© Springer International Publishing Switzerland 2017Christophe Faure, Nikhil Thapar and Carlo Di Lorenzo (eds.)Pediatric Neurogastroenterology10.1007/978-3-319-43268-7_6
6. Integration of Biomedical and Psychosocial Issues in Pediatric Functional Gastrointestinal and Motility Disorders
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Miranda A. L. van Tilburg
KeywordsPediatric functional GI and motility disordersGastrointestinal and motility disorders in childrenMotility disorders in childrenPsychosocial issues in pediatric GI disordersBrain-gut axis
Treating gastrointestinal symptoms in children is often more difficult than it may seem. Consider the following case:
Johnny is a 6-year-old child who presents with nausea and abdominal pain. Upon history taking, the child appears to experience early satiety and some minor weight loss. You notice pallor and irritability. After thorough diagnostic work-up, John is diagnosed with delayed gastric emptying. The family is sent home with a prescription for erythromycin and referral to a dietician. Several months later, Johnny returns to you and appears to be doing well. Pallor has disappeared and weight loss has been stopped. Nevertheless, problems continue at home around feeding. Johnny still refuses food and continues to complain of nausea and abdominal pain. You suspect psychological factors may be playing a role. The symptoms started around the time Johnny’s parents got a divorce. Mother seems anxious and Johnny is out of school regularly around fear of symptoms.
This scenario is recognizable for many clinicians working with children who suffer from functional gastrointestinal and motility disorders. Psychosocial factors often play a role in these disorders, and no clinician working with this group of patients will deny their influence. But the interpretation of how psychological symptoms affect the onset and maintenance of these disorders varies considerably among clinicians. Are psychological issues primary causes of some disorders? Can psychological disturbances affect digestive processes? In the case of Johnny: Were the continuation of his symptoms after successful treatment of the gastric emptying primarily due to (1) anxiety of his family, who may too easily over-interpret normal symptoms as signaling disease, or (2) was there a behavioral component to his symptoms in the first place that was not addressed with medication therapy, thereby leading to less effective treatment? Answers to some of these questions can affect the course of suggested treatments for Johnny and other children like him. In this chapter, first, the theoretical models explaining the role of psychosocial issues in health and disease will be discussed. These are implicit working models guiding clinical care and scientific research and are important to explore. Then, the current scientific evidence for the role of psychosocial factors on physiological functioning will be presented.
Psychological Issues in Health and Disease
Biomedical Model : A Symptom Has Either a Physiological or Psychological Origin
Under guidance of the biomedical model, medicine has seen one of the greatest advances over the past centuries. This model has been responsible for some of the most impressive discoveries of modern medicine such as the development of penicillin, vaccines, etc. It is still widely popular today among many clinicians and patients. The biomedical model envisions a direct relation between disease and symptom : Cause A will lead to symptoms B. The more disease causing A is present, the more symptoms will be observed. If A is eradicated, the symptoms will disappear. This straightforward model of health and disease focuses primarily on biological origins but argues that in lieu of a disease or structural abnormality, psychological factors can cause symptoms. For example, if no biomedical reason can be found for stomachaches (such as lactose intolerance), then these symptoms can be attributed to psychosocial distress, i.e., anxiety or school avoidance . The biomedical model is simple and elegant but completely ignores contextual influences on health and disease: Symptoms are either caused by biological or psychological causes. This straightforward and appealing approach has led to the notion that if symptoms are not in “the body,” it must be “all in the head.” It also explains our fascination with drugs as a “quick fix” for real symptoms worthy of a clinician’s time while behavioral or supportive therapy have become synonym to treating symptoms that are either feigned or a result from being “crazy” and not belonging in a physician’s office.
