Early-Life Events and the Prevalence of Gut–Brain Interaction Disorders in Children
by
, , , ,
Atchariya Chanpong
1
,
Natchayada Ponjorn
2,
Nattaporn Tassanakijpanich
3,
Vanlaya Koosakulchai
3,
Pornruedee Rachatawiriyakul
3,
Sirinthip Kittivisuit
3,
Puttichart Khantee
3 and
Kamolwish Laoprasopwattana
3,* 1
Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
2
Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
3
Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
*
Author to whom correspondence should be addressed.
Children 2025, 12(11), 1430; https://doi.org/10.3390/children12111430
Submission received: 16 September 2025
/
Revised: 14 October 2025
/
Accepted: 20 October 2025
/
Published: 23 October 2025
(This article belongs to the Special Issue Gut-Brain Interaction Disorders in Children: Emerging Insights in the 21st Century)
Highlights
What are the main findings?
- •
- Environmental factors in the first 3 years of life could influence postnatal development and lifelong health and well-being.
- •
- Breastfeeding, particularly for ≥3 months, is the most important protective factor against DGBI, whereas antibiotic/antiviral exposure, particularly in the first year of life, may increase the risk of DGBI development.
What is the implication of the main finding?
- •
- Exclusive breastfeeding should be continuously promoted to prevent the occurrence of DGBI.
- •
- The rational use of antibiotics/antivirals should be advocated to decrease the risk of developing DGBI.
Abstract
Background/Objectives: Disorders of gut–brain interaction (DGBI) include a spectrum of disorders with chronic/recurrent gastrointestinal symptoms, caused by dysregulation of microbiota–gut–brain interaction. Early-life events have been suggested as the main factors influencing the microbiota–gut–brain axis. We aimed to evaluate the prevalence of DGBI in 3-year-old children and its relationship with early-life events. Methods: The parents of children aged 3 years, who had been followed up in a well-baby clinic since they were 2 months old, were asked about any GI symptoms their child had experienced during the check-up visits between September 2023 and June 2024. The final diagnosis of DGBI was based on ROME IV criteria. Demographic data, including early-life factors, were collected. Results: Overall, 568 children (48.6% boys) were included, of whom 139 (24.5%) had symptoms consistent with at least one DGBI diagnosis. The most prevalent DGBI was functional constipation (20.4%), followed by colic (4.6%), infant regurgitation (2.8%), and dyschezia (1.6%). Approximately 48% of the children were breastfed for ≥6 months, and 21% were exposed to ≥1 antibiotic/antiviral drugs in the first year of life. DGBI prevalence was significantly higher in girls than in boys (28.1% vs. 20.7%; p = 0.041). Exclusive breastfeeding was the most significant protective factor against DGBI, particularly if performed for ≥3 months. Conclusions: Sex was the most significant factor affecting DGBI prevalence in children aged ≤3 years; breastfeeding offers the most effective protection against DGBI development.
1. Introduction
Early life, or the first 3 years of age, is a period of rapid parallel growth of the gut, brain, and microbiome [1,2]. The developmental interdependence and bidirectional communication between the microbiome, gastrointestinal (GI) tract, and brain forms part of the microbiota–gut–brain axis [1]. Several studies have shown the importance of environmental factors, especially in the early years of life, that influence postnatal development and lifelong health and well-being [2,3,4,5,6,7,8]. Examples of these factors include antibiotic exposure, the delivery method, and breastfeeding [4,5,6,7,8].
During early life, a combination of genetic and medical or psychosocial factors may disturb the structure or function of the microbiota–gut–brain axis [9]. This could lead to disorders of gut–brain interaction (DGBI), previously known as functional gastrointestinal disorders. Medical events potentially leading to DGBI development include dysbiosis from early use of antibiotics or cesarean section and inflammation due to allergy or infection [5,7,10,11,12,13]. Examples of psychosocial factors that could modulate the gut microbiota and brain development include early-life pain, trauma, and stress [14,15,16]. However, most of the supporting evidence on this etiopathogenesis model is based on in vitro and animal studies.
To date, studies on the relationship between early-life events and the prevalence of DGBI are limited, and current findings are conflicting. Hence, we aimed to evaluate the prevalence of DGBI in children aged ≤3 years and identify whether early-life factors, such as the birth method, breastfeeding, antibiotic exposure, and allergic diseases, affect the prevalence of DGBI.
2. Materials and Methods
A retrospective–prospective cohort study was performed at Songklanagarind Hospital, Prince of Songkla University in Thailand. All healthy children aged 3 years, who had been followed up with in a well-baby clinic for vaccination since they were 2 months old (as part of a vaccine trial [V114-032; REC 63-380-1-1]), were included in this study. Those who were found to have underlying chronic diseases or malnutrition were excluded.
The sample size was calculated using OpenEpi, Version 3 [17]. Data from Chia et al. [18] were used, who reported a 9.3% prevalence of infant colic with an associated odds ratio (OR) of 0.12 for breastfeeding and a 5.6% prevalence of functional constipation with an OR of 0.06 for breastfeeding. Assuming a confidence level of 95% and power of 80%, a sample size of 240 and 330 children was required to detect the prevalence of colic and functional constipation, respectively. Hence, a total sample size of 570 children was recommended.
For the V114-032 study (REC 63-380-1-1), healthy infants were recruited at 2 months of age between October 2020 and August 2023. According to the immunization program, each child was scheduled for vaccine clinic visits every 2 months until 6 months of age, every 3 months until 1 year of age, every 6 months until 2 years of age, and every year thereafter (Figure 1). During the follow-ups, the doctors evaluated the child’s growth and development together with their feeding history. As part of the V114-032 study, pediatric investigators collected data on birth history, infection history during pregnancy, exclusive breastfeeding duration, parental education, family history of atopic diseases, and environment (e.g., secondhand smoking). To determine the age at first antibiotic/antiviral exposure, information was collected between 2 months and 3 years of age. The child’s parents were required to report any illnesses, particularly those requiring hospitalization, and medication use (including dosage and duration). For each report, the child was examined, and their guardians were interviewed before documenting the illness episode and medication use in the system. During the visit at 3 years of age, from September 2023 to June 2024, parents were interviewed by pediatric investigators about any GI symptoms their child had experienced at any time. The final diagnosis of DGBI was made by a pediatric gastroenterologist (Figure 1) based on ROME IV criteria [19]. The investigators evaluated the presence of each condition by asking a set of questions or administering a questionnaire adapted from ROME IV diagnostic criteria. During the first 3 years, the DGBI diagnosis could be infant colic, dyschezia, infantile regurgitation, cyclic vomiting syndrome, functional constipation, or functional diarrhea [19].
