This review summarizes the evidence supporting a role for events occurring early in life in making a child more vulnerable to develop a functional gastrointestinal (GI) disorder. Although not much is known about intrauterine or neonatal factors that can predispose an infant to become “colicky,” several factors have been identified that can sensitize a child to experience a pain-predominant functional disorder at different developmental stages. Several infectious, inflammatory, and psychological noxious events may cause changes in enteric nerves reactivity, immunologic responses, or intestinal microbiota composition that can then lead to irritable bowel syndrome, functional dyspepsia, or functional abdominal pain in children when a second stressful event may ensue. The pathophysiology and possible intervention strategies to lessen the impact of these events are discussed.
PATHOPHYSIOLOGY OF PAIN-PREDOMINANT FUNCTIONAL GI DISORDERS IN CHILDREN
An increasingly large body of evidence suggests that several pain-predominant functional GI disorders (p-FGID) in children and adults are triggered by a stressful experience occurring in an individual with a predisposing genetic background and who has been “primed” by a sensitizing event, often occurring early in life (Fig. 1). Much research has been focused on the role of such early adverse life (EAL) events because although not much can be done to prevent the occurrence of stressful circumstances and it is not possible to modify genetic backgrounds, appropriate interventions after an EAL may be used to modify long-term outcomes. Some investigators have speculated that individuals with a history of EALs have a heightened awareness of bodily sensations and a tendency to amplify these perceptions (1). Patients with a history of EAL abuse also tend to have greater symptom reporting and to use health care more often compared with those without this history (2). In view of the high prevalence of p-FGID, such as irritable bowel syndrome (IBS), functional abdominal pain, and functional dyspepsia in children and adolescents, identification of EALs that put infants and toddler at risk for the development of a p-FGID may have a great impact on decreasing patients’ suffering and health care utilization.
It has been shown that early life trauma exposure may sensitize infants and place them at risk for internalizing or externalizing psychiatric disorders when exposed to subsequent life stressors (3). Children with p-FGID have been known to have a high prevalence of internalizing disorders (anxiety and depression) both at the time of diagnosis and at long-term follow-up. There is evidence that stress plays a significant role in symptom onset and exacerbation in adults with IBS (4) and that childhood trauma is associated with increased stress response in patients with IBS (5). It has been suggested that EALs may be considered a vulnerability factor for the development of stress-related disorders such as IBS. There is also experimental evidence that early life stress may alter behaviour, immunity, and microbiota, and abnormal enteric flora has been thought to play a pathogenic role in children and adults with p-FGID. Thus, there is plenty of rationale to consider that an EAL occurring during a window of vulnerability in the newborn period or the first few months of life may affect epigenetic factors that pose such individuals at risk for a functional disorder or other diseases later in life (6).
EVIDENCE THAT EAL EVENTS PLAY A ROLE IN P-FGID
Table 1 summarizes the published types of clinical EAL events that have been reported to be associated with increased risk for development of p-FGID. A recent systematic review has examined the early life factors contributing to the development of IBS in adolescents and adults (7).
There is little doubt that physical or emotional stress makes children more vulnerable to p-FGID. In 1979, Hislop first suggested that childhood deprivation, defined as loss of a parent through death, divorce, or separation, possibly contributed to the etiology of IBS (8). Of 333 consecutive patients with IBS, he found that by age 15 years, 31% of the patients had lost a parent, 19% had an alcoholic parent, and 61% reported unsatisfactory relationships with or between their parents. There was no control group in that study. There are also several retrospective studies that have reported an increased prevalence of p-FGID in adults who had been subjected to emotional or physical abuse earlier in life. More than 2 decades ago, Drossman et al reported that in a tertiary care GI center, patients with severe functional disorders were more likely than those with organic disease diagnoses to report a history of forced intercourse (odds ratio 2.1) and frequent physical abuse (odds ratio 11.4) (2). This observation was confirmed by other studies, which described that subjects with IBS had much higher rates of childhood sexual abuse (9) and that there was a significant association between IBS and sexual, emotional, or verbal abuse in childhood and adulthood (10). Bradford et al reported that compared with controls, patients with IBS had a higher prevalence of general trauma (78.5% vs 62.3%), emotional abuse (54.9% vs 27.0%), physical punishment (60.6% vs 49.2%), and sexual events (31.2% vs 17.9%) (11). These statistically significant differences were more common in women. Among the EAL domains, emotional abuse was the strongest predictor of IBS. The Longitudinal Studies of Child Abuse and Neglect monitored 845 children from ages 4 through 12 years (12). Every 2 years, information on GI symptoms was obtained from parents, and maltreatment allegations were obtained from Child Protective Services. Allegations of sexual abuse were associated with abdominal pain at age 12 years, and sexual abuse preceded or coincided with abdominal pain in 91% of cases. Recall of ever having been psychologically, physically, or sexually abused was significantly associated with functional abdominal pain, nausea, and vomiting. In that study it was concluded that children who have been maltreated are at increased risk for unexplained GI symptoms and it was suggested that this relation is mediated by psychological distress.
