*Department of Pediatrics, University of Bari, Bari
†Laboratory of Pathophysiology of Nutrition, IRCCS, Castellana Grotte
‡Department of Pediatrics, University “Federico II,” Naples, Italy.
Correspondence to Flavia Indrio, MD, Department of Pediatrics, University of Bari, Bari, Italy (e-mail: email@example.com).
The authors report no conflicts of interest.
Colic usually affects babies in the first few weeks of their lives and persists for about 4 months. Crying can be intense and furious and it may last for several hours per day for several weeks. Although crying can occur at any time, it is usually worse in the late afternoon and evening, and occasionally affects the baby's sleep. Infantile colic is not considered a disease, fulfilling instead criteria for a functional disorder. Research shows that babies with colic continue to eat and gain weight appropriately, despite the crying (1). The main risk for these babies relates to the stress and anxiety that the condition creates at home, especially when it affects the first child. The cause of colic is not known. Painful flatus may contribute to colic, but there is little evidence to prove that it is linked to digestive problems (2). Another theory is that while the digestive system is maturing, some babies are more sensitive to substances such as lactose ingested through breast-feeding and formula milk; however, evidence to support this hypothesis also is limited. Other possible causes relate to the baby's behavior and temperament. Among the gastrointestinal (GI) factors, we focus on non-nutritive pathophysiology such as the relation of colic to gastroesophageal reflux (GER), GI motility disorders, the role of gut hormones, and intestinal microflora.
Uncomplicated GER in otherwise healthy infants is common and is not considered a disease. Approximately 50% of all infants 0 to 3 months regurgitate at least once per day. This frequency drops to 5% by age 10 to 12 months. Three percent of parents of 10- to 12-month-old infants view this as a problem (3). Common contributing factors to excessive regurgitation include overfeeding, air swallowed during feeding, crying, or coughing. In uncomplicated GER (termed functional regurgitation in the Rome III criteria (4)), the physical examination is normal and weight gain is adequate. A thorough history and physical examination are sufficient for a confident diagnosis, and conservative, nonpharmacologic therapy usually is recommended. GER disease (GERD) occurs when the consequences of excessive GER cause a true disease, such as esophagitis, aspiration pneumonia, failure to thrive, and hematemesis. Guidelines for the evaluation and treatment of the infant and child with suspected GERD have been published (5). It is tempting to associate GER (and GERD) with excessive crying in some babies. The recent widespread use of medications aimed at increasing acid suppression in newborns and infants (6) may indeed reflect the belief that excessive esophageal exposure to acid is the culprit in many instances of infant colic. GERD symptoms in infants, however, usually include vomiting and feeding difficulty, and these are not common symptoms in babies with colic.
Normal esophageal pH monitoring scores have not been defined adequately in infants of different ages, and many pH studies have indicated that GER is a common event. Reflux index scores in infants often are higher than those considered clinically significant in adults and children. Reflux parameters are altered by changes in arousal state, type and frequency of feeding, and posture (7–9) factors that are rarely standardized in pediatric intraoesophageal pH–monitoring studies. The development of electronic impedance to study reflux events may shed further light on the relation between reflux and crying and irritability in infants. Interestingly, therapeutic studies that have been aimed at reducing gastric acid secretion to treat “reflux symptoms,” including irritability, in infants have failed to demonstrate superiority of the drugs compared with placebo (10,11). Available data seem to suggest that GER and GERD may play a role only in a small subset of infants with colicky symptoms.
Esophageal and GI motility and enteric nervous system abnormalities have been implicated as possibly being involved in the pathophysiology of infant colic. GI motility matures during infancy and early childhood and may be influenced by various factors, including developmental stage, dietary habits, genetics, arousal state, intercurrent illnesses, congenital anomalies, and effects of medical or surgical interventions. Esophageal motility plays an important role in airway protection during episodes of GER. There is evidence that abnormal esophageal reflexes may contribute to difficulty in feeding infants with some of the consequences of prematurity. The evaluation of these protective mechanisms in infants is now feasible but restricted to a few referral third-level centers (12).