The diagnostic criteria for infant colic included all of the following: (1) an infant <5 months of age when the symptoms start and stop; (2) recurrent, prolonged periods (≥3 h/day on ≥3 days in 7) of crying, fussing, or irritability that occur without obvious cause and cannot be prevented or resolved by caregivers; and (3) no evidence of failure to thrive, fever, or illness [19]. Dyschezia is diagnosed in an infant <9 months of age with ≥10 min of straining and crying before the successful or unsuccessful passage of soft stools without other health problems [19]. Infantile regurgitation is diagnosed in healthy infants 3 weeks to 12 months of age who have regurgitation ≥2 times/day for ≥3 weeks without retching, hematemesis, aspiration, apnea, failure to thrive, feeding or swallowing difficulties, or abnormal posturing [19]. The diagnosis of cyclic vomiting syndrome includes all of the following: (1) ≥2 periods of unremitting paroxysmal vomiting, with or without retching, lasting hours to days within a 6-month period; (2) episodes that are stereotypical in each patient; and (3) episodes separated by weeks to months with return to baseline health between episodes of vomiting [19].
For functional constipation, the child was assessed for successful toilet training. The diagnosis required ≥1 month with ≥2 of the following: (1) ≤2 defecations per week; (2) history of excessive stool retention; (3) history of painful or hard bowel movements; (4) history of large-diameter stools; and (5) presence of a large fecal mass in the rectum. In toilet-trained children, additional criteria included ≥1 episode/week of incontinence and a history of large-diameter stools that may obstruct the toilet [19]. The diagnosis of infant diarrhea required all of the following: (1) daily, painless, recurrent passage of ≥4 large unformed stools; (2) symptoms lasting ≥4 weeks; (3) onset between 6 and 60 months of age; and (4) no failure to thrive if caloric intake is adequate [19].
The duration of exclusive breastfeeding was defined as the period during which the child received only breast milk, either directly or expressed and given via a bottle, with no exposure to formula milk. Exposure to antibiotics and/or antivirals was defined as any use of these medications for a suspected infection.
Data analysis was performed using the R program version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). Baseline characteristics are described as median (interquartile range; IQR) or number (percentage). Continuous and categorical data were compared using Fisher’s exact, Mann–Whitney U, or Kruskal–Wallis test, as appropriate. To explore the relationship between potential risk or protective factors and the presence of DGBI, univariate and multivariate logistic regression analyses were performed. Multivariable analyses were performed on the potential factors with a p-value <0.2 in univariable logistic regression. The results of logistic regression are presented as ORs with corresponding 95% confidence intervals (CIs). Variance inflation factors were assessed to evaluate multicollinearity in the multivariable models. A p-value <0.05 indicated statistical significance. Participants with missing data for key variables were excluded from the respective analyses. The proportion of missing data was assessed, and sensitivity analyses were conducted to ensure the robustness of the findings.
The study was approved by the Ethics Committee of the Faculty of Medicine, Prince of Songkla University (REC 66-317-1-1).
3. Results
During the 3-year vaccination follow-up period, 686 children were followed up with until 3 years of age; of these, 568 (80.9%) participated in the DGBI study after their parents provided informed consent. Among the 568 participants (48.6% boys), 139 (24.5%) children experienced symptoms of at least one DGBI.
3.1. Early-Life Factors
Of the 568 children, 40.1% (n = 228) were born by cesarean section, and 48.1% and 22.4% were exclusively breastfed for ≥6 months and 1 year, respectively. Of the participating children, 62.3% were exposed to secondhand smoke from family members, and 2.5% had a maternal history of infection requiring antibiotics during pregnancy. Additionally, 482 (84.9%) children received bottle-feeding, with a median initiation age of 1 month (IQR 0–3 months); among these children, 47.9% used the bottles exclusively for expressed breastmilk. Notably, the bottle-feeding group included both infants who received formula and those who were administered expressed breast milk in a bottle.
During the first year of life, 21.1% of children were exposed to at least one course of antibiotics, antiviral drugs, or antifungal drugs. Specifically, 15.8% of children received antibiotics, while 5.5% were first treated with an antiviral drug for influenza or COVID-19. Among the 568 children, 4 had antifungal drugs as their first exposure, and 6 received both antivirals and antibiotics within the first year. By age three, the proportion of children exposed to at least one course of antibiotics, antivirals, or antifungals increased to 78.2%. At 3 years of age, most children consumed three meals per day in addition to 3.5 (range 0–20) ounces of milk on average.
3.2. Prevalence of DGBI in Children Aged 3 Years
Regarding the prevalence of DGBI, 24.5% of 3-year-old children had symptoms consistent with at least one DGBI diagnosis. The prevalence of DGBI was significantly higher in girls than in boys (28.1 vs. 20.7%; p = 0.041). Among the children studied, one (0.2%) had cyclic vomiting syndrome (CVS), nine (1.6%) had dyschezia, 16 (2.8%) had infantile regurgitation, 26 (4.6%) had infant colic, and 116 (20.4%) had functional constipation. Most children had only one DGBI diagnosis (20.4%), while 3.3, 0.5, and 0.2% had two, three, and five diagnoses, respectively. Of 139 children with at least one DGBI, nine had constipation and history of infant colic, three had constipation and history of infantile regurgitation, two each had constipation with history of dyschezia, infant colic with dyschezia, and dyschezia with infantile regurgitation, one had infant colic with regurgitation, two had constipation with infant colic and regurgitation, one had constipation with infant colic and dyschezia, and one had constipation, infant colic, regurgitation, dyschezia and CVS.
3.3. Association Between Early-Life Factors and DGBI Within 3 Years of Age
Exclusive breastfeeding was stopped earlier in children with DGBI than in those without. Particularly in girls, exclusive breastfeeding ceased at a median age of 3 (IQR 2–9) months in those with DGBI compared to at 6 (IQR 3–12) months in those without DGBI (p = 0.002; Figure 2). Children with DGBI were exposed to antibiotics at a later age, whereas they received antivirals earlier than children without DGBI (Table 1). No significant differences in sex, weight, height, mode of delivery, history of food allergy, family history of allergic diseases, or socioeconomic status were identified between children with and without a DGBI diagnosis (Table 1).
