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Abstract

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

Disturbed bidirectional pathways between the (central) nervous system and immune system have been implicated in various mental disorders, including depressive and neurodevelopmental disorders. In this minireview, the role of the neuro-immune axis and its targetability in relation to major depression and autism spectrum disorder will be discussed. All together, the management of these and possibly other multi-factorial mental disorders needs a new and integrated therapeutic approach. Pharmacologically bioactive molecules as well as medical nutrition targeting the (gut)–immune–brain axis could be such an approach.


Blalock's Sixth Sense

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

In 1984, Blalock proposed that the immune system also serves a sensory role, a ‘sixth sense’, to detect factors the body cannot otherwise hear, see, smell, taste or touch [1]. The immune system has evolved to detect foreign entities such as pathogens, tumours and allergens with great sensitivity and specificity. Consequently, as a sensory organ, it would be a means to signal and mobilize the body to respond to these challenges including the (central) nervous system. As individual leucocytes are not physically connected to the nervous system, the question arises how such signalling works. Nowadays, a lot of scientific evidence exists demonstrating bidirectional pathways between the (central) nervous system and immune system. In this minireview, the role of the neuro-immune axis and its targetability in relation to neurological disorders, depression and autism will be discussed.

Neuro-Immune Axis: Some Facts

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

Firstly, nerves and immune cells are found in close proximity in the periphery as well as in the central nervous system (CNS). Outside the CNS, this close contact between nerve endings and immune cells is even enhanced during inflammatory responses at interfaces with the external environment, for example in the skin and at mucosal sites. Association between nerve fibres and immune cells helps to determine whether there is a local threat that requires an (immune) response: the so-called neurogenic inflammatory response [2, 3]. The nerve endings originating from peripheral sensory neurons have two functions: firstly, to conduct (electrical) signals from the periphery to the CNS and secondly, the release of neuropeptides and neurotransmitters that can participate in the immune/inflammatory response close by. Although the CNS has long been regarded as an immune-privileged organ, recent research has shown that the CNS is a highly immunologically active organ with complex innate immune responses [4]. Microglial cells are the resident macrophages of the CNS, align neuronal synapses and are important in controlling neuronal proliferation and differentiation [5]. In addition to microglial cells, in the CNS, astrocytes are the most abundant cell type. Astrocytes contribute to the mechanical construction of nervous tissue in the brain and are important for the generation and maintenance of the blood–brain barrier (BBB). There is a lot of evidence that astrocytes can sense inflammatorily an environment and consequently can respond by changing their cell phenotype to react in an immunological way. In addition, astrocytes can regulate the lymphocyte immune response in the brain via the release of chemokines and cytokines [6]. Under pathological conditions in the brain, lymphocytes are found crossing the BBB resulting in additive immune responses in the neuronal network of the brain.

Secondly, the expression of cytokines, chemokines and their receptors has been demonstrated on peripheral as well as central nerves. For examples, enhanced neuronal TNF-α and its receptors TNF-α R1 and R2 have been demonstrated in dorsal root ganglia (DRG) neurons as well as in neurons of the brain strongly associated with inflammation [7, 8]. Research has also demonstrated that neurons express interleukin and chemokine receptors that could play a role in neuronal inflammation, dysfunction via (de)sensitization of nociceptive receptor, pain and CNS-mediated disease symptoms [1, 9]. Besides cytokines and chemokines, also immunoglobulins and their Fc receptors have been detected in neuronal sources. Ig-free light chains and IgE are able to mediate antigen-specific responses (sensitization and activation) in cultured murine DRG [10]. More recently, in murine as well as human PNS and CNS neurons, IgG protein has been detected but further research is necessary to elucidate the biological function of this neuronal IgG in the neuroimmune crosstalk [11]. The direct immunoglobulin–neuron link may reveal a novel potential pathway of antigen-specific neuronal activation in sensations such as pain and itch, but also in local inflammation in chronic inflammatory diseases.

