Transient Lower Esophageal Sphincter Relaxations Research Articles

Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management.

Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. The diagnosis of this disorder depends on both the findings of multi-channel intraluminal impedance-pH monitoring and the subsequent intensified anti-reflux therapy. The strategies of pharmacological treatment for refractory chronic cough due to reflux include the optimization of proton pump inhibitors and add-on therapies with histamine H2 receptor antagonists, baclofen and gabapentin. However, the further study is needed to satisfy its management.

PO-0133 Gastroesophageal Reflux In Infants And Osteophatic Manipolative Treatment: An Alternative Therapy?

Background and aims Several study have been reported that modifying vagus nerve control of transient lower esophageal sphincter relaxation can induce improvement of gastroesophageal reflux disease (GERD). Our aim was to evaluate the efficacy of osteophatic treatment (OMT) in infants with GERD. Methods We enrolled 40 infants (M/F:24/16), age ranged 1–18 months (median 4 month) attending for persistent reflux. Each patient performed I-GERQ-R questionnaire and ultrasonography of the gastro-esophageal junction before and after treatment. The ultrasound score was 0 to 3 on the basis of severity of reflux (number of reflux episodes in 10 min). Moreover each patient did an osteophatic treatment consisting in an extensive physical examination, to evaluate TART parameters (T = tissue texture changes; A = asimmetry; R = restriction of motion; T = tenderness). Then, a specific therapeutic intervention was chosen, treating only the parts of the body presenting greater TART modifications. Results All the somatic dysfunctions observed before OMT (at the scale 32/40 patients, the condyles 36/40 patients, the occipito-mastoid suture 36/40 patients; the stomach 22/40 patients, the small epiploon 30/40 patients) disappeared after treatment. The average score of I GERQ-R questionnaire before and after treatment was 22.7 ± 4.7 and 17.2 ± 4.5 respectively (p Conclusion OMT could be considered as an alternative treatment in infants with gastroesophageal reflux. Further data are needed to confirm our hyphothesis.

Effects of baclofen on the functional anatomy of the oesophago-gastric junction and proximal stomach in healthy volunteers and patients with GERD assessed by magnetic resonance imaging and high-resolution manometry: a randomised controlled double-blind study.

The mechanism of reflux protection may involve a 'flap valve' at the oesophago-gastric junction (OGJ). To assess the effects of baclofen, a gamma-aminobutyric acid receptor type-B (GABA-B) agonist known to suppress reflux events, on the 'functional anatomy' of the OGJ and proximal stomach after a large test meal. Twelve healthy volunteers (HVs) and 12 patients with gastro-oesophageal reflux disease (GERD); with erosive oesophagitis or pathological oesophageal acid exposure completed a randomised, double-blind, cross-over study. On 2 test days participants received 40-mg baclofen or placebo before ingestion of a large test meal. OGJ structure and function were assessed by high-resolution manometry (HRM) and magnetic resonance imaging (MRI) using validated methods. Measurements of the oesophago-gastric angle were derived from three-dimensional models reconstructed from anatomic MRI images. Cine-MRI and HRM identified postprandial reflux events. Mixed model analysis and Wilcoxon rank signed tests assessed differences between participant groups and treatment conditions. In both HVs and GERD patients, baclofen reduced the frequency of postprandial reflux events. The oesophago-gastric insertion angle in GERD patients was reduced (-4.1 ± 1.8, P = 0.025), but was unchanged in healthy controls. In both study groups, baclofen augmented lower oesophageal sphincter (LES) pressure (HVs: +7.3 ± 1.8 mmHg, P < 0.0001, GERD: +4.50 ± 1.49 mmHg, P < 0.003) and increased LES length (HVs: +0.48 ± 0.11 cm, P < 0.0003, GERD: +0.35 ± 0.06 cm, P < 0.0001). Baclofen inhibits transient LES relaxations and augments LES pressure and length. Additionally, baclofen has effects on the 'functional anatomy' of the OGJ and proximal stomach in GERD patients, which may suppress reflux by means of a 'flap valve' mechanism.

Diagnosis and management of gastroesophageal reflux disease.

