Brain-gut axis as an example of the bio-psycho-social model in Childhood Neurobehaviour Disorders


Dr Widodo Judarwanto SpA


ALLERGY BEHAVIOUR CLINiC
PICKY EATERS CLINIC (Klinik Kesulitan Makan Pada Anak)
JL Rawasari Selatan 50, Cempaka Putih Jakarta Pusat
Jl Taman Bendungan Asahan 5 Bendungan Hilir Jakarta Pusat
Rumah Sakit Bunda Jakarta, Jl Teuku cikditiro 28 Jakarta Pusat
telp : (021) 70081995 - 4264126 – 31922005
email : wido25@hotmail.com , htpp://www.childrenfamily.com


Introduction

In research often apply hypothesis testing which assumes a linear, causal relationship between two or more factors. This is a valid way of testing fragments of a complicated chaos of known and unknown elements. Western medical education and research has, for more than a century, been dominated by a dualistic view of human nature, and from the psychoanalytical tradition (based on Freud's work). Focused to differentiate between biological (physical, organic, somatic) on one side and psychological (thoughts and emotions) on the other. This dualistic view, emphasising that psychological and biological are two entirely different aspects of human life, is mechanistic and reductionistic, and in today's world a non-scientific position to hold.1 In spite of many decades of research, there is no evidence that emotions can "pile up" somewhere in the body and that psychological conflicts, if unresolved, are converted to somatic symptoms or diseases. On the contrary, science is moving into a position of integration, and the cognitive science (such as neuroscience) has developed rapidly in recent years. People cannot experience an emotion or think a thought without biological correlates. Unresolved mental conflicts lead to activation of the central nervous system (CNS), and of the autonomic systems. Activation theories, such as the "cognitive activation theory of stress" states that the stress response is the same as activation a general alarm system operating whenever the organism registers that there is a discrepancy between what is expected and what really exists.2 The brain-gut axis is a good example of a circular relationship between different factors, and illustrates that research on interrelationship and interaction is necessary to understand the whole picture (fig 1). Chronic functional gastrointestinal symptoms can be seen as a result of dysregulation of intestinal motor, sensory, and CNS activity.



Figure 1 Brain-gut axis (with emphasis on the central nervous system (CNS) psychological process). ENS, enteric nervous system.