Biopsychosocial Model : Symptoms Can Be Altered by Psychosocial Processes
By the mid-1970s the well-established biomedical model started to show little cracks. It became clear that there was no perfect association between biomedical processes and symptoms . For example, under the biomedical model, the frequency and amount of gastric acid refluxing into the esophagus should explain the intensity of heartburn complaints. However, there are patients with very severe acid reflux for years, who are minimally symptomatic until developing Barrett’s esophagus. On the other hand, there are others with minimal acid reflux whose life is severely affected by their symptoms. The only way to explain these findings with the biomedical model is to see the first person as a “tough” or stoic, silently suffering while continuing with his/her life, while the second is a “wimp” complaining at the tiniest bit of discomfort. The first elicits admiration and the second contempt. However, imperfect associations between biomedical processes and symptoms are so ubiquitous that they seem to be the rule rather than the exemption. The biopsychosocial model, first proposed by Dr. Engel , posits that biochemical alterations do not directly translate into illness. The appearance of symptoms is an interplay between many factors including biomedical, psychological, and social factors , e.g., bacteria A leads to more symptoms under stressful circumstances.
The biopsychosocial model has been widely adopted by researchers and clinicians to explain health and disease and is particularly useful for understanding and studying functional gastrointestinal disorders . There is a robust literature describing the influence of both physiological and psychological factors on the illness presentation of functional gastrointestinal disorders, in particular irritable bowel syndrome (IBS). These studies will be discussed later in this chapter.
System Theory : Physiological and Psychological Processes Are Constantly Interacting to Cause Symptoms
Although the biopsychosocial model was presented by Dr. Engel as a system theory, it is nowadays often presented in a reductionist way. Some authors reduce mental and social phenomena to basic biological phenomena, such as activation of the autonomous or central nervous system (CNS) and hypothalamic-pituitary-adrenal (HPA) axis . Johnny from our case at the beginning of the chapter may be anxious which leads to CNS and HPA axis activation, interacting through the brain-gut axis with the enteric nervous system culminating in gastrointestinal symptoms. Systems theory acknowledges that psychosocial processes undoubtedly have biological correlates. However, it argues that the different systems—biological, psychological, and social—interact with each other but cannot be reduced to the lowest, molecular, level. The reasoning behind this is simple: we cannot understand the meaning of psychosocial processes by purely studying its biological correlates; subjective phenomena are equally important.
The biopsychosocial model is also sometimes reduced to a hierarchy of unidirectional cause and effects relationships which includes causes, precipitants, modulators, or sustaining forces . In Johnny’s case, anxiety and delayed gastric emptying can be thought to independently cause or sustain his symptoms, and it is up to the physician to decide which one is most important and thus should be treated first. Viewing psychosocial and biomedical factors as somewhat independent processes largely denies the reality of the situation in which there are feedback loops between all parts of the system. Johnny’s delayed gastric emptying caused pain and fullness, which made him anxious around food. His fears of having pain after a meal in turn may have led to hypervigilance and increased the sensitivity of his nerves to normal digestive processes thereby worsening his symptoms. Thus, anxiety is both cause and effect in this circular loop.
Systems theory is an attempt to understand these complex feedback loops over time and discovering the interrelated causes that sustain specific symptom over time. Unfortunately, such integrated models of proximal causes and effects over time are difficult to study. The need for complex study designs and statistical methods has seriously hampered the testing of systems theory in functional gastrointestinal and motility disor ders. Recent developments of system theory methodology in other fields show promise for application in functional gastrointestinal and motility disorders.
The Brain-Gut Axis
Nowadays, the role of psychosocial variables in functional gastrointestinal and motility disorders is widely recognized, and the biopsychosocial approach is commonly endorsed in explaining these disorders. The biopsychosocial model postulates that psychosocial factors can interact with the gut through the brain-gut axis: the bidirectional communication between the enteric nervous system in the gut and the brain. This means that emotions and thoughts have the capability to affect gastrointestinal sensation, motility, and inflammation. Reciprocally, gastrointestinal processes are able to affect perception, mood, and behavior. Dysregulation of the brain-gut axis is thought to be at the core of many functional gastrointestinal disorders.