After adjusting for potential confounding factors, including exclusive breastfeeding, sex, maternal allergy history, and exposure to secondhand smoking, exposures to antibiotics and antivirals within the first year of life, exclusive breastfeeding was the most significant protective factor against DGBI, particularly if performed for ≥3 months (Table 2, Figure 3A). Exclusive breastfeeding for ≥3 months could reduce the risk of DGBI by 34%, and the protective effect increased to 53% if breastfed for ≥1 year. Moreover, male sex was identified as a protective factor against DGBI (Table 2). Notably, multivariate analysis did not reveal exposure to antibiotics or antivirals as a significant protective or risk factor for DGBI.
3.4. Functional Constipation in 3-Year-Old Children
Among the participating children, 116 experienced symptoms consistent with functional constipation, based on ROME IV criteria, within 3 years of age. Among these children, exclusive breastfeeding was stopped at a median age of 4 (IQR 2–8) months in those with DGBI, which was earlier than in those without DGBI [median age of 6 (IQR 3–12) months; p = 0.001]. Additionally, children with DGBI were less likely to be toilet-trained than those without DGBI (80.2% vs. 87.4%; p = 0.065) (Table 3). However, the success rate of toilet training was not significantly different between the two groups.
Multivariate analysis adjusted for potential factors, including exclusive breastfeeding ≥6 months, sex, exposure to secondhand smoke, toilet training, and exposures to antibiotics and antivirals within the first year of life, was performed. We found that exclusive breastfeeding for ≥6 months was a significant protective factor against functional constipation (OR = 0.65, 95% CI = 0.423–0.99, p = 0.047). Additionally, lack of toilet training appeared to increase the risk of developing constipation (OR = 1.65, 95% CI = 0.95–2.82, p = 0.070) (Table 4).
Sensitivity analyses were performed by excluding retrospective symptom reports and stratifying the data by sex (Supplementary Tables S1–S3). Among the 69 children diagnosed with functional constipation at 3 years of age, a multivariate analysis was performed by adjusting for exclusive breastfeeding, maternal income, influenza infection, toilet training, and exposure to antibiotics and antivirals during the first year of life. Exclusive breastfeeding for ≥3 months emerged as a significant protective factor against functional constipation (OR = 0.54, 95% CI: 0.32–0.90, p = 0.019). Additionally, the absence of toilet training was associated with an increased risk of developing constipation (OR = 1.92, 95% CI: 0.98–3.58, p = 0.047) (Figure 3C, Supplementary Table S2). Univariate and multivariate analyses examining the associations between potential factors and each pathological condition included in the DGBI criteria are presented in Supplementary Tables S4–S9 and Supplementary Figure S1.
4. Discussion
The concept of early-life programming has been widely accepted as the etiopathogenesis of several diseases, particularly those involved in the gut–brain interaction [2,3,4,5,6,7,8]. The first 3 years of life are critical for postnatal gut and brain development as well as microbial colonization. Within this period, multiple factors or events, such as cesarean section, early-life pain or trauma, early antibiotics use, food allergy, and family stress, can disrupt the bidirectional gut–brain communication and microbiome interaction, leading to DGBI [5,7,10,11,12,13,14,15,16].
In this study, the overall prevalence of DGBI in children aged 3 years was 24.5%, with functional constipation being the most prevalent diagnosis (20.4%). The second-most frequent diagnosis was colic (4.6%) in children <1 year of age, which was retrospectively reported. The overall prevalence of DGBI in our study was similar to that reported in an Italian cohort (19.6–21.1%) [20]. Scarpato et al. also found that the most prevalent DGBI was functional constipation (16.1%) in toddlers (13–48 months) and infant colic (9.3%) among infants (0–12 months) [20]. Compared to Scarpato et al.’s study, our study reported a lower prevalence of infant colic. Given that we interviewed the parents when the child was 3 years old, our findings may have been influenced by recall bias. The prevalence of DGBI in our current study was higher than that reported in a Vietnamese study, which showed that the total prevalence of having at least one DGBI in children aged 0–48 months was 10.0% [18]. This discrepancy may be explained by the different study methods employed (interview vs. questionnaire).
We also demonstrated that exclusive breastfeeding (≥3 months) was the most significant protective factor against DGBI. Notably, there was a sex difference in the prevalence of DGBI in children ≤3 years of age, with a greater prevalence among girls than among boys. Specifically, children with DGBI were exposed to antiviral drugs at an earlier age during their first year of life compared to children without DGBI (8.0 ± 2.4 vs. 10.2 ± 2.0 months; p = 0.008). Breast milk contains human breastmilk microbiota and human milk oligosaccharides (HMOs) that promote the production of specific microorganisms; these microorganisms produce metabolites that can modulate gut–brain physiology [2,8,21,22]. A recent in vitro study by Natividad et al. [21] investigated the effect of different HMO on the gut microbiota composition. They collected stool samples from five healthy infants (2–4 months old) and cultivated them together with different groups of HMOs. The HMOs promoted the growth of Bifidobacterium and other HMO-consuming bacteria (e.g., Bacteroides spp.) and maintained intestinal barrier integrity [21]. Ferrier et al. [22] showed that visceral hypersensitivity-induced mice fed on HMOs had a reduced visceromotor response, as evaluated using colorectal distension, compared with those in the sham group. In line with the findings of Chia et al. [18], we demonstrated that exclusive breastfeeding was the most significant protective factor against DGBI occurrence in children ≤3 years of age. Chia et al. [18] reported that exclusive breastfeeding at 2–3 months and 3–4 months offered protection against infantile regurgitation. However, we found that a longer duration of exclusive breastfeeding was associated with a greater protective effect on DGBI and constipation occurrence (Figure 3). Furthermore, Scarpato et al. revealed that formula feeding was a risk factor for DGBI [20].
