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Nutraceuticals and Pain Disorders of the Gut Brain Interaction in Infants and Children: A Narrative Review and Practical Insights

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23 December 2023

Posted:

25 December 2023

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Abstract
Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through Pubmed-Medline literature search updated to October 2023, focused on the effect of nutraceuticals in infantile colic, functional abdominal pain and irritable bowel syndrome in children and adolescents. Significant reduction of colic episodes and crying time was reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to placebo, in children with functional abdominal pain or irritable bowel syndrome a significant reduction of pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, in one study on corn fiber cookies or partial hydrolysed guar gum or a specific multiple herbal extract (STW-5) or vitamin D supplementation. To date, there is a moderate certainty of evidence with a weak grade of recommendation for Lactobacillus reuteri DSM 17938 (108 CFU/day) for reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 x109 CFU twice daily) for reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.
Keywords: 
Subject: Medicine and Pharmacology  -   Pediatrics, Perinatology and Child Health

INTRODUCTION

“Nutraceutical’ is a term introduced by Stephen Defelice in 1989 and identifies ‘a food or part of a food or a dietary supplement, that has a medical or health benefit, including the prevention and treatment of disease’.1
The medicinal and spiritual applications of plants, herbs and other natural compounds date back to many centuries earlier and was already reported in Egyptians, Romans, Mesopotamian and Greek civilizations and depicted some ancient artworks.2
In ancient Indian literature, Susruta and Charaka mention the use of cardamom, turmeric, ginger, cinnamon, and pepper for their medicinal properties. Some of these spices continue to be used for the treatment of multiple conditions including abdominal pain disorders throughout the world.3 The concept of nutraceuticals has evolved over time but still does not have a well-established definition worldwide.4 Nutraceuticals have been recently classified into traditional and non-traditional nutraceuticals. Traditional nutraceuticals include three subcategories: chemical constituents (nutrients, herbals, phytochemicals, polynsaturated fatty acids); probiotics and prebiotics; nutraceutical enzymes. The non-traditional nutraceuticals are fortified nutraceuticals and recombinant nutraceuticals.5 Nutraceutical compounds are generally considered as products, including minerals, vitamins, amino acids, vegetables or herbs that confer benefit to human health by improving functional, mental and physical activities.6
Despite their wide and long-term use, scientific information about nutraceuticals is limited, there are very few studies evaluating safety7 and efficacy8,9,10,11 and no international regulation regarding their marketing and dosing.5,12
Functional abdominal pain (FAP) disorders are disorders of the gut brain interaction (DGBI) and according to Rome IV criteria, include infantile colic, irritable bowel syndrome, functional dyspepsia and functional abdominal pain not otherwise specified.13,14, 8
They affect more than 20% of infants and children15 throughout the world, with a significant economic impact, decreased quality of life and long-term adverse outcomes.16
According to data published in 2015 from a multicenter trial in The Netherlands total annual costs per patient with FAPs calculated as the sum of medical and nonmedical costs were estimated to be more than 2500 euro, excluded initial diagnostic investigations.17
Despite an increasing recognition of multiple underlying factors, treatment is still challenging and symptoms often persist despite multiple non-pharmacological and pharmacological interventions, including probiotics, diets, spasmolitics, anti-depressants and cognitive-behavior approach. 18 Because of frequent lack of benefit of conventional treatment, almost 40% of parents of pediatric gastroenterology patients search for complementary and alternative medicine (CAM) for their child. More than 90% of these parents also considered important that paediatricians acquired knowledge and initiate CAM research.19
Likewise, a large number of adult patients with functional gastrointestinal disorders use CAMs. 20
The scope of this narrative review is to summarize current evidence of the nutraceuticals effects on abdominal pain disorders in infants and children and to provide health care professionals a practical guide for their possible clinical application.