Thirdly, non-specific leucocytes and lymphocytes produce neurotransmitters and neuropeptides. The neurotransmitter serotonin is long known to have non-neuronal cellular sources such as enterochromaffin cells in the gut and mast cells [12]. Acetylcholine and other ligands for nicotinic acetylcholine receptors are synthesized by activated B and T lymphocytes and are thought to regulate local innate immunity [13] or inhibit vagus-induced cytokine production in an autocrine way [14]. In addition, several neuropeptides are released by lymphocytes, macrophages, dendritic cells, eosinophils and mast cells upon innate activation [15, 16]. Cytokine-primed lymphocytes can locally secrete opioid peptides to induce local analgesic effects via JAK/STA1/3 activation in the cell [1, 17]. Opioid peptides are found in mast cells, granulocytes, lymphocytes and macrophages. The prevailing peptides are b-endorphin and Met-enkephalin, but dynorphin and endomorphins were also detected. It is suggested that in a stressful (e.g. inflammation) situation, opioids are tonically released in inflamed tissue and activate peripheral opioid receptors to attenuate clinical pain [18]. Another example is the production of neurotrophins such as brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) by activated lymphocytes that are suggested to be involved in a neuroprotective effect during autoimmune reactions in the brain [19]. Vice versa, non-specific leucocytes and lymphocytes were reported to express classical neuronal receptors. Besides opioid receptors, a prominent example is nicotinic cholinergic receptors. Non-neuronal α7-nicotinic cholinergic receptors upon activation exert anti-inflammatory and immunomodulating activities on multiple cell types, including as T cells, B cells, dendritic cells, mononuclear phagocytes and polymorphonuclear leucocytes [20, 21]. Dendritic cells express various receptors for neurotransmitters and neuropeptides like acetylcholine, norepinephrine and vasoactive intestinal peptide that alter dendritic cell costimulatory molecule expression, cytokine release and subsequent T-cell activation in an anti-inflammatory fashion [21].

Lastly, cytokines like interleukin 1β (IL1β), IL6 and tumour necrosis factor-α (TNF-α) can directly act on the nervous system to affect behaviour. Cytokines are important for the development and normal brain function and have the ability to affect neural activity and neurotransmitter systems that results in behavioural changes. Inflammation (e.g. activation of the innate and/or adaptive immune system) or inflammatory cytokine administration produces adaptive behavioural responses that serve to safeguard energy use to fight infection or recovery from injury (so-called sickness behaviour) [22-24]. However, chronic exposure to elevated inflammatory cytokines and long-lasting alterations in CNS neurotransmitter levels may contribute to the development of mental disorders such as autism, schizophrenia and depression [23, 25-27]. Mechanisms of cytokine-induced behavioural effects involve activation of inflammatory signalling pathways in the brain that results in changes in monoaminergic, glutamatergic and neuropeptidergic systems, and decreases in growth factors, including BNDF [28, 29].

The hypothalamic–pituitary–adrenal (HPA) axis deserves special attention. Glucocorticosteroids play an important role in regulating homoeostasis under basal and (immune)-challenged conditions. Glucocorticosteroids protect the host from the consequences of an overactive inflammatory immune response and have been shown to be one of the most potent anti-inflammatory compounds ever. A disturbed HPA axis response has been associated with allergic and autoimmune diseases as well as with psychiatric and neurodevelopmental disorders. The latter disorders are in turn associated with an enhanced inflammatory status. Pro-inflammatory cytokines such as TNF-α, IL1 and IL6 act at all three levels of the HPA axis: (1) paraventricular nucleus of the hypothalamus resulting in the release of corticotrophin-releasing hormone (CRH); (2) the pituitary that secretes adrenocorticotropic hormone (ACTH); and 3. the adrenal cortex. The overall chronic inflammation or stress-induced glucocorticosteroid response will eventually lead to glucocorticosteroid resistance at the level of the glucocorticoid receptor [30].

Concept 1: Afferent Pathways of the Neuro-Immune Axis

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

The afferent nerve pathways can be regarded as an immune-sensing pathway. Either innate or adaptive activation of the immune system regulates CNS activity through the release of inflammatory mediators such as cytokines, chemokines and even immunoglobulins that bind to receptors located peripherally on the vagal or sympathetic nerve endings or centrally within the CNS or at the blood–brain barrier (BBB). Cytokines and chemokines act on afferent parasympathetic, sympathetic and sensory nerve endings to cause sickness behaviour and, in relation to chronic inflammation, will eventually lead to behavioural and cognitive changes that are associated with mental disorders. Lymphocyte-derived neuropeptides and neurotransmitters modulate pain sensation by acting on peripheral sensory nerves and under chronic conditions may lead to hyperalgesia. Inflammation-induced cytokine release can also act on the HPA axis to produce CRH and ACTH, respectively, resulting in a glucocorticosteroid response. Finally, white blood cell-derived neurotransmitters, neuropeptides and hormones cross the BBB and affect signalling within the CNS (fig. 1) [1, 31].

image

Figure 1. Immunosensing afferent nerve pathways possibly involved in mental disorders. Cytokines and chemokines act on vagal nerve endings leading to behavioural and cognitive deficits. Lymphocyte-derived neurotransmitters and neuropeptides act on sensory nerve endings and modulate pain sensation. Cytokines, like IL1β, act on the hypothalamus and pituitary to produce CRH and ACTH leading to a corticoid response. Leucocyte-derived cytokines, chemokines and hormones cross the blood–brain barrier (BBB) and affect the CNS. Adapted from [1].

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Concept 2: Efferent Pathways of Neuro-Immune Axis

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

The psychological or inflammatory stress-triggered CNS communicates to the immune system by activating the sympathetic and parasympathetic neurons or the HPA axis to release the neurotransmitter norepinephrine, acetylcholine or corticosteroid hormones, respectively. Lymphocytes and non-specific leucocytes express receptors that bind norepinephrine, epinephrine, acetylcholine and corticosteroids, providing a mechanism for these ligands to activate intracellular signalling pathways, which regulate the level of immune cell activity. Vagal acetylcholine acts on macrophages or dendritic cells to blunt pro-inflammatory cytokine synthesis and consequently down-regulate the adaptive immune system. Sympathetic out-flow also can regulate the function of immune tissues and their cells. Neuroendocrine hormones from the hypothalamic–pituitary–adrenal axis modulate lymphocyte function (fig. 2) [1, 31].

image

Figure 2. Immunomodulating efferent nerve pathways possibly involved in mental disorders. Vagal nerve-derived acetylcholine acts on innate immune cells, such as macrophages and dendritic cells, to dampen pro-inflammatory cytokine release. Hormones from the hypothalamus–pituitary–adrenal axis influence lymphocyte function. Released neurotransmitters and neuropeptides from sympathetic and sensory nerve ending, respectively, regulate the function of immune cells. Adapted from [1].

Download figure to PowerPoint

The Neuro-Immune Axis in Major Depressive Disorder

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

Major depressive disorder (MDD) is characterized by persistent depressed mood, loss of interest and the inability to experience pleasure (anhedonia) that affects day-to-day life. As described above, cytokines have been demonstrated to influence neurocircuitry and neurotransmitter systems in the CNS resulting in behavioural and cognitive changes [1, 28, 32]. Chronic exposure to pro-inflammatory cytokines results in persistent alterations in neurotransmitter function and behaviour that in turn may contribute to the development of mental disorders such as MDD [28]. A growing body of evidence shows increases of pro-inflammatory cytokines, such as TNF-α, IL1-β and IL6 in blood and cerebrospinal fluid of patients suffering from MDD [33, 34]. It has been shown that cytokines (for example, IL2 or interferon-α used for antitumour therapy) induce depression in human beings and laboratory animals [35-37]. In addition, patients suffering from MDD show increased inflammatory responses to stress [38]. Polymorphisms of genes encoding for immune and inflammatory molecules have been identified in association with MDD, further strengthen the role of the neuro-immune axis in depression [39-41]. Nevertheless, the aetiology of cytokine-induced MDD is largely unknown.

Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

The link between immune factors and monoamine transporters

The role of serotonin and the serotonin transporter (SERT) has been studied intensively in MDD, and an important role for altered serotonergic neurotransmission in depression has been proposed [42]. In addition, selective serotonin reuptake inhibitors (SSRIs), the first-line treatment for MDD, have been demonstrated to decrease pro-inflammatory cytokines, such as IL1β, IL6, IL12, TNF-α and transforming growth factor-β as well [43-45]. Furthermore, the pro-inflammatory cytokines TNF-α, interferon-α and IL1β increase SERT function [46-49].

Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria that binds to toll-like receptor 4 (TRL4) leading to the rapid systemic release of pro-inflammatory cytokines, induces anhedonia in rats and mice as shown by increased thresholds in an intracranial self-stimulation (ICSS) paradigm [50-52]. LPS-induced anhedonia was associated with increased extracellular levels of monoamine metabolites of serotonin and dopamine in the nucleus accumbens and prefrontal cortex, suggesting increased SERT and dopamine transporter (DAT) function [53]. Similar results, although less profound, were found after peripheral administration of TNF-α. Anhedonia induced by LPS was totally abolished in SERT(−/−) rats and as expected was still present in SERT(+/+) and to a lesser extent in SERT(+/−) rats [52]. Moreover, simultaneous inhibition of the reuptake of dopamine, serotonin and norepinephrine by a triple reuptake inhibitor (partly) attenuated the LPS-induced increase in monoamine metabolite formation in the brain. This triple reuptake inhibitor induced a long-lasting hedonic effect assessed by the ICSS paradigm in rats [54]. In conclusion, intact SERT function is needed for pro-inflammatory cytokine-induced anhedonia, and therefore, these cytokines can be regarded as novel targets in MDD.

Targeting the cytokines TNF-α, IL1-β and IL6 in major depressive disorder

Nowadays, monoclonal antibodies as well as small molecules targeting cytokines are commonly used for the treatment for chronic inflammatory diseases, such as rheumatoid arthritis or inflammatory bowel diseases. Only limited data are available on the effects of these cytokine-blocking approaches in MDD. Antidepressant and anxiolytic effects of the TNF-α receptor antagonist, etanercept, were demonstrated in rats [55]. Recently, in human beings, the anti-TNF-α-antibody, infliximab, has been shown to improve depressive symptoms in MDD patients that were resistant to antidepressive treatments [56]. The potential beneficial antidepressant effect of infiximab depended on the baseline levels of inflammatory biomarkers. Furthermore, IL1 receptor −/− mice and mice that have brain-restricted over-expression of IL1R antagonist are resistant to develop chronic mild stress-induced depression [57]. In addition, elderly people with high plasma levels of IL1R antagonist, which was associated with a low grade of inflammation, have a higher risk of developing depressive symptoms over time [58]. These results suggest that lowering IL1β brain levels might be beneficial for patients suffering from MDD [59].

In addition to IL1β, IL6 has been identified as a potential biological target for the treatment for MDD. In a meta-analysis, an association between MDD and IL6 has been demonstrated [33]. In addition, in women suffering from MDD, high IL6 levels were associated with low performance in verbal memory [60]. No reports have been published on the effects of blocking IL6 in MDD patients, but in a clinical trial, the anti-IL6 receptor antibody, tocilizumab, improved significant rheumatoid arthritis-associated fatigue in 62% of the patients [61, 62].

Immunomodulating drugs

In animal models for depression induced by LPS and chronic stress, cyclooxygenase (COX) inhibitors have been demonstrated effective [63-65]. In patients suffering from MDD, celecoxib, a selective COX2 inhibitor as well as acetylsalicylic acid, a non-selective COX blocker, improved the antidepressant effect of reboxetine, an norepinephrine reuptake inhibitor [66, 67]. Similar effects were demonstrated for omega-3 fatty acids that have shown to have potent anti-inflammatory effects [68]. In addition, a meta-analysis reported direct effects of omega-3 fatty acids in MDD [69]. In addition, p38 mitogen-activated protein kinase (p38 MAPK) inhibitors may have potential antidepressant effects [28, 49]. P38 MAPK is an inflammatory intracellular signalling molecule that currently is in clinical investigation as target in chronic inflammatory diseases. Nuclear factor (NF)-κB and nitric oxide, other inflammatory signal transducers, might also be a novel target of interest in treatment for MDD. Inhibition of both signal transduction molecules has been shown to have antidepressant effects in animal models [28].

The Gut–Immune–Brain Axis in Autism Spectrum Disorders

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

Autism spectrum disorder (ASD) is a heterogeneous cluster of severe neurodevelopmental disorders. It is characterized by impairments in social interaction and communication and the presence of restricted, repetitive and stereotyped interests and behaviours [70]. Increased immune activation is repeatedly reported in ASD patients. In post-mortem brains of ASD patients as well as in various animal models, marked activation of astroglia and microglia is observed, indicative of neuroinflammation [71-75]. In addition, enhanced levels of a wide range of cytokines and chemokines were found in the brain and in the cerebrospinal fluid of autistic children [76, 77]. Peripheral immune abnormalities in autistic individuals have also been reported, including differential monocyte responses to in vitro stimulation, dysfunctional natural killer (NK) cells and altered serum immunoglobulins, cytokine and chemokine levels [29, 78-88].

The intestinal tract has a very important immune function, but also exerts an important neurological function and is called ‘the second brain’, because of its abundant amount of enteric nerves and networks. Via these nerves, but also through other pathways, the intestinal tract is able to affect the brain and vice versa [89, 90]. Evidence is emerging that intestinal immune disturbances can influence the brain and consequently behaviour and cognition. A higher prevalence of ASD was found in paediatric patients with chronic gastrointestinal diseases [91]. In addition, gastrointestinal discomfort, changes in gut microflora, food aversion and increased intestinal permeability have been shown to correlate with the severity of disturbed behaviour in ASD patients [92-98]. Worthwhile mentioning is the fact that, besides the immunomodulatory role of the microbiome, recent accumulating data now exist showing that intestinal bacteria can communicate with the CNS through neuronal, immune and endocrine pathways and consequently influence brain function, behaviour and cognition [99]. Although still under debate, (non-)IgE-mediated food allergy has been suggested to be involved in ASD [100-103]. In ASD children, allergic reactions against milk protein have been suggested to trigger behavioural abnormalities, and milk intake was reported to be a predictor of constipation in this population [83, 104]. A gluten and milk protein-free diet improved autistic behaviours and reduced the enhanced intestinal permeability [96, 105, 106].

Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

As existing evidence indicates the involvement of the gut–immune–brain axis in ASD, targeting the intestinal tract using immunomodulating medical food concepts could be of potential therapeutic value [107, 108]. In murine models for food allergy disturbed social interaction, repetitive behaviour, anxiety, food aversion and cognitive deficits, all characteristics of ASD have been demonstrated to be associated with neuroinflammation and changed neuronal activation and different monoamine levels in brain areas that are related to social, emotional and cognitive behaviour [98, 109-113]. Moreover, recent research has reported that ASD and accompanying gastro-intestinal symptoms are characterized by distinct and a less diverse gut microbiome [100, 113-115]. Modulation of gut bacteria with short-term antibiotic treatment has been shown to lead to improvement in behavioural deficits in ASD [114]. Specific beneficial bacteria (so-called probiotics, lactic acid-producing bacteria and bifidobacteria) influence the microbiome composition, intestinal barrier and alter the mucosal immune response and possibly influence the brain [116]. In addition, the underlying mechanism of non-digestible oligosaccharides (so-called prebiotic fibres) includes improved microbiome via the induction of growth of beneficial bacteria and via direct action on epithelial cells restoration of intestinal immune homoeostasis [117]. Thus, treatment with specific beneficial bacteria in combination with non-digestible oligosaccharides to induce alterations in the microbiome, restoration of intestinal epithelial barrier and mucosal immune homoeostasis could be a novel approach to ameliorate gastrointestinal problems and even behavioural symptoms in ASD. Several studies have reported that dietary intervention with specific beneficial bacteria in combination with non-digestible oligosaccharides prevented food allergy in mice and man [117-120]. A recent study of food allergic reaction in mice towards hen's eggs protein demonstrated that besides increased levels of antigen-specific IgE levels, diarrhoea and disturbed antigen-specific Th2/regulatory T cell balance in the ileum, impaired behaviour and memory deficits were evident [112]. These aberrations ran in parallel with decreased expression of mRNA of BDNF and a disturbed BBB in the hippocampus. In addition, hippocampal neuroinflammation was found characterized by increased numbers of activated macrophages and Th cells. Dietary intervention with specific beneficial bacteria in combination with non-digestible oligosaccharides (Bifido Breve with short chain galacto-oligosaccharides and long-chain fructo-oligosaccharides, Bb/GF) normalized OVA-induced aberrant behaviour and cognition and cellular and molecular changes in the brain. These data demonstrate that food allergic peripheral inflammation modifies the brain inflammatory status and dampens the behavioural and cognitive abilities suggesting that food allergy may play a role in the development and/or progression of neurodevelopmental disorders. In addition, targeting the gut–immune–brain axis with dietary intervention may have implications for treatment of patients suffering from ASD. The molecular mechanism by which specific beneficial bacteria in combination with non-digestible oligosaccharides is protective in food allergy involves galectins. Galectins are soluble type lectins that bind galactose/b-galactoside containing glycans [117, 121]. Intestinal epithelium-derived galectin 9 is responsible for the immunomodulatory anti-allergic effects of Bb/GF [120, 122]. Not much is known about the role of galectins in neuroinflammation and brain development and function. Microglial galectin 3 is involved in brain injury and neuroinflammation [123-125]. Neuronal galectin 4 is required for neuronal differentiation in CNS [126]. Astrocyte-derived galectins-1 plays a protective role in inflammation-induced neurodegeration and is involved in neurogenesis [127, 128]. As for galectins-9, increased expression is found in IL1β-stimulated human astrocytes and in spinal fluid of ALS patients [125, 129]. Dietary and/or pharmacological modulation with small molecules targeting the galectin response in neurodevelopment disorders such as ASD could be a future therapeutic approach.

Conclusions

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References

In this minireview, the role of disturbed bidirectional pathways between the (central) nervous system and immune system, regarded as the (gut)–immune–brain axis, in mental disorders has been described in relation to MDD and ASD. This concept can be translated to other mental disorders as well, including schizophrenia, attention deficit disorders, Parkinson's Disease and Alzheimer's disease.

The management of these multi-factorial mental disorders needs a new and integrated therapeutic approach, and prospects for novel treatment are as follows:

  1. Targeting the neuroinflammatory response in the CNS that disturbs neurotransmitter levels and connectivity, with existing immunomodulatory and anti-inflammatory drugs or/and medical food concepts such as omega-3 fatty acids.
  2. Targeting the HPA axis and resolve glucocorticosteroid resistance.
  3. Targeting the disturbed (intestinal) immune system with existing immunomodulatory drugs such as cytokine-specific therapeutic antibodies.
  4. Targeting peripheral enteric, parasympathetic or sympathetic nerves with anti-inflammatory neurotransmitters and neuropeptides.
  5. Targeting the disturbed intestinal barrier with immunomodulatory drugs and/or medical food concepts, such as non-digestible oligosaccharides and specific beneficial bacteria.
  6. Targeting the disturbed intestinal microbiome with antibiotics, specific beneficial bacteria and/or non-digestible oligosaccharides.

References

  1. Top of page
  2. Abstract
  3. Blalock's Sixth Sense
  4. Neuro-Immune Axis: Some Facts
  5. Concept 1: Afferent Pathways of the Neuro-Immune Axis
  6. Concept 2: Efferent Pathways of Neuro-Immune Axis
  7. The Neuro-Immune Axis in Major Depressive Disorder
  8. Future Directions for Treatment of Major Depressive Disorder Targeting the Neuro-Immune Axis
  9. The Gut–Immune–Brain Axis in Autism Spectrum Disorders
  10. Future Directions Targeting the Gut–Immune–Brain Axis by Nutrition in ASD
  11. Conclusions
  12. Conflict of interest
  13. References
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