In regard to alteration in gastric motility and its interplay with regurgitation in infants, gastric distension and impaired fundic relaxation as a result of disturbed gastric motility may play a role. Transient lower esophageal sphincter relaxation seems to be triggered by gastric distension via activation of the stretch receptors in the stomach (13,14) and there is evidence that gastric accommodation may be impaired in the first few days of life (15). The enlarged antral area, as a consequence of distal displacement of gastric contents when fundic function is impaired, could trigger nausea and discomfort and consequently provoke regurgitation. Other studies suggest that acid exposure may be reduced in the case of delayed gastric emptying (16). Recent data on infants with cow's-milk allergy show a close link between GI symptoms, GER, and gastric-emptying time (17). Although the available evidence fails to provide insight into the exact triggers of infant colic, the data about the relation among gastric and oesophageal motor function, allergy, and dyspeptic symptoms allow for the hypothesis that certain infants may be predisposed to dietary protein intolerance and disturbed gut motility in the first few weeks of life. These processes also may lead to altered gut perception and normal stimuli (eg, intestinal distension) may be misinterpreted as painful events (18), much as happens in other pain-predominant functional disorders affecting older children, such as functional abdominal pain and irritable bowel syndrome (19,20). In support of the hypothesis that disturbed gut sensory-motor function may play a role in infant colic, there is the finding that ghrelin and motilin (2 hormones that affect gastric emptying) concentrations in blood are higher in infants with colic than in controls. Elucidation of the role of ghrelin in GI motility may open new doors to better understand the etiology of infant colic (21). Treatments of colicky symptoms have included medications with anticholinergic effects with the goal of reducing “spasms” or lessen the amplitude of potentially painful GI contractions. Evidence supporting their use is controversial, suggesting that motility disturbances may be involved only in a subgroup of children with infant colic (22,23).
ROLE OF MICROBIOTA
Reduction in crying time in colicky newborns fed with breast milk with the addition of probiotics has been reported by Savino and coworkers (24) and confirmed by other studies in preterm and term infants (25,26). The action of microbiota and its modulation by probiotics on upper GI motility can be explained in several ways (27). Volume and chemical characteristics of meals in the gut may modulate vagal signaling and affect gastric emptying (28). Fiber content increases gastric antrum motility compared with other diets (29). Intestinal bacteria metabolites such as short-chain fatty acids (SCFA) may stimulate smooth muscle (30). In the colon, these compounds inhibit peristaltic activity and may stimulate tonic activity. SCFA modify upper motility, inducing relaxation of the proximal stomach, lower esophageal sphincter and reducing gastric emptying via the mediation of GI hormones such as polypeptide YY (31). Cross-talk among the digestive nervous and motor activities, immune-related mechanisms, and probiotics has been thoroughly investigated. There is evidence that postinfectious enteric muscle dysfunction represents a state of persistent dysfunction of the neuromuscular tissues maintained by the production of mediators such as transforming growth factor-β and prostaglandin E2 by the intestinal muscle layers themselves (32). The interstitial cells of the Cajal network, the pacemaker of GI electrical activity, also may be damaged by inflammation and such alteration may lead to motor abnormality (33). The administration of probiotics could restore muscle function after a GI infection through action on multiple proteins and other components of excitation-contraction coupling (34). Probiotics also interact with the gut-associated lymphoid tissue (35,36). The coordinated interplay among these components is fundamental for the proper functioning of the gut. De Weerth and coworkers showed a microbiota diversity in children affected by colic in the first week of life compared with healthy controls (37).
Little evidence supports a substantial role of GER or GERD in the majority of infants with colic. It is possible that delayed gastric emptying, associated with abnormal antral contractions, leads to prolonged gastric stasis and antrofundic incoordination, resulting in increased wall tension in the gastric body and the fundus. This, in turn, may activate tension and pain receptors in the stomach to generate the characteristic distress present in children with colic. Heightened visceral sensitivity and altered gut hormones in these children also may contribute to enhanced pain perception. Such hypotheses have not been confirmed yet by in vivo studies and have not translated into viable therapeutic options. The role of microbiota in modifying intestinal environment and host responses in both the peripheral and central nervous systems represents a promising but not yet proven target for therapeutic interventions in dealing with distressed behavior in infants.
