inflammation leaves the CNS vulnerable to inflammation mediators and to substances of bacterial and viral derivation [ 67 ] .

Other animal models have been used to investigate the relationship between gastrointestinal disorders and psychological manifestations. For example, maternal separation is a stressor induced in the early stages of life [ 55 ] . Other examples of chronic stressors are housing problems [ 56 , 57 ] and overcrowding [ 58 ] , such stressors can induce gastrointestinal dysfunction or increase susceptibility to chemically induced colitis. These studies may explain the link between stress and gastrointestinal disorders and therefore IBS-like symptoms in patients with IBD, although not entirely specific to IBD.

IBD results in an inflammatory reaction in the brain, the activation of the hypothalamic-pituitary-adrenal axis and parts of the brain involved in behavioral alteration, an alteration of the blood-brain barrier and an intestinal-microbiota imbalance [ 49 ] . Pro-inflammatory cytokines play a crucial role in the IBD pathogenesis and interact with the CNS directly by means of the blood-brain barrier or via the vagus nerve [ 50 ] . Such inflammatory pathway via cytokines works by dysregulating HPA by over-activating microglia, altering neuroplasticity, and inducing structural and functional changes in the brain [ 49 ] . Several mouse studies showed that cytokines determine the activation of astrocytes, thus affecting neural functions during the processes of inflammation during the period between behavioral effects such as depression [ 51 ] . These in fact can affect the HPA axis, activating it and consequently causing an increase in glucocorticoids involved in pathogenesis of depression [ 52 - 54 ] .

What is the role of the stress, considered to be a perturbating agent of brain-gut-microbiota axis, in IBD?

Stress may have a deleterious effect on IBD, through several pathways, as reviewed by Bonaz et al[68], including the activation of mast cells and the CNS and the inhibition of the vagus nerve on inflammatory pathways, decreasing its anti-inflammatory effects and increasing sympathetic tone[69]; this may lead to the inhibition of immune defenses and development/increase of intestinal inflammation. It has been shown that stress induces an imbalance in the ANS in patients with IBD and a vagal dysfunction in patients with UC[68]. For patients with IBD there is a correlation between ANS imbalance, psychological disorders and pro-inflammatory profiles[70,71].

Important factors are also the effect of early childhood stressful events on colitis (the HPA axis is determined by early childhood events, and neonatal inflammatory stimuli exert long-term changes on HPA activity) and the impact of depression on exacerbation of colitis possibly through proinflammatory cytokines. Last, but not least, stress and CRF increase intestinal permeability as observed in mouse models, with passage of intestinal bacteria through the epithelial barrier[72,73]. In patients with IBD, changes in stress-mediated intestinal microbiota may create susceptibility toinfection and alter neural activity in stress-sensitive areas of the brain[74].

Dysbiosis can directly affect mental health in patients with IBD[75]. Behavioral disorders such as stress, anxiety and depression may change the composition of the intestinal flora and may influence the activity and recurrence of CD as demonstrated by numerous studies[76,77]. Recent studies have highlighted that the most involved mechanisms in stress signaling, on the cellular level, are endoplasmic reticulum stress, oxidative stress and hypoxia[78]. The subsequent host cellular response to these mechanisms interact with gut microbiota, thus modifying the microbiological microenvironment of the gastrointestinal tract[78].

Indeed, exposing mice to stressful stimuli resulted in the alteration of gut microbiota by reducing anti-inflammatory bacteria, in particular Lactobacillus[79-81] and Lachnospiraceae[79,82]. Furthermore, psychological stress reduces the biosynthesis and metabolism of short chain fatty acids, which may increase susceptibility toward intestinal inflammation and further IBD[79,83].

It is now known that IBD is associated with psychological symptoms such as anxiety and depression, prevalent during active disease states and, as also observed in animal models of IBD, there are no differences in occurrence of CD and UC. Mood disorders may also influence the course of IBD because it is hypothesized that stress may be a risk factor for recurrence for patients of this type[84]. Probably, the depressive behavior observed in patients with IBD constitutes a comorbidity[49], which worsens the state of intestinal disease[85].

In the murine models of DSS colitis, induction of depression with olfactory bulbectomy or intracerebroventricular injection of reserpine was associated with the reactivation of inflammation in mice with quiescent colitis, with effects mediated by the increase of pro-inflammatory cytokines[86]. In contrast, the administration of tricyclic antidepressants prevented the reactivation of colitis for depressed mice but not in mice without depression[87]. As previously mentioned, in many studies conducted on adults and children it is clear that both UC and CD are associated with a higher incidence of psychological symptoms[88], with an association between disease and mood. These data are confirmed by a recent systematic review, with equal rates in both sexes, but slightly higher for CD than for UC[89]. Depression and anxiety are 2 to 3 times higher in patients with IBD than in the general population, affecting respectively 25% and 30% of people with IBD[90]. Patients with IBD who suffer from psychiatric illness have a reduced chance of remission, and the condition worsens over a longer period of time[91]. An increased risk of psychiatric disorders is also observed in adolescents and children with IBD[92]. Adolescent patients with IBD are more likely to have mild behavioral and cognitive disturbances, particularly verbal memory loss[93]. Active IBD correlates significantly with increased psychological disorders[94,95] and the highest pain scores are strong predictors of depression in UC and CD[96]. In patients with UC, depression is usually diagnosed in the year before the onset of disease symptoms, while for patients with CD depression follows the diagnosis of the disease[97]. Being female is also a predictor of anxiety and depression with IBD[98,99], with IBD having a bigger effect on health-related quality of life[100] and greater concomitance of symptoms similar to IBS[101]. The manifestation of mood disorders by IBD patients correlates with a greater risk of requiring surgery and of incurring secondary FGID development[102].

In the Manitoba IBD study, a cohort of patients with IBD monitored every 6 mo, and with annual interviews over a period of 12 years, psychological disorders were highlighted as a major factor in health perception for the IBD cohort[103]. In another study involving 600 subjects with IBD, using health problem surveys conducted quarterly for 1 year, about 50% of patients showed a certain type of stress, most frequently family stress, followed by work or school and finance related stress[104]. It was observed that psychological factors, important life events, high anxiety and highly negative feelings during the previous 3 mo were closely associated with the occurrence of a flare up. Targownik et al[105] observed that perceived stress correlated closely with the symptoms of active disease, but without any correlation between the symptom scores and the degree of inflammation associated with CD, and only a weak correlation associated with UC, concluding that there may be an association between the perceived stress and the symptoms of IBD regardless of inflammatory activity.

Furthermore, IBD also influence the volume of gray matter and the size of the brain according to an MRI study, which observed that patients with CD displayed a decrease in the volume of gray matter in the frontal cortex and in the cortex of the anterior cingulate[106].

Interestingly, Gracie et al[107] recently found evidence in a 24 mo study of CD or UC patients of a reciprocal relationship between IBD occurence or severity and psychological illness, thus concluding that IBD patients’ psychological health should be monitored.