Sex differences in DGBI prevalence have been documented in several previous studies [23,24,25]; a majority of these studies examined children aged 4–18 years. We found that among children ≤3 years, male sex was a protective factor against DGBI. According to studies involving animal models, the use of antibiotics in early life could influence the maturation and function of intestinal epithelial cells [26] and disrupt intestinal motility [5]. Additionally, persistent effects on gene expression of intestinal tissue and on gut microbiota diversity were evident [27]. Similar findings were reported in infants receiving antibiotic treatment for suspected early-onset neonatal sepsis; their Bifidobacterium spp. abundance was lower than that in healthy controls [28]. Another study by Yassour et al. [4] assessing the gut microbiota progression in children aged 2–36 months showed that gut microbiomes were less stable in those receiving antibiotic treatment than in those not receiving the treatment [4]. In addition, a recent systematic review that evaluated 11 cohort and 11 case–control studies indicated that early antibiotic use could increase the risk of developing GI disorders, including DGBI, in later life [10]. One of the included studies revealed the relationship between neonatal antibiotic use (in the first month of life) and the occurrence of DGBI within the first year of life [29]. However, it remains unclear why, in this study, children with DGBI were exposed to antivirals earlier but received antibiotics at later age compared to those without DGBI. Since bacteria, viruses, and fungi are constituents of the gut microbiota [30,31], viral infections (e.g., influenza, COVID-19) or exposure to antiviral medications may disrupt the gut microbiota [32,33]. Another possibility is that some children were exposed to both antibiotics and antivirals early in life, potentially compounding the impact on gut microbiota development.
Our study failed to identify a significant difference in the prevalence of DGBI between infants born vaginally and those born by cesarean section, despite multiple studies demonstrating the alteration of gut microbiota diversity and Bacteroides colonization in infants born by cesarean section [4,6,7], as well as the association with DGBI [29]. Furthermore, early-life stress triggers reactions through the hypothalamic–pituitary–adrenal axis, resulting in intestinal microbiota dysbiosis and abnormal behavioral patterns [15,16]. Limited human studies have examined the connection between DGBI and early-life stress. Another limitation of our study was its inability to determine the effect of family socioeconomic status and history of allergic diseases on the presence of DGBI in children aged 0–3 years. Although the study cohort comprised healthy children enrolled in a vaccine clinical trial, the parents were from diverse socioeconomic backgrounds. However, selection bias was minimized, as all parents received incentives to participate in the clinic visits.
The strength of our study is that we recruited several healthy children and prospectively collected data on their early-life factors from the age of 2 months by interviewing their parents during follow-up visits. Although all illnesses and medication use were reported up to 3 years of age, attention to the existence of GI symptoms was limited unless they were severe. Therefore, the occurrence of DGBI before age 3 may be subject to recall bias, potentially affecting prevalence estimates for each DGBI condition. The involvement of experienced and trained pediatricians in conducting interviews has reduced these risks in our study.
Additional research is necessary to determine the role of gut microbiota and dietary factors in DGBI. A follow-up study should be conducted to prospectively collect data on DGBI symptoms and analyze gut microbiota in this group of participants. Future longitudinal studies assessing the role of early-life factors on the incidence of DGBI during adolescence and adulthood are required.
5. Conclusions
We identified a sex difference in the prevalence of DGBI in children ≤ 3 years of age. Breastfeeding is a strong protective factor against DGBI, whereas antibiotic/antiviral exposure may have a negative impact on the prevalence of DGBI, particularly during the first year of life. Allergic diseases, mode of delivery, and socioeconomic status were not associated with the prevalence of DGBI. Hence, exclusive breastfeeding should be continuously promoted, and rational antibiotic/antiviral use should be advocated to prevent the development of DGBI.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/children12111430/s1.
Author Contributions
The data analysis was performed with contributions from A.C., N.T. and A.C. prepared the initialdraft of the manuscript, while A.C., K.L., N.P., N.T., V.K., P.R., S.K. and P.K. provided a critical review. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Faculty of Medicine, Prince of Songkla University (REC.66-317-1-1, date of approval 29/09/2023, and REC. 63-380-1-1, date of approval 23/08/2020).
Informed Consent Statement
Informed consent was obtained from the parents of all participants involved in the study.
Data Availability Statement
Data supporting the findings of this study are provided in the Supplementary File and are available from the corresponding author upon reasonable request.
Acknowledgments