Gutbrain Axis in Childhood Neurology Disorders
In functional gastrointestinal disorders, subjective health complaints, such as nausea, discomfort or abdominal pain, constipation, and diarhhoe are the major targets for treatment. Perception of somatic stimuli is probably different for different patients. Sensitisation is defined as increased reactivity to stimuli in pain pathways, and visceral hypersensitivity is the exaggerated experience of pain in response to mildly painful or even normal visceral stimuli. Nociceptors are activated, and the threshold decreased in the injured part (primary hyperalgesia) and surrounding tissue (secondary hyperalgesia). This increased responsiveness of nociceptors is called sensitisation. Only spinal afferents appear to be involved in the transmission of visceral pain. It is specific to the bowel, and not similar to somatic pain. The opposite of sensitisation is habituation, decreased efficiency due to repeated use. Usually there is no habituation to painful stimuli. Sensitisation may occur in the dorsal horn of the spinal cord but possibly also at the level of the limbic structures.7 The mechanism may be that of kindling, a decreased threshold for electric after-discharge produced by electrical or chemical stimulation of limbic structures (amygdala, hippocampus). The word somatisation is used in modern diagnostic systems such as ICD-10 and DSM-IV. Freud defined the word as a way to express emotions or psychological conflicts, but today the word is a descriptive term meaning somatic complaints not fully explained by any known medical condition. The patient with somatisation has a tendency to notice many bodily sensations and to interpret them as symptoms of organic disease. To obtain a diagnosis of somatisation disorder there must be pain in four different sites or functions: gastrointestinal complaints, sexual dysfunction, muscle skeletal symptoms, and a pseudoneurological complaint (dizziness, vertigo, seizures, etc). Subjective health complaints are very common in the normal population, especially exhaustion, fatigue, muscle pain, and gastrointestinal complaints.8 Some people seem to be more sensitive than others to these normal complaints. These patients have a sensitive mind in a sensitive body. Sensitisation has been suggested as the underlying mechanism for somatisation, and this can occur at different levels of the brain-gut axis. In addition to the mechanisms in the CNS, the model also assumes that psychological factors influence the synaptic mechanisms and feed forward loops from the brain. These central pathways, descending from the brain, modulate the transmission of nociceptive information at the spinal cord level. Melzak and Wall have pointed out the possibility that affective and cognitive factors, such as anxiety, attention, and expectation can influence pain via these descending pathways.9
Patients with somatisation are diagnosed differently in different countries and by different specialists. Common diagnoses are chronic fatigue syndrome, multiple chemical sensitivity, food intolerance, functional dyspepsia, irritable bowel syndrome, fibromyalgia, etc. These conditions should not be seen as psychological problems. Whether symptoms are seen as extraintestinal disturbances of functional gastrointestinal disorders or extramuscular disturbances of fibromyalgia depends on different factors. In our own studies we have found that somatisation differentiates between functional and organic gastrointestinal disorders.10 Some people probably have a sensitive mind and a sensitive body, some a sensitive body and a normal mind, and some a sensitive mind in a normal body. In functional gastrointestinal disorders, sensitisation of specific neurones may be important, and in the brain-gut axis treatment may be aimed at any point where it is possible to influence the individual. This can be a combination of somatic and psychological approaches, including drugs, physical training, and psychotherapy.
Gutbrain Axis in Childhood Behaviour Disorders
Primary gastrointestinal pathology may play an important role in the inception and clinical expression of some childhood developmental disorders, including autism, ADHD, learning disorders etc. During the past 4 years, it has been my privilege to work with one of the finest pediatric gastroenterology teams in the world, headed by John Walker-Smith, on an innovative and challenging investigation of gastrointestinal pathology in children with autism. We believe that this work will provide new and important insights into the pathogenesis of this devastating condition. Although the primary causes of autism may be diverse, clues to the possible origin of the disease may be found in the history and clinical investigation of affected children. This talk focuses on the significance of gastrointestinal symptoms in autistic children, in particular, a subset of children for whom the clinical course is characterized by regression after at least 12 to 15 months of normal development.
In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical, metabolic, and immunologic abnormalities that a primary genetic cause cannot readily account for. The gut-brain axis is central to certain encephalopathies of extracranial origin, hepatic encephalopathy being the best characterized. Certain commonalties between the clinical characteristics of hepatic encephalopathy and an increasingly common autistic phenotype (developmental regression in a previously normal child accompanied by immune-mediated gastrointestinal pathology) have led to the hypothesis that an analogous mechanism of toxic encephalopathy may exist in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and evidence suggests that opioid peptides may be among the central mediators of the respective syndromes. Generating biologically plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extracranial origin.