IntroductionGastroesophageal reflux disease (GERD) is probably one of the most prevalent diseases in the world that also compromises the quality of life of the affected significantly. Its incidence in Brazil is 12%, corresponding to 20 million individuals.ObjectiveTo update the GERD management and the new trends on diagnosis and treatment, reviewing the international and Brazilian experience on it.MethodThe literature review was based on papers published on Medline/Pubmed, SciELO, Lilacs, Embase and Cochrane crossing the following headings: gastroesophageal reflux disease, diagnosis, clinical treatment, surgery, fundoplication.ResultsVarious factors are involved on GERD physiopathology, the most important being the transient lower esophageal sphincter relaxation. Clinical manifestations are heartburn, regurgitation (typical symptoms), cough, chest pain, asthma, hoarseness and throat clearing (atypical symptoms), which may be followed or not by typical symptoms. GERD patients may present complications such as peptic stenosis, hemorrhage, and Barrett's esophagus, which is the most important predisposing factor to adenocarcinoma. The GERD diagnosis must be based on the anamnesis and the symptoms must be evaluated in terms of duration, intensity, frequency, triggering and relief factors, pattern of evolution and impact on the patient's quality of life. The diagnosis requires confirmation with different exams. The goal of the clinical treatment is to relieve the symptoms and surgical treatment is indicated for patients who require continued drug use, with intolerance to prolonged clinical treatment and with GERD complications.ConclusionGERD is a major digestive health problem and affect 12% of Brazilian people. The anamnesis is fundamental for the diagnosis of GERD, with special analysis of the typical and atypical symptoms (duration, intensity, frequency, triggering and relief factors, evolution and impact on the life quality). High digestive endoscopy and esophageal pHmetry are the most sensitive diagnosctic methods. The clinical treatment is useful in controlling the symptoms; however, the great problem is keeping the patients asymptomatic over time. Surgical treatment is indicated for patients who required continued drug use, intolerant to the drugs and with complicated forms of GERD.

Acid infusion into the esophagus increases the number of meal-induced transient lower esophageal sphincter relaxations (TLESRs) in healthy volunteers.

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux (GER) but the regulation of TLESR by stimuli in the esophagus is incompletely understood. If stimuli in the esophagus can influence TLESR, then such regulation may perpetuate or limit GER. We addressed the hypothesis that acid in the esophagus enhances TLESRs. We evaluated the effect of acid infusion into the distal esophagus on TLESRs evoked by a standard meal in a paired randomized study in healthy subjects. TLESRs were evaluated by using high resolution manometry (HRM). We found that acid in the esophagus enhanced meal-induced TLESRs. Compared to control infusion the number of TLESRs (median [interquartile range]) was increased during 2h following the acid infusion (11 [9-14] vs 17 [12.5-20], p<0.01). The average duration of individual TLESRs was not affected. The time-course analysis revealed that a robust increase in TLESRs occurred already in the first hour when the number of TLESRs nearly doubled (6 [5.5-7.5] vs 11 [7.5-12.5], p<0.05). In contrast to the enhancement of TLESRs, the number of swallows was not changed. The acid infusion into the esophagus increases the number of meal-induced TLESRs in healthy subjects. Our results provide evidence for the concept that the stimuli in the esophagus can influence TLESRs. The regulation of TLESR by stimuli in the esophagus may contribute to pathogenesis of GER in some patients.

Mechanism of UES relaxation initiated by gastric air distension.

The aim of this study was to determine the mechanism of initiation of transient upper esophageal sphincter relaxation (TUESR) caused by gastric air distension. Cats (n = 31) were decerebrated, EMG electrodes were placed on the cricopharyngeus, a gastric fistula was formed, and a strain gauge was sewn on the lower esophageal sphincter (n = 8). Injection of air (114 ± 13 ml) in the stomach caused TUESR (n = 18) and transient lower esophageal sphincter relaxation (TLESR, n = 6), and this effect was not significantly (P > 0.05) affected by thoracotomy. Free air or bagged air (n = 6) activated TLESR, but only free air activated TUESR. Closure of the gastroesophageal junction blocked TUESR (9/9), but not TLESR (4/4), caused by air inflation of the stomach. Venting air from distal esophagus during air inflation of the stomach prevented TUESR (n = 12) but did not prevent air escape from the stomach to the esophagus (n = 4). Rapid injection of air on the esophageal mucosa always caused TUESR (9/9) but did not always (7/9) cause an increase in esophageal pressure. The time delay between the TUESR and the rapid air pulse was significantly more variable (P < 0.05) than the time delay between the rapid air pulse and the rise in esophageal pressure. We concluded that the TUESR caused by gastric air distension is dependent on air escape from the stomach, which stimulates receptors in the esophagus, but is not dependent on distension of the stomach or esophagus, or the TLESR. Therefore, the TUESR caused by gastric air distension is initiated by stimulation of receptors in the esophageal mucosa.

Gastroesophageal reflux disease: diagnosis and patient selection.