LITERATURE SEARCH STRATEGY

Medline-PubMed was searched up to 31 October 2023 using the following MESH and Bolean terms: “herbs” OR “herbal supplements” OR “nutraceuticals” OR “ginger” OR “iberogast” OR “STW-5” OR “peppermint” OR “mentha piperita” OR “licorice” OR “liquorice” OR “fennel” OR “vitamins” OR “antioxidants” OR “polyphenols” AND (“functional gastrointestinal disorders” OR “abdominal pain” OR “infantile colic”), limited to English language and children (0-18 years). References of selected studies and reviews were also used to retrieve additional original studies.

NUTRACEUTICALS AND FAP/DGBI IN PEDIATRIC AGE

Only a very limited number of nutraceuticals have been assessed in clinical trials in infants and children with FAP/DGBI disorders.
Recent reviews have extensively covered studies evaluating fibers21,22 probiotics, prebiotics and synbiotics in different pediatric gastrointestinal disorders 23, 24, 8
This review focuses on nutraceuticals other than biotics and fibers in infants and children with infantile colic, functional dyspepsia, functional abdominal pain and irritable bowel syndrome. A summary of studies evaluating these included nutraceuticals in the above disorders in pediatric patients are reported in Table 1.

FENNEL

The fennel taxonomically identified as Foeniculum vulgare is a perennial plant used, in various forms, in traditional medicine for ages. The main component of fennel is the anethole, also known as estragole, that is extracted from its seeds and has a chemical structure similar to dopamine, with a reported relaxing effect on the intestinal smooth muscles.25
Two studies reported a beneficial effect of fennel on crying in colicky infants.
In 2003 a randomized placebo-controlled trial tested the effect of fennel seed oil emulsion in 125 infants (2 to 12 weeks of age) with infantile colic.26
Colic, as defined according to Wessel’s criteria, disappeared in 65% (40/62) of infants in the fennel group compared to 23% (14/59) of the placebo group (P < 0.01). A significant reduction of weekly crying time was also found in the treatment group compared with the placebo group [Absolute Risk Reduction (ARR) = 41% (95% CI 25 to 57), Number Needed to Treat (NNT) = 2 (95% CI 2 to 4)]. No side effects were reported in the two groups of infants. 26
A prospective randomised-controlled study involved 35 colicky infants who were treated with herbal (fenel) tea (35 ml three times a day for 7 days). Crying time significantly decreased from 5.11 ± 1.43 hours/day at baseline to 3.20 ± 1.23 hours/day after one week of intervention ( -1.51 hours/day vs. -0.09 hours/day in the control group, p < 0.001)27

GINGER

Ginger is the rhizome of the Zingiber officinale commonly used as food and in Asian traditional medicine for gastrointestinal symptoms.28
Ginger contains many different compounds, carbohydrates, lipids, terpenes, phenolic components, 6-gingerol,8-gingerol,10-gingerol and 6-shogaol which may act through cholinergic and calcium antagonist mechanisms, M3 and 5-HT3 receptors and synthesis of prostaglandins. 29,30
Ginger has been studied mostly for nausea, in pregnancy31, in adults and children on chemotherapy32,33 or post-surgery.34
Wu et al. showed that ginger accelerates gastric emptying and stimulates antral contractions in healthy adult individuals. 35
One study reported an antiemetic effect in children with gastroenteritis 36 but we did not find studies evaluating ginger in FAPs or DGBI in children.
Nonetheless, a survey about the use of complementary and alternative therapies in 100 children with abdominal pain disorders found that 11% of IBS children used ginger as treatment. 37
Ginger is generally considered as safe. The most common adverse effects, at the dosage above 5 g per day, are mouth and throat irritation, abdominal discomfort, heartburn, burping, and diarrhea. These symptoms may be avoided or reduced by taking ginger in capsule form.38

LICORICE

Licorice root (Glycyrrhiza glabra) is an ancient herb mostly used in Chinese medicine. It contains triterpentoid saponin glycyrrhizin, flavonoids, isoflavonoids, chalcones, cumarins, triterpenoids and sterols which have anti-inflammatory, immune, metabolic, endocrine and possible gastric activities. 39
After more than 2 weeks of intake, not deglycyrrhizinated licorice can cause hypertension and hypokalemia via mineralcorticoid effect (sodium and water retention). 40
There are currently no pediatric studies evaluating licorice as single supplementation in abdominal pain disorders.