1. Cohen-Silver J, Ratnapalan S. Management of infantile colic: a review. Clin Pediatr (Phila)
2. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics
3. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med
4. Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology
5. Vandenplas Y, Rudolph CD, Di LC, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr
6. Barron JJ, Tan H, Spalding J, et al. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr
7. Tobin JM, McCloud P, Cameron DJ. Posture and gastro-oesophageal reflux: a case for left lateral positioning. Arch Dis Child
8. Heacock HJ, Jeffery HE, Baker JL, et al. Influence of breast versus formula milk on physiological gastroesophageal reflux in healthy, newborn infants. J Pediatr Gastroenterol Nutr
9. Omari TI, Barnett CP, Benninga MA, et al. Mechanisms of gastro-oesophageal reflux in preterm and term infants with reflux disease. Gut
10. Orenstein SR, Hassall E, Furmaga-Jablonska W, et al. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr
11. van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: a systematic review. Pediatrics
12. Jadcherla SR, Peng J, Chan CY, et al. Significance of gastroesophageal refluxate in relation to physical, chemical, and spatiotemporal characteristics in symptomatic intensive care unit neonates. Pediatr Res
13. Massey BT, Simuncak C, LeCapitaine-Dana NJ, et al. Transient lower esophageal sphincter relaxations do not result from passive opening of the cardia by gastric distention. Gastroenterology
14. Penagini R, Carmagnola S, Cantu P, et al. Mechanoreceptors of the proximal stomach: Role in triggering transient lower esophageal sphincter relaxation. Gastroenterology
15. Zangen S, Di LC, Zangen T, et al. Rapid maturation of gastric relaxation in newborn infants. Pediatr Res
16. Herculano JR Jr, Troncon LE, Aprile LR, et al. Diminished retention of food in the proximal stomach correlates with increased acidic reflux in patients with gastroesophageal reflux disease and dyspeptic symptoms. Dig Dis Sci
17. Ravelli AM, Tobanelli P, Volpi S, et al. Vomiting and gastric motility in infants with cow's milk allergy. J Pediatr Gastroenterol Nutr
18. Gupta SK. Update on infantile colic and management options. Curr Opin Investig Drugs
19. Di Lorenzo C, Youssef NN, Sigurdsson L, et al. Visceral hyperalgesia in children with functional abdominal pain. J Pediatr
20. Van Ginkel R, Voskuijl WP, Benninga MA, et al. Alterations in rectal sensitivity and motility in childhood irritable bowel syndrome. Gastroenterology
21. Savino F, Grassino EC, Guidi C, et al. Ghrelin and motilin concentration in colicky infants. Acta Paediatr
22. Savino F, Brondello C, Cresi F, et al. Cimetropium bromide in the treatment of crisis in infantile colic. J Pediatr Gastroenterol Nutr
23. Oggero R, Garbo G, Savino F, et al. Dietary modifications versus dicyclomine hydrochloride in the treatment of severe infantile colics. Acta Paediatr
24. Savino F, Pelle E, Palumeri E, et al. Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics
25. Indrio F, Riezzo G, Raimondi F, et al. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr
26. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr
27. Di Mauro, Neu J, Riezzo G, et al. Gastrointestinal function development and microbiota. Ital J Pediatr
28. Schwartz GJ, Moran TH. Duodenal nutrient exposure elicits nutrient-specific gut motility and vagal afferent signals in rat. Am J Physiol
1998; 274 (5 Pt 2):R1236–R1242.
29. Bouin M, Savoye G, Maillot C, et al. How do fiber-supplemented formulas affect antroduodenal motility during enteral nutrition? A comparative study between mixed and insoluble fibers. Am J Clin Nutr
30. McManus CM, Michel KE, Simon DM, et al. Effect of short-chain fatty acids on contraction of smooth muscle in the canine colon. Am J Vet Res
31. Cherbut C. Motor effects of short-chain fatty acids and lactate in the gastrointestinal tract. Proc Nutr Soc
32. De Giorgio R, Guerrini S, Barbara G, et al. Inflammatory neuropathies of the enteric nervous system. Gastroenterology
33. Wang XY, Berezin I, Mikkelsen HB, et al. Pathology of interstitial cells of Cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry. Am J Pathol
34. Verdu EF, Bercik P, Verma-Gandhu M, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut
35. Ruiz PA, Hoffmann M, Szcesny S, et al. Innate mechanisms for Bifidobacterium lactis to activate transient pro-inflammatory host responses in intestinal epithelial cells after the colonization of germ-free rats. Immunology
36. Holtta V, Klemetti P, Sipponen T, et al. IL-23/IL-17 immunity as a hallmark of Crohn's disease. Inflamm Bowel Dis
37. de Weerth C, Fuentes S, Puylaert P, et al. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics