Delayed orocecal transit in pediatric gut-brain interaction disorders: A comparative study using the lactulose breath test

Abstract

BACKGROUND

Functional abdominal pain disorders (FAPDs) are common gut–brain interaction disorders with unclear pathophysiology. While impaired gastrointestinal motility is thought to play a key role, small intestinal dysmotility remains largely unexplored. Orocecal transit time (OCTT), an indirect indicator of small intestinal transit, offers an insight into its potential contribution to FAPD's pathophysiology.

AIM

To assess OCTT in children with FAPDs compared with healthy children using the lactulose breath hydrogen test.

METHODS

Thirty-four children (44.1% males, age 5–12 years, mean 7.2 ± 2.4 years) with FAPDs attending North Colombo Teaching Hospital, Ragama, Sri Lanka, were included in the analysis. FAPDs were diagnosed using the Rome IV criteria. None had clinical or laboratory evidence of organic diseases. They were compared with 19 healthy controls (47.1% males, age 5-12 years, mean 7.8 ± 2.7 years) from the same geographical area. OCTT was calculated after an 8-hour fast using a previously validated technique. Breath hydrogen levels were measured at baseline and 15-minute intervals for 180 minutes post-lactulose ingestion (10 g in 10% solution). At each time point, 3 breath samples were collected and analyzed. OCTT was quantified as the time taken to achieve a sustained breath hydrogen increase > 10 parts per million above baseline. Symptoms were recorded using the Rome IV questionnaire, and symptom severity was graded on a 0-4 Likert scale.

RESULTS

Patients with FAPDs had increased OCTT (median, 90 minutes; interquartile range, 75-120 minutes) compared to controls (median, 75 minutes; interquartile range, 60-75 minutes) (P = 0.0045, Mann-Whitney U-test). Children with functional dyspepsia had the longest mean OCTT (110.8 ± 26.7 minutes). There was no significant correlation between abdominal pain severity and OCTT (r = 0.18, P = 0.35, Spearman correlation coefficient). OCTT did not differ between those exposed to stressful events and those not exposed to such events (P > 0.05).

CONCLUSION

Children with FAPDs have longer OCTT than healthy controls. However, the lack of a significant correlation between OCTT and symptom severity suggests that delayed small intestinal transit alone is not a substantial contributor to FAPD pathophysiology.

Key Words: Abdominal pain; Child; Disorders of gut-brain interaction; Functional gastrointestinal disorders; Gastrointestinal transit; Lactulose breath test

Core Tip: This study evaluated orocecal transit time (OCTT) in children with functional abdominal pain disorders (FAPDs) using the breath hydrogen test. Results showed significantly longer OCTT in patients compared to healthy controls, suggesting that impaired small intestinal transit may be a feature of FAPDs. However, the lack of correlation between OCTT and symptom severity indicates that delayed transit is unlikely to be a major contributor to symptom generation. These findings highlight the complexity of FAPD pathophysiology and suggest that while small intestinal motility disturbances are present, other mechanisms likely play a key role in symptom expression.

INTRODUCTION

Disorders of gut-brain interaction (DGBIs), previously referred to as functional gastrointestinal disorders, are frequently seen in the pediatric population, with global prevalence estimates ranging from 10% to 30%[1-3]. Among these, functional abdominal pain (FAP) disorders (FAPDs), including irritable bowel syndrome (IBS), functional dyspepsia (FD), abdominal migraine (AM), and FAP, are the most prevalent, affecting approximately 11% of children worldwide[4]. The prevalence of FAPD in Sri Lanka ranges from 10% in teenagers (13-18 years) to 24% in younger children (5-12 years)[5,6]. The most common FAPD in children is IBS[4]. AM is less common and is relatively understudied compared to other FAPDs[7-9].

Similar to other DGBIs, FAPDs are among gastrointestinal disorders with unclear pathophysiology. The primary suggested etiology for FAPDs is gut-brain axis dysfunction[10]. The observed pathophysiological abnormalities in FAPDs include enhanced visceral sensitivity, gastrointestinal dysmotility, altered gut regulatory mechanisms (e.g. enteric, autonomic and central neural regulation), mucosal inflammation, increased gut permeability, altered gut microbiota, and immune dysfunction[11,12]. Genetic predisposition, psychological factors, gastrointestinal infection, and diet are recognized risk factors[13,14].