Gastroesophageal reflux disease (GERD) has a high prevalence worldwide. Recent reports have noted a high prevalence even in Asian countries. GERD significantly affects the quality of life and can present with a wide variety of symptoms. Not all reflux is acid, and non-acid reflux disease can be more difficult to diagnose and can lead to a variety of extra-esophageal symptoms. Although proton pump inhibitors (PPIs) are effective in the majority of patients, but they are not without side effects, and their effect often diminishes with time. For patients who do not desire to be on long-term PPIs or have incomplete symptom resolution with medication, various endoscopic and minimally invasive treatment modalities are now available. The etiology of GERD can be multifactorial including dysfunctional LES, presence of a hiatal hernia, and transient lower esophageal sphincter relaxations (TLESRs). We hence believe that the treatment should be individualized to the cause of the reflux. In the following review, we describe the etiology of reflux disease and attempt to lay a framework for the diagnosis and selection of patients for the various interventions available for treatment, along with their evidence base.

14 Identification of Transient Lower Esophageal Sphincter Relaxation (TLESR) in High Resolution Manometry Combined With Impedance (HRM-Z): Toward a Consensus Definition

14 Identification of Transient Lower Esophageal Sphincter Relaxation (TLESR) in High Resolution Manometry Combined With Impedance (HRM-Z): Toward a Consensus Definition

Tu1994 Increased Frequency of Transient Lower Esophageal Sphincter (LES) Relaxation in Cascade Stomach

Background: In the Chicago Classification (CC) peristaltic integrity is determined by the size of the largest break in the isobaric contour. However, bolus clearance might be affected by the occurrence of non-continuous breaks. The aim of the study was to assess the effect of peristaltic integrity on bolus clearance by using pressure-flow analysis. Methods: 22 solidstate high-resolution impedance manometry (HRIM) tracings of 10 liquid swallows of healthy asymptomatic adults (6M; mean age 36.1 SD 11.7 years) were retrospectively analysed using MMS analysis software (version 9.1). Measures of peristaltic integrity (largest break and total break size in cm of the 20mmHg isobar) were derived. Pressure-flow analysis was performed using purpose designed MATLAB-based software (AIMplot, T. Omari) which derived peak pressure (PeakP), intra-bolus pressure (IBP), bolus flow relative to peak pressure (PNadImp) and its timing to peak pressure (TNadImp-PeakP). In addition the pressure-flow index (PFI), a composite measure of bolus pressurisation relative to flow and the impedance ratio (IR) a measure of the extent of bolus clearance failure were calculated. Results: Out of 220 swallows, 214 were suitable for analysis. A strong correlation between total break size and the largest break in the isobaric contour was found (r=0.846,p=0.000). There was a trend towards larger break size and higher IR, with a stronger correlation for the largest break (table 1). Both largest break and total break size correlated with lower PeakP, lower PNadImp, lower IBP and longer TNadImp-PeakP. However, no correlation was found between larger break size and PFI. Conclusion: Largest break and total break size seem to characterize peristaltic integrity equally. Larger break size is associated with lower peristaltic pressurization and impaired bolus movement. There seems to be little quantifiable difference between the largest break and total breaksize in relation to bolus pressurization. Esophageal break size and AIM-derived pressure-flow metrics

Symptomatic reflux disease: the present, the past and the future

The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications,...

Republished: Symptomatic reflux disease: the present, the past and the future

The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications,...

The gastric accommodation response to meal intake determines the occurrence of transient lower esophageal sphincter relaxations and reflux events in patients with gastro‐esophageal reflux disease