We received permission from Merck Sharp & Dohme LLC to collect data from the participants of the V114-032/PNEU-ERA research study at Site 0005 (NCT04193215). Also, we would like to acknowledge Kemmapon Chumchuen and Sarawut Sukkhum for their assistance with data analysis. Additionally, we extend our thanks to Rusvira Seng and Chachaya Suwanmala for their contributions to data management.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript:
| CI | Confidence interval |
| DGBI | Disorders of gut–brain interaction |
| GI | Gastrointestinal |
| HMO | Human milk oligosaccharides |
| IQR | Interquartile range |
| OR | Odds ratio |
References
- Jena, A.; Montoya, C.A.; Mullaney, J.A.; Dilger, R.N.; Young, W.; McNabb, W.C.; Roy, N.C. Gut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective. Front. Integr. Neurosci. 2020, 14, 44. [Google Scholar] [CrossRef]
- Ratsika, A.; Codagnone, M.C.; O’Mahony, S.; Stanton, C.; Cryan, J.F. Priming for Life: Early Life Nutrition and the Microbiota-Gut-Brain Axis. Nutrients 2021, 13, 423. [Google Scholar] [CrossRef] [PubMed]
- Chanpong, A.; Borrelli, O.; Thapar, N. Recent Advances in Understanding the Roles of the Enteric Nervous System. Fac. Rev. 2022, 11, 7. [Google Scholar] [CrossRef]
- Yassour, M.; Vatanen, T.; Siljander, H.; Hämäläinen, A.-M.; Härkönen, T.; Ryhänen, S.J.; Franzosa, E.A.; Vlamakis, H.; Huttenhower, C.; Gevers, D.; et al. Natural History of the Infant Gut Microbiome and Impact of Antibiotic Treatment on Bacterial Strain Diversity and Stability. Sci. Transl. Med. 2016, 8, 343ra81. [Google Scholar] [CrossRef] [PubMed]
- Hung, L.Y.; Boonma, P.; Unterweger, P.; Parathan, P.; Haag, A.; Luna, R.A.; Bornstein, J.C.; Savidge, T.C.; Foong, J.P.P. Neonatal Antibiotics Disrupt Motility and Enteric Neural Circuits in Mouse Colon. Cell Mol. Gastroenterol. Hepatol. 2019, 8, 298. [Google Scholar] [CrossRef]
- Jakobsson, H.E.; Abrahamsson, T.R.; Jenmalm, M.C.; Harris, K.; Quince, C.; Jernberg, C.; Björkstén, B.; Engstrand, L.; Andersson, A.F. Decreased Gut Microbiota Diversity, Delayed Bacteroidetes Colonisation and Reduced Th1 Responses in Infants Delivered by Caesarean Section. Gut 2014, 63, 559. [Google Scholar] [CrossRef]
- Fouhy, F.; Watkins, C.; Hill, C.J.; O’Shea, C.-A.; Nagle, B.; Dempsey, E.M.; O’Toole, P.W.; Ross, R.P.; Ryan, C.A.; Stanton, C. Perinatal Factors Affect the Gut Microbiota up to Four Years after Birth. Nat. Commun. 2019, 10, 1517. [Google Scholar] [CrossRef] [PubMed]
- Fichter, M.; Klotz, M.; Hirschberg, D.L.; Waldura, B.; Schofer, O.; Ehnert, S.; Schwarz, L.K.; Ginneken, C.V.; Schäfer, K.-H. Breast Milk Contains Relevant Neurotrophic Factors and Cytokines for Enteric Nervous System Development. Mol. Nutr. Food Res. 2011, 55, 1592. [Google Scholar] [CrossRef] [PubMed]
- Thapar, N.; Benninga, M.A.; Crowell, M.D.; Di Lorenzo, C.; Mack, I.; Nurko, S.; Saps, M.; Shulman, R.J.; Szajewska, H.; van Tilburg, M.A.L.; et al. Paediatric Functional Abdominal Pain Disorders. Nat. Rev. Dis. Primers 2020, 6, 89. [Google Scholar] [CrossRef] [PubMed]
- Kamphorst, K.; Van Daele, E.; Vlieger, A.M.; Daams, J.G.; Knol, J.; van Elburg, R.M. Early Life Antibiotics and Childhood Gastrointestinal Disorders: A Systematic Review. BMJ Paediatr. Open 2021, 5, e001028. [Google Scholar] [CrossRef] [PubMed]
- Collins, J.; Borojevic, R.; Verdu, E.F.; Huizinga, J.D.; Ratcliffe, E.M. Intestinal Microbiota Influence the Early Postnatal Development of the Enteric Nervous System. Neurogastroenterol. Motil. 2014, 26, 98. [Google Scholar] [CrossRef]
- Nurgali, K.; Qu, Z.; Hunne, B.; Thacker, M.; Pontell, L.; Furness, J.B. Morphological and Functional Changes in Guinea-Pig Neurons Projecting to the Ileal Mucosa at Early Stages after Inflammatory Damage. J. Physiol. 2011, 589, 325. [Google Scholar] [CrossRef]
- Pensabene, L.; Salvatore, S.; D’Auria, E.; Parisi, F.; Concolino, D.; Borrelli, O.; Thapar, N.; Staiano, A.; Vandenplas, Y.; Saps, M. Cow’s Milk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children? Nutrients 2018, 10, 1716. [Google Scholar] [CrossRef]
- Sudo, N.; Chida, Y.; Aiba, Y.; Sonoda, J.; Oyama, N.; Yu, X.-N.; Kubo, C.; Koga, Y. Postnatal Microbial Colonization Programs the Hypothalamic-Pituitary-Adrenal System for Stress Response in Mice. J. Physiol. 2004, 558, 263. [Google Scholar] [CrossRef]
- Usui, N.; Matsuzaki, H.; Shimada, S. Characterization of Early Life Stress-Affected Gut Microbiota. Brain Sci. 2021, 11, 913. [Google Scholar] [CrossRef]
- Zhu, J.; Zhong, Z.; Shi, L.; Huang, L.; Lin, C.; He, Y.; Xia, X.; Zhang, T.; Ding, W.; Yang, Y. Gut Microbiota Mediate Early Life Stress-Induced Social Dysfunction and Anxiety-Like Behaviors by Impairing Amino Acid Transport at the Gut. Gut Microbes 2024, 16, 2401939. [Google Scholar] [CrossRef] [PubMed]
- Kelsey, J.L.; Whittemore, A.S.; Evans, A.S.; Thompson, W.D. Methods in Observational Epidemiology, Tables 12–15 Fleiss, Statistical Methods for Rates and Proportions, Formulas 3.18 & 3.19, 2nd ed.; Oxford University Press Inc.: Oxford, UK, 1996. [Google Scholar]
- Chia, L.W.; Nguyen, T.V.H.; Phan, V.N.; Luu, T.T.N.; Nguyen, G.K.; Tan, S.Y.; Rajindrajith, S.; Benninga, M.A. Prevalence and Risk Factors of Functional Gastrointestinal Disorders in Vietnamese Infants and Young Children. BMC Pediatr. 2022, 22, 315. [Google Scholar] [CrossRef] [PubMed]
- Benninga, M.A.; Faure, C.; Hyman, P.E.; St James Roberts, I.; Schechter, N.L.; Nurko, S. Childhood Functional Gastrointestinal Disorders: Neonate/Toddler. Gastroenterology 2016, 150, 1443–1455.e2. [Google Scholar] [CrossRef] [PubMed]