Interest is growing in the role of the gut in childhood developmental disorders, principally autism. Some of the earliest commentators on pathobiologic mechanisms in autism made the observation that gastrointestinal symptoms are common in children with developmental disorders. Dohan wrote: K Soddy (University College Hospital, London) wrote me that he noted that recurrent gastrointestinal upsets were a constant feature of autistic children and that, among other symptoms, the deteriorating autistic child often has acute diarrhea (12). These observations have been iterated in parental accounts (13), but largely ignored by the medical profession (Bauman M, personal communication). More recently, in a systematic analysis of an unselected population of 385 children on the autistic spectrum, clinically significant gastrointestinal symptoms occurred in 46% compared with 10% of 97 developmentally normal pediatric controls (odds ratio, 7.4; confidence intervals, 3.60-15.65;P < 0.0001) (14). We investigated gastrointestinal symptoms in more than 150 autistic children and reported out initial experience (15,16). In this cohort, developmental regression and loss of acquired skills, sometimes occurring precipitously over a period of days to weeks, followed a period of initial normal development; in short, the children became encephalopathic. Longstanding intestinal symptoms, including chronic constipation with overflow, and provocation of both gastrointestinal and behavioral symptoms by certain foods, are typical of this group of children and have been described by others (17). However, even among some pediatric gastroenterologists, the perception remains that such symptoms are to be expected in children with developmental disorders, reflecting effect rather than possible cause. In the absence of thorough investigation, the basis for this presumption is unclear. It is essential, ab initio, to ask whether these symptoms reflect underlying pathology of the gastrointestinal tract.
In addition to frequent gastrointestinal symptoms, children with autism often manifest complex biochemical, metabolic, and immunologic abnormalities that a primary genetic cause cannot readily account for. The gut-brain axis is central to certain encephalopathies of extracranial origin, hepatic encephalopathy being the best characterized. Certain commonalties between the clinical characteristics of hepatic encephalopathy and an increasingly common autistic phenotype (developmental regression in a previously normal child accompanied by immune-mediated gastrointestinal pathology) have led to the hypothesis that an analogous mechanism of toxic encephalopathy may exist in patients with liver failure and some children with autism. Aberrations in opioid biochemistry are common to these two conditions, and evidence suggests that opioid peptides may be among the central mediators of the respective syndromes. Generating biologically plausible and testable hypotheses in this area may help to identify new treatment options in encephalopathies of extracranial origin.
Interest is growing in the role of the gut in childhood developmental disorders, principally autism. Some of the earliest commentators on pathobiologic mechanisms in autism made the observation that gastrointestinal symptoms are common in children with developmental disorders. Dohan wrote: K Soddy (University College Hospital, London) wrote me that he noted that recurrent gastrointestinal upsets were a constant feature of autistic children and that, among other symptoms, the deteriorating autistic child often has acute diarrhea (12). These observations have been iterated in parental accounts (22), but largely ignored by the medical profession (Bauman M, personal communication). More recently, in a systematic analysis of an unselected population of 385 children on the autistic spectrum, clinically significant gastrointestinal symptoms occurred in 46% compared with 10% of 97 developmentally normal pediatric controls (odds ratio, 7.4; confidence intervals, 3.60-15.65;P < 0.0001) (14). We investigated gastrointestinal symptoms in more than 150 autistic children and reported out initial experience (15,516). In this cohort, developmental regression and loss of acquired skills, sometimes occurring precipitously over a period of days to weeks, followed a period of initial normal development; in short, the children became encephalopathic. Longstanding intestinal symptoms, including chronic constipation with overflow, and provocation of both gastrointestinal and behavioral symptoms by certain foods, are typical of this group of children and have been described by others (17). However, even among some pediatric gastroenterologists, the perception remains that such symptoms are to be expected in children with developmental disorders, reflecting effect rather than possible cause. In the absence of thorough investigation, the basis for this presumption is unclear. It is essential, ab initio, to ask whether these symptoms reflect underlying pathology of the gastrointestinal tract.
In 1972, Walker-Smith and Andrews (7) reported low concentrations of α-1-antitrypsin in children with classic autism, a finding indicative of intestinal protein loss. We have subsequently reported increased fecal excretion of calprotectin in children with autistic regression associated with enterocolitis. There was a high degree of correlation between fecal calprotectin and neutrophil infiltration of the colonic mucosa (8). Calprotectin is a stable neutrophil product, and its presence in feces is an established marker of active inflammation in inflammatory bowel disease.
Intestinal permeability, as measured by urinary excretion of metabolically inert sugars after oral dosing, is a surrogate marker of mucosal integrity and is increased in the presence of intestinal inflammation, as in Crohn disease (9) and celiac disease (10). D'Eufemia et al. (11) reported that approximately half of a cohort of autistic children without gastrointestinal symptoms had increased intestinal permeability. Horvath et al. (12) have confirmed the increased intestinal permeability in children with autism. D'Eufemia's detection of aberrant intestinal permeability in asymptomatic autists indicates that reliance on overt symptomatology will substantially underestimate the proportion of autistic children with possible gastrointestinal pathology. The combination of an increased pain threshold, commonly observed in affected children, (24), and restricted ability to communicate symptoms will compound this underestimation.