PEPPERMINT

Peppermint is a species of mint, a perennial herb of the Lamiaceae family, used for ages for its presumed anti-inflammatory, analgesic and antispasmodic effects.41,42,43
Peppermint oil, obtained by steam distillation from the fresh leaves, is reported to induce smooth muscle relaxation (by blocking calcium channel44 or direct enteric nervous system effects); modulate visceral sensitivity (via transient receptor potential cation channels) and psychosocial distress; exert anti-microbial and anti-inflammatory effects. 45
Among the main compounds of peppermint are flavonoids and phenolic acids.
Moreover, menthol may act on Cajal interstitial cells, stimulate the production of prostaglandins and have a nociceptive action in the brain by the activation of GABA receptors type A. 46
A double-blind randomized crossover study enrolling 30 colicky infants showed that episodes of colic decreased in infants treated with Mentha piperita and with simethicone (from 3.9 per day at baseline to 1.6 per day after one week of intervention), duration of crying was similar between the two groups of treatment and colic disappeared in 40% of infants treated with Mentha piperita vs. 43% of infants on simethicone.47
In one pediatric randomized, double-blind, placebo-controlled study43, peppermint oil enteric coated capsules (1-2 capsules containing 187 mg, three times per day) were administered to 42 children (aged 8-12 years) with IBS for two weeks. The intervention group reported more frequently reduced symptoms (71% vs. 43%) and severity (79% vs. 16%) but not significant changes in Gastrointestinal Symptom Rating Scale.
Another randomized placebo-controlled trial compared the effects of peppermint oil (1-2 capsules of 187 mg, three times per day) (34 children), a symbiotic (Bacillus coagulans and fructooligosaccharide) (29 patients), and placebo (folic acid) (25 patients) for one month in children with FAPs (30 with IBS). The group who received peppermint oil had a significant reduction in severity of pain (as assessed on a one to ten scale), duration (minutes per day) and frequency of abdominal pain (episodes per week) compared to placebo and compared to symbiotic.48
No adverse events were noted. Two other studies performed in children with abdominal pain disorders pointed out that peppermint oil has no effect on microbiome composition49 or small bowel/colonic transit time.50

MULTIPLE HERBAL EXTRACTS

A prospective double-blind randomized controlled study including 68 colicky infants showed that colic disappeared in 19/33 (57%) infants taking herbal tea (up to 150 ml three times per day during episodes of colic, for 7 days) vs. 9/35 (26%) infants in the placebo group (p < 0.01). The tea contained extracts of chamomile (Matricaria chamomilla), vervain (Verbena officinalis), licorice (Glycyrrhiza glabra), fennel (Foenieulum vulgare), and balm-mint (Melissa officinalis) plus glucose and the placebo was made by glucose and natural flavors.51
A randomized, double-blind, placebo-controlled trial investigated the effect of a phytotherapeutic agent (combination of Matricariae recutita, Foeniculum vulgare and Melissa officinalis) in 88 colicky breastfed infants. After one week of intervention crying time was significantly reduced in more infants treated with the combination of herbs than in infants of the placebo group (85% vs, 49%, p < 0.005). The daily average crying time also decreased significantly more in the intervention group than in the placebo group (-124.3 min vs. -28.8 min, (p < 0.005) and these results were maintained fifteen days after the end of therapy (average crying time 82.1 min/day vs. 165.3 min/day, p<0.005), No side effects were reported.52
A recent open-label single-group study was conducted in 30 colicky infants (age 3-16 weeks) evaluating the effect of a product containing Carbo vegetabilis (vegetable charcoal), Prunus spinosa (Blackthorne), Carum carvi (Caraway), Matricaria chamomilla (Chamomile), Foeniculum vulgare (Fennel), Zingiber officinale (Ginger), Melissa officinalis (Lemon Balm), and Mentha piperita (Peppermint). The product was administered 1.25 ml orally during a colic episode and repeated after 120 minutes, if needed, Average daily crying time was recorded using a modified Barr’s diary and analysed after 7 and 14 days from recruitment. Daily crying time and flatulence significantly decreased (P < .05) with a reduction of ≥50% in 73% of infants by day 7 and in 80% by day 14. After stopping the intervention 40% of infants had a relapse of colic. 53

STW 5 (IBEROGAST)

STW-5 is a herbal combination of nine alcoholic extracts from Iberis amara, Angelicae radix, Cardui mariae fructus, Chelidonii herba, Liquiritiae radix, Matricariae flos, Melissae folium, Carvi fructus, and Menthae piperitae.54
This combination is supposed to have a synergic action on reducing gastrointestinal contraction and inflammation and stimulating gastric secretion.55
STW-5 was introduced to the market in the 1960s and in the last 30 years clinical trials have been conducted.56. 57
Among the nine herbal extracts, Iberis amara selectively inhibits muscarinic M3 receptors, while chelandine herb and chamomile flowers act on 5-HT4 and liquorice root on 5-HT3 receptors.
In the esophagus, it acts as a mucosal protector by increasing mucin and prostaglandin E2 secretion and increase the pressure of the LES (lower esophageal sphincter). 58
In the stomach, STW5 relaxes the fundus and corpus and increases antral region contractions. 59. 60
A prospective observational study included 980 children (age 3-14 years) with FGID (IBS in 43 %, FD in 26 %). STW-5 was administered 10-20 drops three times a day for 1 week. During the treatment period, an adapted gastrointestinal symptom score (GIS) decreased 76% from baseline score and 39% percent of children reported complete relief of their symptoms, with similar effect among different patients’ groups. Seven patients (0.7 %) reported adverse events (skin rash, nausea, vomiting, abdominal pain, and increased gastrointestinal complaints).54
In a retrospective study on 154 children (aged 4-18 years) affected by functional dyspepsia, STW5 showed significant benefit only in boys.61

FIBERS AND PREBIOTICS

In the last decades many dairy companies have added fibers/prebiotics, such as short-chain galactoligosaccharides and long-chain fructooligosaccharides in infant formulas to improve infant gut microbiota composition and possibly ameliorate digestive disturbs. However, since these formulas also present hydrolyzed proteins, reduced lactose content, modified fat and, eventually, probiotics, the clinical benefit in reducing crying and colic, reported in some studies, cannot be clearly correlated to the fibers. 21
We identified only two studies evaluating the effect of fibers in infantile colic 62, 63
Soy-polysaccharide was supplemented in a specific infant formula and assessed in 27 colicky infants (aged 2-8 weeks) in a placebo-controlled crossover trial for 9 days. No significant difference in daily crying time and fussing was found between the two groups.62
In the other randomized double-blind controlled study, 94 infants received galactoligosaccharides and polydextrose or a specific strain of probiotic (Lactobacillus GG) or placebo for the first two months of life. The group receiving prebiotics and probiotics reported significantly less frequent excessive crying compared to the placebo group (19% and 19% vs. 47%, p=0.02).63
We refer to three recent reviews15,21,22 for a detailed analysis of the role of fibers in children with abdominal pain and gastrointestinal disorders.
In brief, in children with FAPs, corn fiber cookies for two weeks 64 significantly reduced the frequency of abdominal pain compared to placebo. Likewise, partial hydrolysed guar gum supplementation in 60 children with chronic abdominal pain or IBS significantly decreased an IBS score, while improving stool consistency, compared to the placebo group. 65
Conversely, glucomannan did not show any significant benefit on abdominal pain. 66
In another randomized controlled trial on 71 children with IBS, inulin for 4 weeks was less effective than probiotics and synbiotics. 67
Psyllium fiber (6–12 g/day for 6 weeks) 68 reduced the mean number of abdominal pain episodes but not pain intensity.
More recently, the same dosage of psyllium supplementation significantly improved the IBS severity scoring scale and showed a higher remission rate, compared to placebo. 69

PROBIOTICS

As reported by the 2023 ESPGHAN position paper on probiotics for the management of pediatric gastrointestinal disorders 23, in infantile colic there is a moderate certainty of evidence and a weak grade of recommendation for Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breastfed infants. No recommendation can currently be made for or against probiotics in formula-fed infants or for preventing infantile colic. There is also a moderate certainty of evidence and a weak grade of recommendation for Lactobacillus reuteri DSM 17938 (108 CFU/day) for reducing pain intensity in children with FAPs and for L. rhamnosus GG (1-3 x109 CFU twice daily) for reducing pain frequency and intensity in children with IBS. 23

SYNBIOTICS

The recent ESPGHAN position paper on the use of synbiotics for the management of children with gastrointestinal disorders 70 concluded that currently no recommendation can be formulated on the use of any specific symbiotic preparation in the treatment of infant colic, FAP or IBS.

VITAMINS AND ANTI-OXIDANTS

We identified only one pediatric study assessing the effect of vitamin on abdominal pain in children. A randomized controlled trail in 112 adolescents with IBS and vitamin D deficiency showed that oral vitamin D3 2000IU/day for 6 months normalized the vitamin D level and significantly improved different IBS symptom score systems (IBS-SSS, IBS-QoL and total score) compared to the group receiving placebo. 71
Vitamin D may act by reducing inflammation by immune modulation and by regulating the synthesis of serotonin. 72

LIMITATIONS OF THIS REVIEW

We are aware of some limitations of this review. First, we did not perform a systematic review and we limited the literature search to Medline and English language. However, we retrieve additional studies by references of selected articles and recent reviews to reduce the chance to miss original studies. Second, many herbal extracts have long been used in traditional medicine but data are not reported in clinical trials. Third, we aimed to help health care professionals orienting in the nutraceutical field for children who are affected from pain disorder of the gut-brain interaction but we did not provide any clear recommendation. Likewise, the European Medicine Agency currently does not recommend any herbal product for gastrointestinal disorders in the pediatric population because of lack of adequate data on efficacy and safety.73
Caution and medical supervision on the use of nutraceuticals in pediatric subjects have also been advocated in other recent reviews. 15, 10, 8, 22

CONCLUSIONS

Nutraceuticals are often considered by parents to treat their child with infantile colic and abdominal pain disorders. However, there is a very limited number of studies assessing efficacy and tolerance of herbs, spices and nutritional supplements in children with these conditions. A growing evidence of efficacy in reducing infant colic episodes and crying time is emerging for fennel (seeds oil or tea or in different multiple herbal extracts), for Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12, in breast-fed infants. In children and adolescents with functional abdominal pain or irritable bowel syndrome, reduction of pain was reported in patients supplemented with Lactobacillus reuteri DSM 17938 or Lactobacillus rhamnosus GG and in two studies using peppermint oil capsules or psyllium fibers; the benefit of corn fiber cookies or partial hydrolysed guar gum or a specific multiple herbal extract (STW-5) or vitamin D supplementation was demonstrated only in one study for each product (Figure 1). No recommendation can currently be provided for other nutraceuticals and possible adverse effects should always be considered. Moreover, current pediatric studies present small sample size, heterogeneity in the population recruited, product and dosage used, outcome measures, lack of long-term assessment of efficacy and safety.

Author Contributions

S.S., M.C., M.A and L.P. contributed to conception and design of the review, collection and interpretation of data, drafting the article and approval of the manuscript; S.S. and D.C. contributed to the literature search, interpretation of data, drafting the article and approval of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This review received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors have no conflict of interest to declare.

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Figure 1. Evidence of nutraceuticals efficacy in Infantile Colic (A), Functional Abdominal Pain (B), Irritable Bowel Syndrome (C).
Figure 1. Evidence of nutraceuticals efficacy in Infantile Colic (A), Functional Abdominal Pain (B), Irritable Bowel Syndrome (C).
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