- Scarpato, E.; Salvatore, S.; Romano, C.; Bruzzese, D.; Ferrara, D.; Inferrera, R.; Zeevenhooven, J.; Steutel, N.F.; Benninga, M.A.; Staiano, A. Prevalence and Risk Factors of Functional Gastrointestinal Disorders: A Cross-Sectional Study in Italian Infants and Young Children. J. Pediatr. Gastroenterol. Nutr. 2023, 76, e27. [Google Scholar] [CrossRef]
- Natividad, J.M.; Marsaux, B.; Rodenas, C.L.G.; Rytz, A.; Vandevijver, G.; Marzorati, M.; Van den Abbeele, P.; Calatayud, M.; Rochat, F. Human Milk Oligosaccharides and Lactose Differentially Affect Infant Gut Microbiota and Intestinal Barrier In Vitro. Nutrients 2022, 14, 2546. [Google Scholar] [CrossRef]
- Ferrier, L.; Eutamène, H.; Siegwald, L.; Marquard, A.M.; Tondereau, V.; Chevalier, J.; Jacot, G.E.; Favre, L.; Theodorou, V.; Vicario, M.; et al. Human Milk Oligosaccharides Alleviate Stress-Induced Visceral Hypersensitivity and Associated Microbiota Dysbiosis. J. Nutr. Biochem. 2022, 99, 108865. [Google Scholar] [CrossRef] [PubMed]
- Lewis, M.L.; Palsson, O.S.; Whitehead, W.E.; van Tilburg, M.A.L. Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents. J. Pediatr. 2016, 177, 39. [Google Scholar] [CrossRef] [PubMed]
- Scarpato, E.; Kolacek, S.; Jojkic-Pavkov, D.; Konjik, V.; Živković, N.; Roman, E.; Kostovski, A.; Zdraveska, N.; Altamimi, E.; Papadopoulou, A.; et al. Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents in the Mediterranean Region of Europe. Clin. Gastroenterol. Hepatol. 2018, 16, 870. [Google Scholar] [CrossRef] [PubMed]
- Cenni, S.; Pensabene, L.; Dolce, P.; Campanozzi, A.; Salvatore, S.; Pujia, R.; Serra, M.R.; Scarpato, E.; Miele, E.; Staiano, A.; et al. Prevalence of Functional Gastrointestinal Disorders in Italian Children Living in Different Regions: Analysis of the Difference and the Role of Diet. Dig. Liver Dis. 2023, 55, 1640. [Google Scholar] [CrossRef]
- Garcia, T.M.; van Roest, M.; Vermeulen, J.L.M.; Meisner, S.; Smit, W.L.; Silva, J.; Koelink, P.J.; Koster, J.; Faller, W.J.; Wildenberg, M.E.; et al. Early Life Antibiotics Influence In Vivo and In Vitro Mouse Intestinal Epithelium Maturation and Functioning. Cell Mol. Gastroenterol. Hepatol. 2021, 12, 943. [Google Scholar] [CrossRef] [PubMed]
- Schokker, D.; Zhang, J.; Vastenhouw, S.A.; Heilig, H.G.H.J.; Smidt, H.; Rebel, J.M.J.; Smits, M.A. Long-Lasting Effects of Early-Life Antibiotic Treatment and Routine Animal Handling on Gut Microbiota Composition and Immune System in Pigs. PLoS ONE 2015, 10, e0116523. [Google Scholar] [CrossRef] [PubMed]
- Reyman, M.; van Houten, M.A.; Watson, R.L.; Chu, M.L.J.N.; Arp, K.; de Waal, W.J.; Schiering, I.; Plötz, F.B.; Willems, R.J.L.; van Schaik, W.; et al. Effects of Early-Life Antibiotics on the Developing Infant Gut Microbiome and Resistome: A Randomized Trial. Nat. Commun. 2022, 13, 893. [Google Scholar] [CrossRef]
- Salvatore, S.; Baldassarre, M.E.; Di Mauro, A.; Laforgia, N.; Tafuri, S.; Bianchi, F.P.; Dattoli, E.; Morando, L.; Pensabene, L.; Meneghin, F.; et al. Neonatal Antibiotics and Prematurity Are Associated with an Increased Risk of Functional Gastrointestinal Disorders in the First Year of Life. J. Pediatr. 2019, 212, 44. [Google Scholar] [CrossRef]
- Chanpong, A.; Borrelli, O.; Thapar, N. The Potential Role of Microorganisms on Enteric Nervous System Development and Disease. Biomolecules 2023, 13, 447. [Google Scholar] [CrossRef] [PubMed]
- Foong, J.P.P.; Hung, L.Y.; Poon, S.; Savidge, T.C.; Bornstein, J.C. Early Life Interaction between the Microbiota and the Enteric Nervous System. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 319, G541. [Google Scholar] [CrossRef] [PubMed]
- Yeoh, Y.K.; Zuo, T.; Lui, G.C.-Y.; Zhang, F.; Liu, Q.; Li, A.Y.; Chung, A.C.; Cheung, C.P.; Tso, E.Y.; Fung, K.S.; et al. Gut Microbiota Composition Reflects Disease Severity and Dysfunctional Immune Responses in Patients with COVID-19. Gut 2021, 70, 698–706. [Google Scholar] [CrossRef] [PubMed]
- Sencio, V.; Gallerand, A.; Gomes Machado, M.; Deruyter, L.; Heumel, S.; Soulard, D.; Barthelemy, J.; Cuinat, C.; Vieira, A.T.; Barthelemy, A.; et al. Influenza Virus Infection Impairs the Gut’s Barrier Properties and Favors Secondary Enteric Bacterial Infection through Reduced Production of Short-Chain Fatty Acids. Infect. Immun. 2021, 89, e00734-20. [Google Scholar] [CrossRef] [PubMed]
Figure 1.
Study flow diagram. DGBI, Disorders of gut–brain interaction.
Figure 2.
Duration of exclusive breastfeeding in children with and without DGBI. Girls with DGBI stopped being exclusively breastfed earlier than those without DGBI (* p = 0.002). DGBIs, Disorders of gut–brain interaction.
Figure 2.
Duration of exclusive breastfeeding in children with and without DGBI. Girls with DGBI stopped being exclusively breastfed earlier than those without DGBI (* p = 0.002). DGBIs, Disorders of gut–brain interaction.
Figure 3.
Multivariate analysis showing that exclusive breastfeeding is the most significant protective factor against DGBI (A) and constipation (B) within 3 years of age. Sensitivity analysis conducted in 69 children who were diagnosed with DGBI (constipation) at 3 years of age showing similar outcomes (C). DGBI, Disorders of gut–brain interaction; EBM, Exclusive breastmilk.
Figure 3.
Multivariate analysis showing that exclusive breastfeeding is the most significant protective factor against DGBI (A) and constipation (B) within 3 years of age. Sensitivity analysis conducted in 69 children who were diagnosed with DGBI (constipation) at 3 years of age showing similar outcomes (C). DGBI, Disorders of gut–brain interaction; EBM, Exclusive breastmilk.
Table 1.
Characteristics of 568 children aged 0–3 years with and without DGBI.
| Characteristics | No DGBI (n = 429) | DGBI (n = 139) | p-Value |
|---|---|---|---|
| Male sex, n (%) | 219 (51.0) | 57 (41.0) | 0.050 |
| Weight, kg (IQR) | 13.4 (12.2–14.7) | 13.8 (12.2–15.0) | 0.482 |
| Height, cm (IQR) | 93.5 (91.0–96.0) | 93.0 (91.0–96.0) | 0.850 |
| Infection history during pregnancy, n (%) | 11 (2.6) | 3 (2.2) | 1.000 |
| Cesarean section, n (%) | 174 (41.0) | 54 (38.8) | 0.721 |
| Low Apgar score (≤7) at 1 min, n (%) | 6 (1.4) | 3 (2.2) | 0.463 |
| Duration of exclusive breastfeeding, months (IQR) | 6.0 (3.0–12.0) | 4.0 (2.0–9.0) | 0.001 |
| ≥3 months of exclusive breastfeeding, n (%) | 295 (68.8) | 81 (58.3) | 0.030 |
| 1-year breastfeeding, n (%) | 108 (25.2) | 19 (13.8) | 0.007 |
| Bottle feeding, n (%) | 365 (85.1) | 117 (84.2) | 0.902 |
| Age at first antibiotics/antiviral exposure, months (IQR) | 17.0 (11.0–23.0) | 18.0 (11.0–24.0) | 0.227 |
| Age at first antibiotics/antiviral exposure, n (%) | 0.611 | ||
| No exposure | 93 (21.7) | 31 (22.3) | |
| ≤6 months | 37 (8.6) | 7 (5.0) | |
| >6–12 months | 55 (12.8) | 21 (15.1) | |
| >12–24 months | 169 (39.4) | 52 (37.4) | |
| >24–36 months | 75 (17.5) | 28 (20.1) | |
| Exposure to antibiotics within the 1st year of life, n (%) | 75 (17.5) | 16 (11.5) | 0.125 |
| Age at 1st exposure to antibiotics within the 1st year of life, months * | 6.4 ± 2.4 | 7.8 ± 2.1 | 0.035 |
| Exposure to antivirals within the 1st year of life, n (%) | 20 (4.7) | 12 (8.6) | 0.120 |
| Age at 1st exposure to antivirals within the 1st year of life, months * | 10.2 ± 2.0 | 8.0 ± 2.4 | 0.008 |
| Exposure to secondhand smoke, n (%) | 260 (60.6) | 94 (67.6) | 0.166 |
| History of gastroenteritis requiring hospitalization, n (%) | 40 (9.3) | 14 (10.1) | 0.924 |
| Influenza infection within 3 years, n (%) | 12 (2.8) | 9 (6.5) | 0.083 |
| COVID-19 infection within 1st 6-month, n (%) | 0 (0) | 2 (1.4) | 0.060 |
| History of food allergy, n (%) | 29 (7.4) | 8 (6.3) | 0.831 |
| Asthma, n (%) | 11 (2.8) | 2 (1.6) | 0.744 |
| Atopic dermatitis, n (%) | 24 (6.1) | 7 (5.5) | 0.960 |
| Family history of allergic diseases | |||
| - Father, n (%) | 56 (13.1) | 19 (13.7) | 0.966 |
| - Mother, n (%) | 50 (11.7) | 23 (16.5) | 0.176 |
| - Sibling, n (%) | 173 (40.3) | 60 (43.2) | 0.623 |
| Socioeconomic status | |||
| - Paternal income, Baht/month (IQR) | 15,000 (9500–20,000) | 15,000 (9000–20,000) | 0.906 |
| - Maternal income, Baht/month (IQR) | 9000 (0–15,000) | 10,000 (0–15,000) | 0.867 |
| Paternal education, n (%) | 0.807 | ||
| - Bachelor’s degree | 98 (23.5) | 33 (24.4) | |
| - Higher than bachelor’s degree | 8 (1.9) | 2 (1.5) | |
| - Less than or equal to high school | 235 (56.4) | 71 (52.6) | |
| - Vocational training | 76 (18.2) | 29 (21.5) | |
| Maternal education, n (%) | 0.700 | ||
| - Bachelor’s degree | 185 (43.1) | 53 (38.1) | |
| - Higher than bachelor’s degree | 13 (3.0) | 4 (2.9) | |
| - Less than or equal to high school | 173 (40.3) | 59 (42.4) | |
| - Vocational training | 58 (13.5) | 23 (16.5) |
* Mean ± standard deviation; IQR, interquartile range; DGBI, Disorders of gut–brain interaction.
Table 2.
Multivariate analysis showing factors associated with the prevalence of DGBI in 3-year-old children (n = 566).
Table 2.
Multivariate analysis showing factors associated with the prevalence of DGBI in 3-year-old children (n = 566).
| Factor | Crude OR (95% CI) | Adj. OR (95% CI) | p-Value (Wald’s Test) | p-Value (LR-Test) |
|---|---|---|---|---|
| Exclusive breastfeeding for ≥3 months: Yes vs. No | 0.63 (0.43, 0.94) | 0.66 (0.44, 0.99) | 0.043 | 0.044 |
| Sex: Male vs. Female | 0.67 (0.45, 0.98) | 0.66 (0.44, 0.97) | 0.038 | 0.037 |
| Maternal history of allergy: Yes vs. No | 1.50 (0.87, 2.54) | 1.65 (0.94, 2.83) | 0.073 | 0.080 |
| Exposure to secondhand smoke: Yes vs. No | 1.36 (0.91, 2.05) | 1.29 (0.86, 1.96) | 0.231 | 0.228 |
| Exposure to antibiotics within 1 year: Yes vs. No | 0.61 (0.33, 1.07) | 0.60 (0.32, 1.05) | 0.086 | 0.074 |
| Exposure to antivirals within 1 year: Yes vs. No | 1.93 (0.89, 4.01) | 2.02 (0.92, 4.30) | 0.071 | 0.079 |
OR, odds ratio; CI, confidence interval; Adj., adjusted; DGBI, disorders of gut–brain interaction; LR, likelihood ratio.
Table 3.
Characteristics of 568 children with and without constipation.