Numerous gastrointestinal motility disturbances have been documented in children with FAPDs. Among them, delayed gastric emptying is the most frequently observed abnormality[15-20], followed by abnormal gastric myoelectrical activity[21-27] and impaired antral contractility[26,27]. Impaired gastric accommodation is also commonly identified in FD[28,29]. In IBS, both accelerated and delayed colonic transit have been reported[30].

The small intestine is the principal segment of the gastrointestinal tract responsible for digestion and nutrient absorption. Optimal small intestinal function is essential for effective digestive and absorptive processes. Impaired small intestinal motility can disrupt these processes, leading to gastrointestinal symptoms such as abdominal pain, nausea, vomiting, bloating and in rare cases, nutritional deficiencies or even intestinal failure. However, in contrast to the relatively robust literature on gastric and colonic motor dysfunction, only a limited number of studies have explored the role of small intestinal transit in FAPDs.

Orocecal transit time (OCTT), measured using the lactulose hydrogen breath test (LHBT), provides a non-invasive estimate of small intestinal transit based on hydrogen production from colonic fermentation of lactulose[31]. Although validated against scintigraphy with reasonable accuracy[32,33], the LHBT has limitations, particularly in the presence of small intestinal bacterial overgrowth (SIBO), which may cause premature hydrogen peaks due to small bowel fermentation[34,35]. Differentiating colonic from small intestinal hydrogen production is challenging. However, concurrent scintigraphic studies have shown that the increase in hydrogen levels during LHBT reflects the arrival of lactulose in the cecum, rather than indicating SIBO[36]. Despite limitations, LHBT remains the safest method for assessing OCTT in children.

Given the existing evidence of abnormal gastrointestinal motility, particularly involving the stomach and colon, we hypothesized that children with DGBI would exhibit prolonged small intestinal transit compared to healthy controls. The main objective of this study was to evaluate small intestinal transit abnormalities in a cohort of children with FAPDs, using the OCTT measured by the LBHT, and to compare these findings with those of an age and sex-comparable group of healthy children.

MATERIALS AND METHODS

Study design

This was a cross-sectional observational study conducted at the Gastroenterology Research Laboratory, Faculty of Medicine, University of Kelaniya, Sri Lanka.

Selection of study participants

Children aged 5-12 years, presenting to the University Pediatric Unit, North Colombo Teaching Hospital, Sri Lanka, with abdominal pain for at least 1 month, were screened using the Rome IV criteria[37]. Children who met the diagnostic criteria for at least one FAPD underwent a clinical evaluation by a consultant pediatrician to exclude underlying organic pathology. Screening was conducted through a detailed history and physical examination, along with a set of routine investigations, including stool and urine microscopy, urine culture, erythrocyte sedimentation rate, complete blood count, and Helicobacter pylori (H. pylori) stool antigen testing. Additional diagnostic tests were performed selectively based on the consultant’s clinical judgment. These included abdominal ultrasound (in 12 patients), X-ray of the kidneys, ureters, and bladder (in 18 patients), upper gastrointestinal endoscopy (in 9 patients), colonoscopy (in 1 patient), barium contrast study (in 1 patient), and serum amylase level (in 1 patient).

Children who fulfilled the Rome IV criteria for at least one FAPD[37] and had no clinical or laboratory evidence of underlying organic pathology were recruited after obtaining written informed consent from a parent or a legal guardian. They were classified into FAPD types; IBS (n = 10), FD (n = 9), AM (n = 1) and FAP (n = 15) using the same classification. Symptom severity was rated from 0-4 (0 = no symptom; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe).

Twenty healthy children aged 5 to 12 years, residing in the same geographical area, were recruited as controls. These children had no history of gastrointestinal disorders or associated symptoms.

Inclusion criteria: (1) Fulfilling the Rome IV criteria for at least one FAPD; (2) No evidence of organic disorders in history, examination or investigation; (3) A comprehensive clinical evaluation by a consultant pediatrician confirmed the absence of any underlying organic pathology; and (4) A parent/guardian provided written informed consent to participate.

Exclusion criteria: (1) Having a history of chronic gastrointestinal disorder or any other disorder that can alter gastrointestinal motility (e.g. inflammatory bowel disease, celiac disease, gastroparesis, intestinal obstruction, etc.); (2) Having a history of acute gastrointestinal disorder or any other disorder that can alter gastrointestinal motility (e.g. gastroenteritis) during the previous month; (3) Having a history of abdominal surgery involving the gastrointestinal tract other than appendicectomy; (4) Long-term use of motility-altering medicines (e.g. prokinetics, erythromycin, cholinergic, anticholinergics, laxatives and antidiarrheal agents), acid-lowering drugs and antibiotics; (5) Having a history of systemic infection during the previous 1 month; and (6) Use of antibiotics or probiotics in the last 1 month[31].

Lactulose breath hydrogen test

Patients were advised to eat a low-residue diet the day before the test[38]. The LHBT was conducted after an 8-hour fast. A 1% chlorhexidine mouthwash was used to clean the oral cavity before the test to prevent lactulose fermentation by oral microorganisms[39]. Each participant ingested 10 g of lactulose dissolved in a 10% aqueous solution[31]. End-expiratory breath samples were collected at baseline and at 15-minute intervals following lactulose administration. At each time point, three breath samples were obtained and analyzed using a Quintron DP MicroLyzer gas chromatograph (Quintron Instruments, Milwaukee, WI, United States). If the baseline breath hydrogen level was ≥ 10 parts per million (ppm), the test was not performed[40,41]. Children did not participate in exercise or intense physical activity during the test.

Breath hydrogen measurements were acquired for up to 180 minutes in participants who demonstrated a significant increase in hydrogen concentration. For those without a notable increase, sampling was extended to 240 minutes to ensure adequate assessment. OCTT was defined as the time from lactulose ingestion to the first sustained increase in breath hydrogen of ≥ 10 ppm above fasting baseline, confirmed by elevations at two consecutive 15-minute sampling intervals[40-42].

Sample size

The sample size was calculated based on a previous study assessing OCTT in children with constipation[43] using WINPEPI version 11.65, 2016. The following parameters were used in sample size calculation: Power 90%, significance level (alpha) 0.01, mean OCTT 75.7 (SD 8.02) in children with constipation vs 66.4 (SD 8.11) in controls[43], sample ratio 1.5. The required minimum sample size was 42, with 25 with FAPDs and 17 controls. Thirty-five children with FAPDs and 20 healthy controls were recruited.

Statistical analysis

Data were analyzed using IBM SPSS Statistics 21. The statistical significance of differences in OCTT between groups was assessed using a Mann-Whitney U-test. A generalized linear model with a gamma distribution and log link was used to determine the effect of FAPDs on intestinal transit time, adjusting for age, sex, BMI and exposure to stressful events. The Spearman correlation coefficient was calculated to determine the correlation between OCTT and symptoms. A P value < 0.05 was considered statistically significant.

Ethical considerations

Ethical approval for the study was granted by the Ethics Review Committee of the Faculty of Medicine, University of Kelaniya, Sri Lanka.

Written informed consent was obtained from a parent or a guardian of each participant.

All data collected for this study were anonymized to ensure privacy. Data security was maintained throughout the study. Access to participant data was restricted to the first author, and data were stored securely to prevent unauthorized access or disclosure. No personally identifiable information was included in the manuscript.

All testing was performed in a child-friendly setting. To help children remain calm and engaged throughout the 3-hour duration of the LBHT, they were offered storybooks and puzzles and entertained with age-appropriate songs and carefully selected animated films, which were played on a television screen in the laboratory.

RESULTS

Characteristics of the study sample

OCTT could be calculated in 34 patients [15 (44.1%) males, mean age 7.2 years, SD 2.4 years] and 19 controls [9 (47.4%) males, mean age 7.8 years, SD 2.7 years]. One patient (2.8%) and one control (5%) failed to demonstrate a significant increase in breath hydrogen concentration in two consecutive tests and were considered non-responders and excluded from the analysis. One control developed loose stools for a day following lactulose ingestion. There was no significant difference between FAPD patients and controls in terms of father’s social class, monthly family income or maternal educational level.

Comparison of OCTT between FAPDs and controls

OCTT was significantly prolonged in patients with FAPDs (Table 1). In a Generalized Linear Model adjusting for age, sex, BMI, and exposure to stressful events, children with FAPDs had significantly longer OCTT compared to controls [Exp(B) = 1.32, 95%CI: 1.01–1.71, P = 0.039]. Age, BMI, sex, and exposure stress were not significant predictors of prolonged OCTT in FAPDs (P > 0.05 for all).

Table 1 Comparison of orocecal transit times between patients with functional abdominal pain disorders and controls.

Group	Mean (minutes)	Median	IQR	SD	P value1
FAPDs (n = 34)	93.3	90	75-120	30.6	0.0045
Controls (n = 19)	68.4	75	60-75	17.0

¹Mann-Whitney U-test.

FAPD: Functional abdominal pain disorders; IQR: Interquartile range.

Figure 1 shows the number of children with normal and delayed OCTT according to individual FAPD type. The number of children with increased OCTT was higher in FAPD types (IBS, FD, FAP), except for AM, which had a small sample size.

Figure 1 Number of patients with normal and increased orocecal transit time. ^aP < 0.05 vs controls (χ² test). AM: Abdominal migraine; FD: Functional dyspepsia; FAP: Functional abdominal pain; FAPDs: Functional abdominal pain disorders; IBS: Irritable bowel syndrome; OCTT: Orocecal transit time; Normal range of OCTT: 45-90 minutes (10^th to 90^th percentiles in controls).

Correlation between OCTT and symptom severity

There was no significant correlation between OCTT and abdominal pain severity scores (Table 2), which is the primary symptom in this group of children with FAPDs. Similarly, there was no significant correlation between OCTT and severity scores for nausea, bloating, feeling of abdominal fullness and bowel symptoms (P > 0.05).

Table 2 Correlation between orocecal transit time and abdominal pain severity scores in children with functional abdominal pain disorders, mean ± SD.

FAPD type	OCTT (minutes)	Symptom score	Correlation between OCTT and symptom score
			r1 (95%CI)	P value
Functional abdominal pain	93.2 ± 36.8	2.33 ± 1.3	0.47 (-0.01-0.78)	0.12
Irritable bowel syndrome	95.6 ± 22.6	2.88 ± 1.0	0.06 (-0.59-0.66)	0.89
Functional dyspepsia	110.8 ± 26.7	2.17 ± 1.0	0.46 (-0.29-0.86)	0.25
Abdominal migraine	60.0 ± 0.0	4.00 ± 0.0	-	-
FAPDs total	93.3 ± 30.3	2.56 ± 1.1	0.18 (-0.17-0.49)	0.35

¹Spearman correlation coefficient.

FAPDs: Functional abdominal pain disorders; OCTT: Orocecal transit time.

Relationship between OCTT and exposure to stress

The percentage of patients with FAPDs and controls who were exposed to at least one stressful event during the previous 6 months was 55.9% and 31.6%, respectively (P = 0.089). Children with FAPDs exposed to stressful events had a longer OCTT (mean, 97.37 minutes; SD, 29 minutes) compared to those not exposed to such events (mean, 86.36 minutes; SD, 32.8 minutes), but this difference was not statistically significant (P = 0.35, Mann-Whitney U-test).

DISCUSSION

Using the LHBT, we identified a significantly increased OCTT in children with FAPDs compared to the control group, after adjusting for age, sex, BMI and exposure to stress. This suggests the possibility of prolonged small intestinal transit times in affected children. However, we failed to demonstrate a relationship between symptom severity and OCTT, questioning the clinical significance of this finding.

Previous studies have reported small intestinal motor abnormalities in children with FD. In a study by Chitkara et al[44], small bowel transit was slow in 40% of affected children, which is consistent with our finding of increased OCTT in 50% of patients with FAPDs, specifically IBS, FD and FAP. Some adult studies have also reported longer OCTT in FD[45,46], while other studies failed to show such a difference[45,46]. Similarly, contrasting results have been reported in IBS. Some adult studies failed to report a significant difference in OCTT between patients with IBS and controls[47]. In contrast, other studies reported shorter small bowel transit times in patients with diarrhea-predominant IBS and prolonged transit in constipation-predominant IBS[48-51]. In addition, rapid small intestinal transit has been associated with bloating in IBS[52]. Multiple confounding factors, including genetic, environmental, dietary, and methodological differences, may account for the variability in reported results and could also explain discrepancies between our findings and those of some earlier studies.

There was no significant correlation between OCTT and the severity of abdominal pain and other symptoms in all FAPD types in this study, consistent with a previous study in children with IBS[53] and adult studies in FD[45,51] and IBS[54]. In contrast, other studies identified a significant association between symptoms such as abdominal bloating and slow small intestinal transit in patients with FD[55] and IBS[51].

Breath hydrogen analysis is a widely used, straightforward technique for evaluating small intestinal transit[40]. Studies comparing this method with scintigraphy have shown that the increase in breath hydrogen levels corresponds to the arrival of non-absorbable carbohydrates in the cecum[32,56]. As gastric emptying begins shortly after ingestion, the interval between lactulose consumption and the first notable rise in breath hydrogen level provides an approximate estimate of small bowel transit time[57]. Compared to other available tests for measuring small intestinal motility, this is the safest and least invasive test for pediatric patients. Side effects reported in this test are abdominal pain, bloating, borborygmi, and nausea. Some studies have reported a significantly higher frequency of these side effects in patients with FD compared to healthy controls[58]. However, apart from the development of loose stools in one control, participants in our study did not suffer any side effects.

The exact cause for increased OCTT in our patients with FAPDs is not clear. Emotional stress has been suggested as a possible cause for abnormal gastrointestinal motility in DGBIs[59]. In a previous study in children with IBS, we found significantly reduced gastric emptying and antral motility in those exposed to stressful events[20]. However, in this study, there was no association between OCTT and exposure to stressful life events. Consistent with our results, Thorén et al[60] failed to detect a significant alteration in OCTT following the induction of cold pain stress. Gilja et al[61] found an association between H. pylori infection and gastrointestinal motility abnormalities in patients with FD. At the same time, other studies have failed to demonstrate such an association[62,63]. None of the children with FAPDs in our study tested positive for H. pylori by stool antigen test. Additionally, the autonomic nervous system is one of the primary regulators of gastrointestinal motility. A previous study proposed maladaptive parasympathetic flow and functional external denervation as possible pathophysiological mechanisms of gastric dysmotility in children with FAPDs[15]. Autonomic dysfunction is commonly demonstrated in small intestinal motility disorders, such as chronic intestinal pseudo-obstruction[64]. However, the association between autonomic dysfunction and slow small intestinal transit has not been studied in patients with FAPDs. Furthermore, diet significantly influences gastrointestinal motility. Some studies in adults and children have shown that fiber supplements increase small intestinal transit time[65,66] by enhancing inhibitory signals originating from the distal gut[65]. In contrast, other studies have shown a fiber-induced accelerated small intestinal transit[67]. Therefore, the exact role of diet in increasing OCTT in our cohort of children with FAPDs is unclear.

The therapeutic potential of drugs that normalize small intestinal transit remains poorly studied and inadequately documented in children. In addition to reducing visceral hypersensitivity, 5-HT4 receptor antagonists, such as Tegaserod, enhance small intestinal transit in adults with IBS, particularly in those with the diarrhea-predominant subtype[68-70]. They have favorable safety and tolerability profiles[71] and are therefore recommended in the management of IBS[72]. In contrast, psychological interventions used in IBS, such as gut-directed hypnotherapy, failed to demonstrate significant improvement in small intestinal transit or antroduodenal motility[73]. Although dietary fiber can alter small intestinal transit, its therapeutic value is unclear in children with DGBIs and therefore not recommended in their management[74]. Future studies should be directed at confirming the exact role of small intestinal motility abnormalities in the pathogenesis of childhood FAPDs and evaluating the clinical value of therapies that normalize small intestinal transit.

The current study has several limitations. First, the number of children within each FAPD subtype was small, limiting our ability to assess differences in OCTT between specific FAPD categories (e.g. AM) and the exact relationship between OCTT and symptoms. Secondly, the assessment of OCTT using the lactulose breath hydrogen test relies on the presence of hydrogen-producing colonic microorganisms. Individuals who lack these microorganisms do not exhibit a rise in breath hydrogen levels, rendering the measurement of OCTT impossible[75]. In agreement, a significant rise in breath hydrogen levels was not observed in two individuals in this study, and OCTT measurements were not obtained. Thirdly, SIBO, which is common in FAPDs, has been reported to be associated with prolonged small intestinal transit time[76]. However, using simultaneously performed scintigraphy, Yu et al[36] have shown that the rise in breath hydrogen in patients with IBS results from lactulose reaching the cecum but not due to SIBO. In addition, a recent critical appraisal of the European and American Neurogastroenterology and Motility Societies reported that LHBT is primarily a measure of intestinal transit, with low sensitivity and specificity for diagnosing SIBO[77]. Therefore, the increased OCTT observed in our children with FAPDs is more likely to represent slow small intestinal transit rather than SIBO.

CONCLUSION

This study showed that children with FAPDs have a prolonged OCTT, indicating the presence of delayed small intestinal transit. The lactulose breath test remains a simple, non-invasive, and safe method for assessing OCTT. However, the absence of a clear relationship between prolonged OCTT and symptoms raises questions about the clinical significance of delayed small intestinal transit in the pathophysiology of FAPDs. While OCTT measurement may be useful in identifying small intestinal dysmotility in DGBIs, its utility in guiding targeted therapeutic interventions remains uncertain and warrants further investigation.

ACKNOWLEDGEMENTS

We acknowledge Mrs. J Liyanage, Former Technical Officer, Department of Physiology, Faculty of Medicine, University of Kelaniya, for her technical assistance.