Gastro-esophageal reflux (GER), the retrograde flow of gastric contents into the esophagus is a physiologic phenomenon, which can evoke symptoms and/or lesions in the esophagus (=gastro-esophageal reflux disease or GERD). Proton pump inhibitors (PPIs) reduce gastric acidity; however, as they are unable to control transient lower esophageal sphincter relaxations (TLESRs), the main mechanism for reflux in GERD, they do not abolish reflux. TLESRs occur predominantly in the postprandial period, and they are believed to be triggered by gastric distention. Gastric accommodation (GA) is the physiologic response to gastric distention and serves to prevent a rise in gastric wall tension during food intake. We aimed to study the relationship between GA and TLESRs, as they both are triggered by gastric distention. We studied 12 GERD patients (average age 37 years [range 18-62], 7m/5f) and nine healthy volunteers (average age 27 years [range 22-36], 2m/7f) using high resolution manometry-impedance measurement before and after a mixed meal challenge. We determined the number of TLESRs (with or without reflux) and measured pre- and postprandial IGP. The change in IGP between the pre- and postprandial period (ΔIGP) is used as surrogate for GA. We also measured LES pressure before and after the meal and calculated the change (ΔLESp). There were no statistical differences between pre- and postprandial IGP in GERD and healthy volunteers and similarly, there was no significant difference between pre- and postprandial LES pressures in GERD patients and healthy volunteers. The number of TLESRs (with or without reflux) was similar in GERD and healthy volunteers. More importantly, we did observe a negative correlation between ΔIGP and the number of TLESRs, irrespective of whether they were associated with reflux or not, in the GERD patients (without reflux r = -0.67, p = 0.017; with reflux r = -0.81, p = 0.0014). The same observations were found in healthy volunteers, where ΔIGP and the number of TLESRs are significantly inversely correlated (without reflux r = -0.87, p = 0.0045; with reflux r = -0.75, p = 0.021). We could not establish a correlation between ΔLESp and the number of TLESRs, neither in GERD patients nor in healthy volunteers. This is the first study showing a clear negative correlation between ΔIGP and the number of TLESRs, irrespective of whether they were associated with reflux or not, both in GERD patients and in healthy subjects. These results suggest that TLESRs and GA are closely linked, probably through activation of mechanoreceptors involved in triggering of TLESRs.

Electroacupuncture at PC6 or ST36 Influences the Effect of Tacrine on the Motility of Esophagus.

Aim. To investigate the mechanisms of gastrointestinal side effects of tacrine, and find treatment methods with electroacupuncture (EA). Methods. Twenty-five healthy cats were randomly divided into 5 groups: gastric-distention group (model group), tacrine group (cholinesterase inhibitor), tacrine + sham acupoint group (control group), tacrine + PC6 (neiguan) group, and tacrine + ST36 (zusanli) group, with 5 cats in each group. Saline 2 mL i.p. was given 30 min before gastric distention in model group. Tacrine 5.6 mg/kg i.p. was given 30 minutes before gastric distention in the other groups. Tacrine + sham acupoint group (control group), tacrine + PC6 group, and tacrine + ST36 group received EA at corresponding acupoints during gastric distention. The frequency of TLESRs and LESP were recorded by using a perfused sleeve assembly. Results. Compared with the model group, tacrine significantly increased the frequency of gastric distention-induced TLESR (P < 0.05) but did not influence the rate of common cavity during TLESR. Tacrine significantly increased the LESP, which could not remain during gastric distention. EA at PC6 could decrease the frequency of TLESR and maintain the increase of LESP, but EA at ST36 did not have these effects. Conclusion. Tacrine can significantly increase the gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs). Electroacupuncture (EA) at PC6 may reverse the above side effect.

The Effects of Baclofen for the Treatment of Gastroesophageal Reflux Disease: A Meta-Analysis of Randomized Controlled Trials

Objectives. Baclofen can relieve gastroesophageal reflux-related symptoms in healthy subjects and gastroesophageal reflux disease (GERD) patients by reducing the incidence of transient lower esophageal sphincter relaxation. This meta-analysis aimed to evaluate the efficacy and safety of baclofen for the treatment of GERD. Methods. We systematically searched randomized controlled trials published prior to November 2013 from PubMed, Medline, Embase, ScienceDirect, ClinicalTrials.gov, and the Cochrane Central Register of Randomized Controlled Trials. We performed a meta-analysis of all eligible trials. Results. Nine studies were identified with a total of 283 GERD patients and healthy subjects. Comparative analysis provided high quality data supporting the ability of baclofen to promote a short-term decrease in the number of reflux episodes per patient, the average length of reflux episodes, and the incidence of transient lower esophageal sphincter relaxation. No serious adverse events or death events were reported, and there were no significant differences in the overall adverse events between baclofen and placebo. All reported side effects of baclofen were of mild-to-moderate intensity, and the drug was well tolerated. Conclusion. Abundant evidence suggests that baclofen may be a useful approach for the treatment of GERD patients; however, a larger well-designed research study would further confirm this recommendation.

Esophageal motility abnormalities in gastroesophageal reflux disease.

Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophageal motility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from non-erosive reflux disease to erosive reflux disease and Barrett's esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.

GERD and obesity: is the autonomic nervous system the missing link?