The clinical evidence about the sensitizing role of events occurring either at birth or in the first few months of life for the development of p-FGID is less strong, yet it goes in the direction of other observations that have suggested an increased reactivity to stress after experiencing painful procedures conditions in the first weeks of life. There is evidence that early experiences with pain are associated with altered pain responses later in infancy. Full-term neonates exposed to extreme stress during delivery or to a surgical procedure react to later noxious procedures with heightened behavioral responsiveness (13). Circumcision without anesthesia results in increases in cortisol production (14), modification of the mother–infant interaction (14), and alteration of behavioral responses (crying time, facial action) at the time of vaccinations (15), but only if local anesthetic was not used. Adverse childhood experiences increase even the risk of chronic obstructive pulmonary disease in adults. This increased risk seems to be only partially mediated by cigarette smoking, suggesting that other mechanisms contribute to its development (16).
Regarding p-FGID, low birth weight resulting from impaired fetal growth has been reported to have a significant influence on the development of IBS later in life. In a study of Norwegian twins, birth weight <1500 g doubled the risk for a child to develop IBS and influenced age at onset (>7 years earlier in the lower-birth-weight children), suggesting that prenatal factors may contribute to the development of IBS later in life (17). There is clinical and laboratory experimental evidence that a relatively benign noxious stimulus such as the insertion of a nasogastric catheter followed by suction of gastric contents occurring soon after birth may lead to the development of long-term visceral hypersensitivity and cognitive hypervigilance, factors which are associated with an increased prevalence of IBS in adulthood (18,19). The study by Anand et al is particularly noteworthy because it adjusted for other confounding variables, such as neonatal traumatic events and maternal factors (18).
Other events involving trauma or inflammation of the GI tract during childhood also have been associated with the development of p-FGID. The strongest evidence comes from studies that have demonstrated that p-FGIDs may develop as sequelae to acute infectious gastroenteritis in children and adults. A cohort of 44 children 3 to 19 years old with a positive result on a bacterial stool culture was matched to an age- and sex-matched control group and was contacted at least 6 months after the infectious episode. It was found that 36% of exposed patients and 11% of control subjects complained of abdominal pain, 87% had IBS, and 24% had functional dyspepsia (20). This observation matched well with several studies conducted in adult patients who had been exposed to outbreaks of bacterial infections (21). Conversely, a viral gastroenteritis, such as rotavirus infection, does not seem to place children at increased risk for p-FGIDs after at least 3 years of follow-up (22).
Saps and Bonilla reported that the occurrence of pyloric stenosis in infancy and factors involved in its perioperative care constitute risk factors in the development of chronic abdominal pain in children at long-term follow-up (23). In a case-control study by the same group, children between 4 and 18 years diagnosed with dietary cow's-milk allergy in the first year of life were found to have a higher prevalence of abdominal pain (odds ratio 4.3) compared with a control group (24). Patients with Henoch–Schönlein purpura, an acute leukocytoclastic systemic vasculitis that often involves the GI tract, were found to have an increased risk of developing p-FGID when they experienced severe abdominal pain during the acute phase, compared with a control group of sibling who had not had the disease (25). This study suggests that intestinal inflammation resulting from noninfectious causes could lead to p-FGID. Along the same lines, Turco et al reported that children with celiac disease on a strict gluten-free diet for at least 1 year had a higher prevalence than controls of functional GI symptoms (odds ratio 3.9) (26). The patients with FGID also experienced more anxiety and depression than those without FGID, and whether the experience of functional symptoms was caused by a persistence of a chronic inflammatory process or by psychological factors could not be ascertained. Finally, EALs have been identified as negative prognostic factors in patients with p-FGID. Childhood adversity was noted to be associated with poorer quality of life in patients with functional dyspepsia, noncardiac chest pain, 2 types of FGIDs, and the greatest impairment occur when lack of social support accompanies reported childhood EALs (27). None of these EALs have been shown to play a role in predisposing a newborn or an infant to the development of infant colic.