With regularity the question is asked whether psychological issues are a cause or consequence of the brain-gut axis dysregulation. Some authors have found increased anxiety before a diagnosis of functional gastrointestinal and motility disorders , while others have argued that increased psychosocial distress may be a consequence of having to deal with a chronic, unpredictable condition . A large community-based study found that both positions may be right: psychosocial comorbidity was as likely to be present before as after seeking care for abdominal pain . The question is if it really helps to know which one came first. If we conceive of our body as a system in which psychosocial and biomedical factors interact continually, then the question of what came first is not relevant. Both factors will interact to cause symptoms and understanding the disorder is exploring this interaction. For example, in the case of fecal incontinence, we don’t ask if the child was constipated first and then became anxious about evacuation of large bowel movements or anxious about potty training and then experienced large stools due to withholding. Both may be true and will lead to the same symptom: fecal incontinence . Both factors need to be addressed to ensure successful resolution of symptoms. Thus, rather than trying to solve the “chicken-and-egg” dilemma, we should focus on understanding how the different components of the system interact to create these symptoms. In the following section, we will summarize the literature on psychosocial influences on functional gastrointestinal and motility disorders.
Psychosocial Influences on Functional Gastrointestinal and Motility Disorders
There are many psychosocial aspects relevant to functional gastrointestinal and motility disorders such as personality , self-esteem [8, 9], and early childhood experiences [10, 11], to name only a few. Out of all the possibly relevant psychosocial factors, the most often studied is the concept of stress. We all know what stress is and what it feels like. However, defining stress is more elusive than it seems. First, there are the events that may be stressful: being stopped by a policeman for speeding, giving a speech in front of several colleagues, and taking your child to the emergency room. These are called stressors. Second, there are individual reactions to stress: feelings of anger/fear, trouble in concentrating, and physical reactions such as accelerated heartbeat, tensed muscles, and increased perspiration. It is important to realize that not all potential stressors lead to stress reactions and that stress can be both positive and negative. What is stressful for one person may be pleasurable to another or have little impact whatsoever to a third person. A parachute jump or deep sea dive may elicit enormous fear and anxiety in some, while others find it highly pleasurable, and for very experienced professionals, it may be just a simple routine. Therefore, stress is a subjective experience created by the appraisal of an environmental demand as harmful, threatening, or challenging and appraisal of our ability to meet this demand . If a person has adequate resources to deal with a difficult situation, he or she may not experience stress; but if the demand (almost) exceeds one’s resources, a person will be under a great deal of stress. When the term “stress” is used, it may refer to (1) the stressors, which are usually major life events such as trauma, abuse, or divorce, but can also be the cumulative effect of small daily hassles; (2) the subjective experience of stress which is usually measured by self-reports of perceived stress; and (3) stress reactions which includes behavioral (e.g., withdrawal or confrontation), emotional (e.g., anger, fear, anxiety, depression), and physiological reactions (e.g., skin conductivity, blood pressure, cortisol, and catecholamines). Thus, stress in addition to being itself is also causing itself and resulting itself. It is important to realize which aspect of stress is being referred to when reading and interpreting the scientific literature on stress.
Stress can be felt in the gut. We are all familiar with the typical butterflies associated with young love, feeling squeamish when being forced to deliver bad news, and the run to the bathroom before the start of an important race or game. Stress has been found to alter gut functioning. It has effects on GI sensory, motor, and immune functioning, which are also etiological pathways for many functional gastrointestinal and motility disorders.