Gastroesophageal reflux disease (GERD) is a common chronic condition that not only impairs the quality of life of those who are affected by it but also poses a significant economic burden. It encompasses a wide spectrum of symptoms as a result of gastric content moving into the esophagus. The most common cause of GERD, other than a hiatus hernia, is considered to be transient lower esophageal sphincter relaxation. The lower esophageal sphincter (LES) normally has a higher resting tone than the stomach, thus preventing the reflux of gastric contents into the esophagus. The greater prevalence of GERD and GERD symptoms in obese individuals has generated significant interest in understanding the association between these 2 conditions and the underlying physiological mechanisms. The potential relationship between GERD and obesity and the exact mechanism by which obesity may cause reflux, however, remains uncertain. It has been proposed that patients with GERD have altered autonomic nervous function and, more specifically, have reduced parasympathetic activity. Obese individuals also have shown diminished parasympathetic activity, which may be reversed after weight reduction through exercise, diet control, and bariatric surgery. Given that contraction and relaxation of the LES are vagally mediated, the question that arises is whether the autonomic nervous system is, in fact, the missing link between obesity and GERD. In this article we examine the current evidence and hypothesize that the potential imbalance in sympathovagal stimulation to the LES is a key contributing factor to the increased prevalence of GERD symptoms in obese individuals.

New and Future Drug Development for Gastroesophageal Reflux Disease

Medical therapy remains the most popular treatment for gastroesophageal reflux disease (GERD). Whilst interest in drug development for GERD has declined over the last few years primarily due to the conversion of most proton pump inhibitor (PPI)'s to generic and over the counter compounds, there are still numerous areas of unmet needs in GERD. Drug development has been focused on potent histamine type 2 receptor antagonist's, extended release PPI's, PPI combination, potassium-competitive acid blockers, transient lower esophageal sphincter relaxation reducers, prokinetics, mucosal protectants and esophageal pain modulators. It is likely that the aforementioned compounds will be niched for specific areas of unmet need in GERD, rather than compete with the presently available anti-reflux therapies.

Enhanced nicotinic receptor mediated relaxations in gastroesophageal muscle fibers from Barrett's esophagus patients

Increased nicotinic receptor mediated relaxation in the gastroesophageal antireflux barrier may be involved in the pathophysiology of reflux. This study is designed to determine whether the defects we previously identified in gastroesophageal reflux disease patients in- vivo are due to abnormalities of the gastric sling, gastric clasp, or lower esophageal circular (LEC) muscle fibers. Muscle strips from whole stomachs and esophagi were obtained from 16 normal donors and 15 donors with histologically proven Barrett's esophagus. Contractile and relaxant responses of gastric sling, gastric clasp, or LEC fibers were determined to increasing concentrations of carbachol and to nicotine after inducing maximal contraction to bethanechol. Muscarinic receptor density was measured using subtype selective immunoprecipitation. Barrett's esophagus gastric sling and LEC fibers have decreased carbachol-induced contractions. Barrett's esophagus sling fibers have decreased M2 -muscarinic receptors and LEC fibers have decreased M3 receptors. Relaxations of all three fiber types are greater in Barrett's esophagus specimens to both high carbachol concentrations and to nicotine following bethanechol precontraction. The maximal response to bethanechol is greater in Barrett esophagus sling and LEC fibers. The increased contractile response to bethanechol in Barrett's specimens indicates that the defect is likely not due to the smooth muscle itself. The enhanced nicotinic receptor mediated response may be involved in greater relaxation of the muscles within the high-pressure zone of the gastroesophageal junction during transient lower esophageal sphincter relaxations and during deglutitive inhibition and may be involved in the pathophysiology of gastroesophageal reflux disease.

Dysmotility and reflux disease

In the last decade, with the advent of new oesophageal testing [i.e. 24-h impedance-pH monitoring, combined impedance-manometry, high-resolution manometry (HRM)], relevant progress in understanding the mechanisms contributing to the development of gastro-oesophageal reflux disease (GORD) has been made, allowing a better management of patients with this disorder. The aim of our review is to report the state-of-the-art about oesophageal motor disorders in patients with reflux disease and to stimulate new research in this field. Hypotensive lower oesophageal sphincter (LOS), transient LOS relaxations, impairment of oesophagogastric junction including hiatal hernia, oesophageal bolus transit abnormalities and presence of ineffective oesophageal motility have been strongly implicated in GORD development. In particular, the majority of recent studies carried out with HRM and impedance-pH testing reported that these motor abnormalities are increasingly prevalent with increasing severity of GORD, from nonerosive reflux disease and erosive oesophagitis to Barrett's oesophagus. Defining and characterizing oesophageal dysmotility in patients with reflux disease is of maximum importance in order to properly diagnose these patients and to treat them with the best management of care. New studies are needed in order to better understand the physiomechanic basis of oesophageal dysmotility in GORD patients.

Gut Motility Alterations in Neonates and Young Infants

C olic 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.