MECHANISMS BY WHICH EALS AFFECT THE DEVELOPMENT OF FUTURE FGIDS
Four main mechanisms have been associated with increased vulnerability to p-FGID after having experienced an EAL: neuronal plasticity, altered stress response, modification of the immunology of function of enteric mucosa, and changes in gut microbiome. Neonatal rats that are subjected to chemical colitis or that endure repeated colorectal distensions develop visceral hypersensitivity and increased colonic motility (typical features of IBS) as adult animals. This phenomenon is mediated by sensitization of primary sensory neurons and spinal dorsal neurons and is not seen when the noxious stimuli are applied to older rats, confirming the presence of a specific “window of vulnerability” for the effect of EALs (28,29). In a rat model of maternal separation, a standard animal experimental model of neonatal stress, time-dependent changes in the density of mucosal nerve fibers, and the development of enteric nervous system density have been reported (30).
Among patients with IBS with EALs, there was a trend to exhibit higher cortisol levels in response to a sigmoidoscopy, which acted as an experimental stressor (5). In that study, hypothalamic–pituitary–adrenal axis hyperresponsiveness seemed to be related more to a history of EALs than to the presence of IBS. Orogastric suctioning during the neonatal period results in somatic and visceral hyperalgesia in adult rats and is prevented by preemptive administration of the corticotropin-releasing factor-1 receptor antagonist, antalarmin (19). In another study, different handling of neonatal rats permanently altered the developmental setpoint of central corticotropin-releasing factor systems, potentially influencing the expression of behavioral and endocrine responses to stress (31). Finally, maternally deprived neonatal rats display as young adults elevated basal pituitary-adrenal activity and significantly increased basal plasma adrenocorticotropin hormone and corticosterone concentrations (32). Genetic factors may influence the response to subsequent stressors among vulnerable animals (33).
Maternal separation in rats is associated with increased colonic adherence and penetration of bacteria into the lamina propria relative to nonseparated controls (34). It also promotes long-term alterations in the colonic epithelial barrier associated with an exaggerated immune response to an external immune stimulus (35). Adults with postinfectious IBS show increased enterochromaffin cells and lamina propria T lymphocytes in the rectal biopsies compared with patients with IBS not related to a previous infection (36). Interleukin-1β mRNA levels are increased in the mucosa of those who develop postinfectious IBS and show increased gut permeability (37). Mast cells play an important role in the brain–gut axis and they seem to mediate the stress signals into the release of several neurotransmitters and proinflammatory cytokines that can stimulate enteric nerve endings, profoundly affecting the function of the GI tract (38). It has been suggested that exposure to noxious life events determines a defective jejunal epithelial response to successive stimuli, with increases in luminal tryptase, a marker for mast cell activation. This abnormal response may represent an initial step in the development of prolonged mucosal dysfunction, a finding that could be linked to enhanced susceptibility for IBS (39).
It is becoming increasingly clear that gut microbiota can affect pain sensitivity, the response to stress, and behavior. In the model of maternal separation, marked perturbations in gut microbiota were observed, confirming that there is a link between stress physiology and gut microbiota (33). Human data on the association between EAL and changes in enteric flora are lacking.
Little doubt exists that EAL have a great impact on future morbidity and that they may predispose to the development of p-FGID in children and adults. Future research needs to focus on decreasing the occurrence of sensitizing traumatic events and minimizing the long-term risk associated with EAL. Use of adequate anesthesia in newborns undergoing minor surgical procedures should be promoted. Early interventions, possibly through cognitive therapies, self-management strategies, and appropriate environmental (parents, friends, teachers) responses have the potential of optimizing a child's reaction to future stressful events and prevent p-FGID. The role of modifications of mucosal permeability, decrease in gut inflammation, and changes in enteric flora needs to be explored further. Future research also may uncover events occurring during pregnancy and either during or soon after birth, which may influence the development of infant colic.
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