Stress and Gastrointestinal Motor Functioning
Motility disturbances are a hallmark symptom of many functional gastrointestinal and motility disorders which may result in symptoms such as altered stool consistency, nausea, or bloating. There is evidence to suggest that stress induces changes in motility. For example, under stressful conditions, gastric emptying decreases and colonic transit accelerates . These stress-induced motility changes are caused by increases in corticotrophin-releasing factor (CRF), especially CRF1. CRF is best known as the principal instigator of the physiological response to stress through the hypothalamic-pituitary-adrenal (HPA) axis, and CRF 1 receptors have been found to regulate behavioral reactions to stress [14–17]. Brain CRF stimulation is associated with accelerated colonic transit, defecation, and diarrhea and stimulates similar brain areas as anxiety and depression . But the effects of stress on motility seem to also operate outside of this system. It has been reported that activation of CRF receptors in the brain induces propulsive motor function and diarrhea without involving the HPA axis, but rather through stimulation of autonomic nervous system [19, 20] such as the stimulation of the sacral parasympathetic outflow . Central CRF stimulates the vagal nerves innervating the proximal colon which results in release of colonic serotonin [19, 22]. Serotonin is involved in various gastrointestinal motility processes such as the gastric accommodation reflex, the small bowel transit, and the colonic response to feeding [23, 24]. Therefore, serotonin abnormalities in the gut can lead to motility disturbances in functional gastrointestinal and motility disorders [23, 24]. This is supported by the fact that medications aimed at altering gut serotonin have been found to be effective in treating several functional gastrointestinal and motility disorders including IBS, constipation, functional dyspepsia, and gastroparesis [23, 24]. In addition to motility, CRF receptors have also been implicated in visceral hypersensitivity and immune functioning (for an overview see Tache et al. ).
Stress and Gastrointestinal Sensory Functioning
One of the most consistent findings in painful functional gastrointestinal and motility disorders is visceral hypersensitivity. Hypersensitivity to gut distension—the reporting of first sensation of pain at lower levels of pressure than normal—has been found in more than half of adult patients who suffer from IBS and functional dyspepsia . Visceral sensitivity is usually measured by using the barostat technique. The barostat inflates a balloon to different pressure levels in the stomach, colon, or rectum while the patient is asked to report level of discomfort and pain (for guidelines on using the barostat in children, see van den Berg et al. ). As the barostat technique is invasive, studies in children are limited, but similar findings as in adults have been reported showing that visceral hypersensitivity is a common phenomenon in children with painful functional gastrointestinal disorders [26–30]. In addition, visceral hyposensitivity in the rectum has been reported in children with constipation [31, 32]. Reduced sensation in the rectum corroborates the fact that these children do not easily feel an urge to defecate.
The role of stress on visceral sensitivity has only been examined in abdominal pain-related functional gastrointestinal disorders. Many studies have found lower pain thresholds in reaction to stress—which is equivalent to more easily reporting pain under stress. Studies in rats have shown that early-life stress is associated with colonic hypersensitivity in adulthood [33–39]. In fact, early-life stress induced visceral hypersensitivity which was transferrable to the next generation in mice, possibly due to changes in maternal care . Less conclusive evidence is available for acute stress and chronic stress in adulthood, with effects dependent on various factors such as previous experiences, diurnal variation in stress reactivity, etc. , One study reported that stress in adult mice leads to increased visceral hypersensitivity only if combined with an infection , which mimics the findings of post-infectious IBS in humans. In humans, acute stress, induced by cold-water hand immersion (physical stressor) or dichotomous listening (mental stressor), seems to reduce pain thresholds as well [42, 43]. But other types of stressor have yielded mixed effects. Past stressful experiences (e.g., abuse history) and psychological distress (e.g., anxiety or depression) have been associated with decreased pain thresholds in some studies [27, 44–47], increased in others , while others have reported no effects of stress at all [27, 46, 49–51]. Thus, most studies report increased sensitivity with stress, but some did not find any effects, and one study actually found decreased sensitivity . The reason for the inconclusive evidence may be related to the way visceral sensitivity is measured. In most barostat protocols, increasing levels of pressure are presented to the patient who is asked to indicate first perception of discomfort. This experimental design is believed to be vulnerable to psychological response biases in particular fear of pain . Naliboff and colleagues found that when offering unpredictable changes in volume, differences in pain thresholds between IBS patients and controls disappeared . Dorn and colleagues added to these findings by showing that rather than increased neurosensory sensitivity (the ability to discriminate between pressure levels), lower pain thresholds in IBS are explained primarily by an increased psychological tendency to report pain . One of the nonsensory cues that influence pain threshold ratings is hypervigilance to symptoms. IBS patients have a higher tendency to label visceral sensations as unpleasant during barostat testing . Thus, visceral hypersensitivity can either be caused by hypervigilance or perceptual sensitivity, and both may have associations with stress. Dorn found some indication that increased psychological distress is associated with hypervigilance, but others have not been able to replicate this observation [54–56].
If we assume that under certain circumstances, stress can affect visceral sensitivity, an important question becomes at what level in the neural system these effects are most dominant. Sensations from the gastrointestinal tract are relayed to spinal dorsal horn. Visceral sensory information is then conveyed to supraspinal sites and finally to cortical areas where they are perceived [57, 58]. Descending emotional pathways via the periaqueductal gray to the dorsal horn can amplify or suppress new afferent signals from the gut. Amplification of these signals can occur at any level in this neural pathway. Evidence is building that the central nervous system is an important site of modulating the pain response. Brain responses to visceral stimuli are increased in IBS patients compared to controls in areas related to conscious experience of visceral sensations (specifically the insular cortex) as well as areas related to emotion modulation and emotional response to threat including the anterior cingulate the cortex, the hypothalamus, and the amygdala. In addition, structural changes in the brain have been described in IBS, such as decreased gray matter density in areas associated with corticolimbic inhibition and increased gray matter density in areas involved in stress. Thus, IBS patients tend to respond with more affective and attentional responses to visceral stimuli, and stress can alter the brain response to gut stimuli. This effect is both through central modulation of afferent gut stimuli and decreased efferent inhibition of pain signals [57, 58].
Though the brain is the most likely level for psychological input to interface with visceral input, very few studies have investigated the role of psychological factors in modulating the central nervous system response to visceral sensations. Berman and colleagues studied anticipation of visceral pain . They found that negative affect reduces anticipatory brain stem inhibition. Reduced anticipatory brain stem inhibition in turn was associated with increased brain responsiveness to actual distention . Ringel and colleagues observed that during rectal distension, patients with IBS and abuse history show greater posterior/middle dorsal and anterior cingulate cortex activation, as well as reduced activity of the supragenual anterior cingulate (a region implicated in pain inhibition and arousal) [60, 61]. Gupta and colleagues reported increased connectivity in the left putamen and decreased connectivity in the supplementary motor area, insular, anterior cingulate cortex, parietal, and frontal regions in IBS patients with a history of early adverse life events . This suggests that early life events may potentiate changes in the brain salience network resulting in increased attention/behavior toward gut sensations. In a case report of a patient with severe IBS and post-traumatic stress disorder, resolution of emotional distress was associated with reduction in activation of the midcingulate cortex, prefrontal area 6/44, and the somatosensory cortex areas associated with pain intensity encoding . Thus, there is evidence that psychological factors can influence brain reactions to visceral pain, specifically areas related to emotion modulation and attention control, but the exact mechanism still needs to be determined.
Stress and Gastrointestinal Inflammation, Gut Barrier Functioning, and Gut Microbiome
The role of the immune system in functional gastrointestinal and motility disorders, specifically IBS, initially focused on patients who developed IBS following an infectious gastroenteritis. Interestingly, stress around the time of the infection is one of the most robust predictors to develop post-infectious IBS. Later, low-grade inflammation within the gut wall as well as altered immunological function and alterations in gut flora were found in functional gastrointestinal disorders of noninfectious origin including IBS, functional dyspepsia, and noncardiac chest pain [64–66]. Many innate and adaptive immune parameters have been studied, but among the most robust findings are increased levels of mast cells, monocytes, and T-cells as well as increased intestinal permeability (for a review, see Ohman and Simren ). Although most studies have been done in adults, increased gut inflammation has also been shown in children who suffer from functional abdominal pain [68–71]. Gut inflammation in IBS is modest and subclinical as most patients have normal or near-normal fecal calprotectin concentrations [68, 72–74]. Nowadays, the role of the microbiota is being studied as contributing to gut inflammation. Dysbiosis of the microbiota has been found in IBS [75–78] and may also play a role in infant colic [79, 80]. Furthermore, probiotics are efficacious in reducing IBS and colic symptoms [81, 82]. The role of the microbiota is considered so central to the disorder that some have proposed to broaden the traditional brain-gut axis to include the microbiota: a brain-gut-microbiota axis .
There are many studies which suggest that psychological distress affects the immune system in healthy adults (for a meta-analysis see Denson et al. ). For example, stress reduces antigens production following vaccinations [85, 86] and increases susceptibility to colds , and meditation decreases IL-6 responses to a laboratory psychosocial stressor . The role of stress on the immune system in functional gastrointestinal and motility disorders has received little attention. In rats and rodents, stress increased low-grade inflammation in the gut [89, 90, 91] as well as esophageal and intestinal permeability . Inhibition of cytokines, such as Il-6, normalized stress-induced defecation, suggesting that immune and stress interactions are important in predicting stress-induced IBS symptoms . Studies in humans also suggest that stress is associated with low-grade inflammation in functional gastrointestinal disorders. Depression and anxiety scores in IBS patients are correlated with increased mast cells [71, 94]. How close these mast cells are to gut nerves was also associated with ratings of stress and depression . Stress has been associated with increased Il-6 levels in IBS patients [96, 97]. Anxiety has been reported to be associated with increases in cytokine levels in IBS but only after exposure to Escherichia coli lipopolysaccharides . A recent study found that early-life stress in IBS patients was associated with brain changes in areas of mood and effect and inflammatory genes . Stress also increases intestinal permeability in healthy volunteers .
These are indicators that stress and the immune system interact in functional gastrointestinal and motility disorders. Psychological distress may affect immunological response and reducing stress could be helpful. But there is also data to suggest that immune activation may drive psychological distress and brain-related changes. Activation of the immune system either by viral infection or by administration of cytokines or lipopolysaccharide (found on the outer membrane of gram-negative bacteria) induces cytokine secretion and triggers depression and anxiety in healthy volunteers [101, 102]. In addition, immune-targeted therapies such as interferon-alpha treatment for Hepatitis C or cancer have been known to induce anxiety and depression in a significant percentage of patients [103–105]. Those who develop major depression during treatment have increased pretreatment IL-6 and IL-10 concentrations . These findings suggest that that increased immune activation is a causal risk for the development of major depression. Based on these observations, Goehler et al.  have suggested that “Some of the negative affective experiences associated with gastrointestinal disorders may not be under the voluntary control of the patient.”
Although it yet has to be determined how infections in the gut influence the brain and mood, it has been suggested that the brain may react directly to the bacterial composition of the GI tract [107, 108]. The gut contains different species of microbiota, many of which still need to be characterized. Imbalances in gastrointestinal microbiota, or “dysbiosis,” have been found in many chronic gastrointestinal disorders such as IBD , antibiotic-induced diarrhea [110, 111], IBS [75, 83], and infant colic [79, 80]. Inducing dysbiosis, either with the use of oral antibiotics or by replacing the microbiota, leads to low-grade inflammation, visceral hyperalgesia, and behavioral changes in mice, symptoms changes that are also characteristic of many functional gastrointestinal disorders [112–114]. Furthermore, treatments that change the microbiota such as rifaximin and probiotics have been found to improve functional gastrointestinal symptoms [75, 82, 83].
A hypothesized model of how gut microbiota dysbiosis can influence the brain is through regulating intestinal barrier function resulting in increased gut permeability . This could potentially allow antigens or pathogens to enter intestinal tissues and generate an inflammatory reaction. The resulting circulating cytokines are proposed to bind to brain endothelial cells, increasing the permeability of the blood-brain barrier and enhancing infiltration of immune parameters in the brain, which may cause or exacerbate mood/behaviors . This pathway is largely untested, but studies have found increased gut permeability and immune activation among children with IBS [68, 117, 118] as well as changes in the microbiota in stressed individuals ; both of these findings are supportive of the suggested model. On the other hand, stress may alter gastrointestinal motility (as discussed previously) or induce changes in diet, which can modify the microbiota, suggesting a bidirectional association between stress and microbiota.