Identifying decreased serum α-1-antitrypsin, increased fecal calprotectin, and increased intestinal permeability in a patient is not a diagnostic endpoint, but indicates the need for further detailed investigation. As a corollary to these changes, does evidence suggests that children with autism and gut symptoms have demonstrable organic pathology of the gastrointestinal tract? The answer seems to be yes. We recently described a characteristic pattern of intestinal pathology-ileocolonic lymphoid nodular hyperplasia and enterocolitis-in a large cohort of autistic children. The endoscopic and histopathologic characteristics of this condition have been reported in detail elsewhere (25,26). A comparison of the mucosal lesion in the colon and small intestine, with appropriate controls, shows a subtle but characteristic disease process. Briefly, the colonic lesion consists of a mucosal infiltrate of γδ T cells and CD8+ T cells, significantly in excess of that seen in either healthy or disease control groups (25). Crypt cell proliferation is substantially enhanced, and the epithelial basement membrane is thicker than in either healthy or disease control groups. Neutrophil and eosinophil infiltration of the mucosa is evident. The absence of colonic epithelial HLA-DR in autistic children suggests a Th2-dominated immune response (25,26). Studies of the corresponding small intestinal lesion also indicate a distinct cell-mediated immunopathology in which immune-mediated epithelial damage is predominant, serum immunoglobulin G colocalizes with complement (C1q) at the epithelial basolateral membrane, and epithelial proliferation is grossly increased (27). This is not seen in either healthy children or those with cerebral palsy. The intestinal changes are consistent with an autoimmune pathology and, in view of the increasing evidence for gut epithelial dysfunction in autism, are indicative of a specific and possibly important lesion. Sabra and Bellanti (28) presented preliminary evidence of similar findings in children with attention deficit hyperactivity disorder, suggesting that gastrointestinal pathology may be relevant to a broader spectrum of childhood developmental/behavioral disorders.
Horvath et al. (17) reported their findings in the upper gastrointestinal tract in 36 autistic children whose symptoms included chronic diarrhea, gaseousness, abdominal discomfort, and distension. They detected grade I to II reflux esophagitis in 25 (69%), chronic gastritis in 15 (42%), and chronic duodenitis with associated Paneth cell hyperplasia in 24 (67%). Digestive enzyme activity was decreased in 21 (58%) autistic children, and pancreaticobiliary fluid output in response to intravenous secretin was increased in 27 (75%). Subsequent to Horvath's early report (6), we have included upper gastrointestinal endoscopy in our routine assessment of affected children and our findings support his.
Cognitions, defined as verbal or pictorial events in our stream of consciousness, are often divided into three aspects: cognitive events are thoughts that go through our minds, cognitive processes are evaluations, opinions, abstractions, more elaborated reflections, and values, and cognitive schemata are often called basic assumptions or life rules. Our schemata are developed from previous experiences, and are activated in specific situations. The relationship between cognition and emotion is illustrated when you experience something threatening or dangerous. Our inner dialogue is dominated by automatic thoughts, based on our basic assumptions. This interpretation of the situation (cognition) is immediately followed by the emotion of anxiety (often called fear). All emotions have physiological correlates; in anxiety, sympathetic, and to a lesser degree parasympathetic, activation leads to tachycardia, hyperventilation, sweating, nausea, need to defecate, etc. Anxiety is a biological warning system to react mentally and bodily to threatening or dangerous situations. Attention is directed towards the threat, and the body prepares for fight, flight or freeze, necessary for survival. We experience this biological reaction every time we interpret a situation or a physical symptom as threatening or dangerous. The body does not control whether our interpretation is, in fact, correct. Imagined danger is just as anxiety provoking as real danger. A person with basic cognitions such as "The world is unsafe", "Physical symptoms are not normal and always a sign of serious disease" or "I will soon die of cancer" will screen the world and body for signs of threat, and hence experience more anxiety reactions than if they did not have these cognitions (termed "catastrophising").
The terminology in human research reflects the fact that there is great variance and individual differences. In animal research there is more clarity and consensus in terminology. Words such as emotion or "feeling" have different meanings. There are two main theories underlining different aspects of emotions: emotions are primarily brain events with physiological concomitants the efferent link; on the other hand, an essential part of emotions is feedback from peripheral physiological activation the afferent link.3 Different labels are attached to emotions. The most commonly used are glad, sad, anxious, mad, surprised, confused, and jealous. Shame and disgust are also defined by some as basic emotions.
A central aspect of functional gastrointestinal disorders is pain. Pain is often defined as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. Nociception refers to the reception of signals in the CNS, evoked by activation of specialised sensory receptors (nociceptors) that provide information about tissue damage. The brain-gut axis is bidirectional and integrative. There is input from sensory sources (sight, smell, etc) and somatosensory/viscerosensory sources, modified by cognitions and affect, and a neural circuit in the CNS, the spinal cord, autonomic nervous system, and enteric nervous system.
Anxiety is seen as an important modulating factor in the perception of pain: increased anxiety is associated with increased pain reports. Adrenaline is released at sympathetic nerve endings which may sensitise nociceptors, and triggers somatic reflexes by increasing muscle tension. However, anxiety and pain may be methodologically confounded as they both lead to a general sympathetic physiological arousal and share common response patterns. During threatening situations, endogenous opioids are released, contributing to an analgesic effect. The picture is complicated: anxiety for pain leads to attention towards pain and may increase it, while anxiety for something else leads to distraction from pain, thereby decreasing it. This may be an explanation for the finding that patients with irritable bowel syndrome are sensitive to distension in the gut but are not fearful of sensations from other areas, and hence are less sensitive than normal controls to painful stimulation of the skin.4 Attention, defined by William James as "withdrawal from some things in order to deal effectively with others", is like a selective filter, an important factor in pain perception, and incorporated in several theories of pain.3 5 Patients with anxiety disorders frequently have somatic complaints. Constitutional predisposition (biological vulnerability) and psychological factors probably determine whether the patient has primarily muscular, cardiovascular, or gastrointestinal symptoms.6