| Characteristics | No Constipation (n = 437) | Constipation (n = 116) | p-Value |
|---|---|---|---|
| Male sex, n (%) | 228 (50.4) | 48 (41.4) | 0.101 |
| Weight, kg (IQR) | 13.4 (12.2–14.7) | 13.8 (12.3–15.0) | 0.414 |
| Height, cm (IQR) | 93.5 (91.0–96.0) | 93.0 (91.0–96.0) | 0.918 |
| Infection history during pregnancy, n (%) | 13 (2.9) | 1 (0.9) | 0.320 |
| Cesarean section, n (%) | 183 (40.9) | 45 (38.8) | 0.754 |
| Low Apgar score (≤7) at 1 min, n (%) | 8 (1.8) | 1 (0.9) | 0.694 |
| Duration of exclusive breastfeeding, months (IQR) | 6.0 (3.0–12.0) | 4.0 (2.0–8.0) | 0.001 |
| ≥6 months of exclusive breastfeeding, n (%) | 228 (50.4) | 45 (38.8) | 0.033 |
| 1-year breastfeeding, n (%) | 111 (24.7) | 16 (13.8) | 0.017 |
| Bottle feeding, n (%) | 383 (84.7) | 99 (85.3) | 0.985 |
| Age at first antibiotics/antiviral exposure, months (IQR) | 17.0 (11.0–23.0) | 18.0 (11.8–23.2) | 0.271 |
| Days of antibiotics/antiviral exposure within 6 months, days (IQR) | 7.0 (3.0–10.0) | 7.0 (5.0–11.0) | 0.494 |
| Days of antibiotics/antiviral exposure within 12 months, days (IQR) | 7.0 (5.0–10.0) | 5.0 (5.0–10.0) | 0.281 |
| Exposure to antibiotics within the 1st year of life, n (%) | 77 (17.0) | 14 (12.1) | 0.246 |
| Age at 1st exposure to antibiotics within the 1st year of life, months * | 6.4 ± 2.4 | 7.8 ± 2.3 | 0.040 |
| Exposure to antivirals within the 1st year of life, n (%) | 25 (5.5) | 7 (6.0) | 1.000 |
| Age at 1st exposure to antivirals within the 1st year of life, months * | 10.0 ± 2.0 | 7.2 ± 2.5 | 0.004 |
| Exposure to secondhand smoke, n (%) | 275 (60.8) | 79 (68.1) | 0.183 |
| Influenza infection within 3 years, n (%) | 13 (2.9) | 8 (6.9) | 0.053 |
| COVID-19 infection within 1st 6-month, n (%) | 0 | 2 (1.7) | 0.041 |
| COVID-19 infection within 1st year, n (%) | 25 (5.5) | 7 (6.0) | 1.000 |
| Toilet training, n (%) | 395 (87.4) | 93 (80.2) | 0.065 |
| Successful toilet training, n (%) | 333 (84.3) | 74 (80.4) | 0.456 |
| History of food allergy, n (%) | 33 (8.0) | 4 (3.8) | 0.207 |
| Asthma, n (%) | 12 (2.9) | 1 (1.0) | 0.482 |
| Atopic dermatitis, n (%) | 26 (6.3) | 5 (4.7) | 0.710 |
| Family history of allergic diseases | |||
| - Father, n (%) | 61 (13.5) | 14 (12.1) | 0.802 |
| - Mother, n (%) | 54 (11.9) | 19 (16.4) | 0.264 |
| - Sibling, n (%) | 183 (40.5) | 50 (43.1) | 0.685 |
| Socioeconomic status | |||
| - Paternal income, Baht/month (IQR) | 15,000 (9500–20,000) | 14,000 (9000–20,000) | 0.857 |
| - Maternal income, Baht/month (IQR) | 9000 (0–15,000) | 10,000 (0–15,000) | 0.689 |
| Paternal education, n (%) | 0.608 | ||
| - Bachelor’s degree | 102 (23.2) | 29 (25.9) | |
| - Higher than bachelor’s degree | 8 (1.8) | 2 (1.8) | |
| - Less than or equal to high school | 250 (56.8) | 56 (50.0) | |
| - Vocational training | 80 (18.2) | 25 (22.3) | |
| Maternal education, n (%) | 0.988 | ||
| - Bachelor’s degree | 190 (42.0) | 48 (41.4) | |
| - Higher than bachelor’s degree | 13 (2.9) | 4 (3.4) | |
| - Less than or equal to high school | 185 (40.9) | 47 (40.5) | |
| - Vocational training | 64 (14.2) | 17 (14.7) |
* Mean ± standard deviation; IQR, interquartile range.
Table 4.
Multivariate analysis showing factors associated with the prevalence of constipation in 3-year-old children (n = 566).
Table 4.
Multivariate analysis showing factors associated with the prevalence of constipation in 3-year-old children (n = 566).
| Factor | Crude OR (95% CI) | Adj. OR (95% CI) | p-Value (Wald’s Test) | p-Value (LR-Test) |
|---|---|---|---|---|
| Exclusive breastfeeding for ≥6 months: Yes vs. No | 0.62 (0.41, 0.94) | 0.65 (0.43, 0.99) | 0.047 | 0.046 |
| Sex: Male vs. Female | 0.69 (0.46, 1.05) | 0.69 (0.45, 1.05) | 0.085 | 0.083 |
| Exposure to secondhand smoke: Yes vs. No | 1.37 (0.90, 2.14) | 1.28 (0.83, 2.00) | 0.277 | 0.273 |
| Lack of toilet training: Yes vs. No | 1.71 (0.99, 2.89) | 1.65 (0.95, 2.82) | 0.070 | 0.077 |
| Exposure to antibiotics within 1 year: Yes vs. No | 0.67 (0.35, 1.20) | 0.68 (0.35, 1.22) | 0.213 | 0.199 |
| Exposure to antivirals within 1 year: Yes vs. No | 1.10 (0.43, 2.48) | 1.13 (0.44, 2.59) | 0.787 | 0.789 |
OR, odds ratio; CI, confidence interval; Adj., adjusted; DGBI, disorders of gut–brain interaction; LR, likelihood ratio.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Chanpong, A.; Ponjorn, N.; Tassanakijpanich, N.; Koosakulchai, V.; Rachatawiriyakul, P.; Kittivisuit, S.; Khantee, P.; Laoprasopwattana, K. Early-Life Events and the Prevalence of Gut–Brain Interaction Disorders in Children. Children 2025, 12, 1430. https://doi.org/10.3390/children12111430
AMA Style
Chanpong A, Ponjorn N, Tassanakijpanich N, Koosakulchai V, Rachatawiriyakul P, Kittivisuit S, Khantee P, Laoprasopwattana K. Early-Life Events and the Prevalence of Gut–Brain Interaction Disorders in Children. Children. 2025; 12(11):1430. https://doi.org/10.3390/children12111430
Chicago/Turabian StyleChanpong, Atchariya, Natchayada Ponjorn, Nattaporn Tassanakijpanich, Vanlaya Koosakulchai, Pornruedee Rachatawiriyakul, Sirinthip Kittivisuit, Puttichart Khantee, and Kamolwish Laoprasopwattana. 2025. "Early-Life Events and the Prevalence of Gut–Brain Interaction Disorders in Children" Children 12, no. 11: 1430. https://doi.org/10.3390/children12111430
APA StyleChanpong, A., Ponjorn, N., Tassanakijpanich, N., Koosakulchai, V., Rachatawiriyakul, P., Kittivisuit, S., Khantee, P., & Laoprasopwattana, K. (2025). Early-Life Events and the Prevalence of Gut–Brain Interaction Disorders in Children. Children, 12(11), 1430. https://doi.org/10.3390/children12111430
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