The Gut-Brain Axis
Neuroactive compounds derived from the intestinal lumen can permeate the mucosa; cross the blood-brain barrier; and cause psychiatric, cognitive, and behavioral disturbances. Indeed, this axis is critical in, for example, oral medication of psychopathology. Awareness is growing, particularly within the field of childhood developmental disorders, that in a substantial proportion of affected children, gut-brain interactions may be central to abnormal neural development and the subsequent expression of aberrant behaviors. Difficulties in accepting the biologic plausibility of such a model, particularly among those whose interests have focused on primary pathogenetic mechanisms operating within the central nervous system, may reflect, in part, a perceived lack of an analogous gut-brain interaction in either human or experimental models of encephalopathy. Among gastroenterologists and hepatologists, however, the evidence for such a mechanism is readily apparent. Seeking analogy with circumstances in which clear evidence shows an influence of the gut on the normal brain may help advance the argument.
Untreated celiac disease-an aberrant immune response to dietary gliadin-is associated with intestinal mucosal inflammation, increased intestinal permeability (21), increased absorption and urinary excretion of neuroactive dietary peptides (29), autistic and psychotic behaviors (30,31), and neurologic complications(32,33). The precise mechanism(s) of central nervous system sequelae has not been established, although toxicity from the gut (129) and autoimmunity (34) are pathogenetic forerunners. D-lactic acidosis, a complication of acid-tolerant bacterial overgrowth in patients with short bowel syndrome and those undergoing intestinal bypass surgery for obesity, is associated with a range of psychiatric and neurologic sequelae (35). Patients may experience altered mental state, aggression, stupor, ataxia, and asterixis; these symptoms respond rapidly to oral antibiotic treatment. Encephalopathy is a recognized presenting feature of intestinal intussusception in infants (36-38) and, intriguingly, may be reversible with naloxone (36).
Hepatic encephalopathy-a variable impairment of cerebral functioning in patients with acute or chronic liver disease-is the result of multiple biochemical influences oncentral neurotransmitter systems. In addition to the neurotoxic effects of ammonia (39), derangements in the gamma-aminobutyric acidergic (30) and serotoninergic (40) systems are evident (reviewed by Butterworth (41), and Albrecht and Jones (42)). It may be more than just coincidence that changes in these neurotransmitter systems also have been described in autism (43,44). Central to changes in the activity of these various systems in hepatic encephalopathy is a failure of the diseased liver to metabolize or eliminate toxic compounds derived from the gut, which may itself be entirely healthy. Accordingly, porta-systemic shunting (rerouting the venous drainage of the gut to bypass the liver and directly enter the systemic circulation) may produce encephalopathy for the amelioration of portal hypertension. Precipitants of hepatic encephalopathy in patients with liver disease include a high enteroluminal protein load, constipation, and sepsis (41,42). The clinical management of hepatic encephalopathy includes restricting dietary protein, promptly treating constipation, and antibiotic therapy directed against luminal colonic bacteria. As such, hepatic encephalopathy represents a prototypic afferent gut-brain interaction that may provide insights into other encephalopathic states that have been linked to extracranial disease.
During the course of clinical assessment and management of these children, we have been impressed by the symptomatic improvement in their behavior and general well-being after bowel clearance before colonoscopy; treatment of intestinal inflammation with 5-amino salicylate-based compounds or a polymeric diet (45); relief of chronic constipation; and, in particular, the elimination of certain proteins (casein or gluten) from the diet (45). Bolte (46) proposed a role for intestinal clostridial dysbiosis in autism, specifically through neurotoxic encephalopathy. In seeking to test this hypothesis Sandler et al. (47) noted objective cognitive improvement in autistic children in an open label study of oral vancomycin, an antibiotic that exhibits minimal systemic absorption. Children regressed after cessation of therapy, suggesting that any colonic dysbiosis and associated toxic sequelae probably were secondary to underlying intestinal disease rather than the primary problem. Failure of vancomycin to eliminate clostridial spores is also a possibility, although less likely, given the efficacy of this drug in treating Clostridium difficile. These observations, although empirical or observed in open label studies, were largely unexpected. In addition, they are reminiscent of certain aspects of the clinical course of hepatic encephalopathy, in which gut-brain interactions are paramount. An analogous interaction may be operating in a subset of autistic children; any biochemical basis for such an interaction in autism might be identifiable in syndromes such as hepatic encephalopathy.

Summary
Within the neurobehaviour disorders, a substantial group of children have what may be primary intestinal pathology. The constellation of developmental disorder and gastrointestinal pathology (provisionally termed autistic enterocolitis) combines the paradoxic elements of a motility disorder-esophageal reflux and constipation with spurious diarrhea-and enterocolonic mucosal inflammation, a feature more commonly associated with frank diarrhea. Understanding the neurochemical basis of any gut-brain interaction in autistic enterocolitis may help to resolve this paradox and help to develop rational therapeutic approaches.


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