According to Yang et al, the gut microbiome can be described as a key mediator between exposures to internal and external environmental factors, including diet and stress and health and developmental outcomes. Inadequate gut colonisation during the first three years of an infant’s life may lead to dysbiosis (an imbalance in the gut microbial community that is associated with disease).² 

What factors influence an infant’s microbiome? 

Yang et al explain that during the first three years of life, the development of the gut microbiome is influenced by the gut-brain axis and maternal and neonatal exposures.² 

The gut-brain axis consists of bidirectional communication between the central and the enteric nervous system, linking the emotional and cognitive centres of the brain with peripheral intestinal functions. Recent studies show that gut microbiota influence these interactions.⁴ 

Maternal and neonatal exposures include for example the mode of delivery, antibiotic exposure, and feeding patterns. Infants born vaginally have a gut microbiome very similar to that of their mother’s vaginal and faecal flora.² 

The gut microbiome of an infant born by caesarean section comprises bacteria transferred horizontally from the mother’s and others’ skin surfaces and, to a lesser extent, the place of birth.²  

Studies show that infants born by caesarean section, have less Bacteroides (a pleomorphic group of non-spore-forming gram-negative anaerobic bacteria) and more hospital-associated pathobionts (opportunistic microbes that emerge as a result of perturbations in the healthy microbiome) such as Enterococcus spp and Klebsiella spp.⁵ 

Antibiotic exposure influences the gut microbiome https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583026/  and administration during pregnancy. Antibiotics alter vaginal microbiology prior to birth, with potential long-term effects on the early gut colonisation of infants. Exposure to antibiotics prenatally and in infancy increases risk of becoming overweight and developing asthma in childhood, according to Walker et al.¹ 

A stable gut requires two big transitions during infancy:⁴  

• The first transition occurs soon after birth, during lactation, and results in the dominance of the gut microbiota by Bifidobacterium. 
• The second transition occurs during the weaning period, with the introduction of solid foods and continuation of breast milk feeding, and results in the establishment of an adult-type complex microbiome dominated by the bacteroidetes and firmicutes. Bacteroidetes and firmicutes are gram-negative organisms that colonise the entire gastrointestinal tract. 

Laursen found that the type of milk feeding and complementary feeding is particularly important in early and late infancy. Breastfeeding, due to the supply of human milk oligosaccharide into the gut, promotes the growth of specific human milk oligosaccharide (HMO) utilising Bifidobacterium species that dominate the ecosystem as long as the infant is primarily breastfed.⁶  

These species perform saccharolytic fermentation in the gut and produce metabolites with physiological effects that may contribute to protection against infectious and immune-related diseases.⁶  

Formula feeding, due to its lack of HMOs and higher protein content, gives rise to a more diverse gut microbiota that contains more opportunistic pathogens and results in a more proteolytic metabolism in the gut.⁶  

Complementary feeding, due to the introduction of dietary fibres and new protein sources, induces a shift in the gut microbiota and metabolism away from the milk-adapted and toward a more mature and diverse adult-like community with increased abundances of short-chain fatty acid-producing bacteria.⁶ 

Disruption of the microbiome in infancy 

Apart from the risk of obesity and asthma, Tanaka et al, state that dysbiosis has also been associated with other diseases later in life including inflammatory bowel disease, irritable bowel syndrome, allergies, autoimmune disease, and brain disorders.³ 

In infancy, disruption of the microbiome has been linked to the development of colic. The prevalence of infantile colic ranges from 8%-20% and accounts for 10%-20% of paediatric visits during the first four months of an infant’s life.⁷ 

Infantile colic is classified as a functional gastrointestinal disease (FGID). The Rome Foundation defines infantile colic as: ‘recurrent and prolonged periods of infant crying, fussing, or irritability reported by caregivers that occur without obvious cause and cannot be prevented or resolved by caregivers’.⁷  

Studies show a reduction in overall microbiota diversity in infants with colic compared to healthy infants – particularly a reduction in the proportions of Bifidobacteria, bacteroides, and Lactobacilli. Studies have also noted an increase of Clostridium, Staphylococcus – particularly Enterobacteria such as Escherichia, Shigella, Klebsiella or Enterobacter.⁷ 

According to Colome et al, high proportion of Bifidobacterium and Lactobacillus in the infants microbiota is protective against colicky crying and fussing. Lactobacillus are able to induce the expression of anti-inflammatory genes, improving gut function and motility and exerting a reduction of visceral pain. In addition, Lactobacilli and Bifidobacteria may protect against colic by modulating immune response.⁷ 

Why does colic resolve around four to six months?  

Numerous theories have been put forward to explain this. The two most widely accepted are:⁷ 

• Bile acid metabolism is altered during the first months of life (as demonstrated by the fact that cholic to chenodeoxycholic acids ratio in duodenum and bile acid levels in serum are increased during the first months of life). Bile acids represent a key environmental factor modulating gut bacteria at high taxonomic levels.
• The overall diversity of the intestinal microbiome increases in an age-related manner during the first months of life, and increased diversity is known to make ecosystems more resistant to perturbations by opportunistic organisms (such as Enterobacteria in the gut).

Use of probiotics for colic gaining momentum 

Recommended management strategies usually centre around parental support and reassurance that the infant is otherwise healthy. However, parents are often in a state of crisis and feel that they want to take action, write Ellwood et al.⁸  

A number of treatment options exist, which include pharmacological treatments (eg dicyclomine hydrochloride, cimetropium bromide, simethicone and proton pump inhibitors), probiotics, complementary therapies (including herbal agents and sucrose), manual therapies (for example chiropractic, osteopathy and physiotherapy), dietary interventions and parental behavioural interventions.⁸ 

Research into the use of probiotics (live microorganisms which, when administered in adequate amounts, confer a health benefit on the host) for colic has been rapidly gaining momentum.⁹  

Lactobacillus reuteri (L. reuteri) is a well-studied and one of the most widely used probiotics. In humans, L. reuteri is found in different body sites, including the gastrointestinal tract, urinary tract, skin, and breast milk. Furthermore, L.reuteri has been shown to be one of the truly indigenous bacteria of the human GI tract.⁹  

L. reuteri  is the most studied probiotic for infantile colic and is supported by the strongest evidence in the treatment of infantile colic and reduction of its symptoms (decrease in crying time and fussing).^{9,10,11,12,13,14,15,16,17,18,19} 

Ellwood et al  (2020) conducted a comprehensive review to compare the efficacy of manual therapy to three of the most common interventions (probiotics, simethicone and proton pump inhibitors) on colic symptoms in infants, including crying time, sleep and infant distress and adverse events. The review included 32 studies.⁸ 

According to the authors, high-level evidence showed that probiotics were most effective for reducing crying time in breastfed infants (range −25 min to −65 min over 24 hours).⁸  

Manual therapies had moderate to low-quality evidence showing reduced crying time (range −33 min to −76 min per 24 hours). Simethicone had moderate to low evidence showing no benefit or negative effect. One meta-analysis did not support the use of proton pump inhibitors for reducing crying time and fussing.⁸ 

REFERENCES 

1. Walker RW, Clemente JC, Peter I, Loos RJF. The prenatal gut microbiome: are we colonized with bacteria in utero? Pediatr Obes, 2017.
2. Yang I, Corwin EJ, Brennan PA, et al. The Infant Microbiome: Implications for Infant Health and Neurocognitive Development. Nurs Res, 2016.
3. Tanaka M, Nakayama J. Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int, 2017.
4. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol, 2015.
5. Marrs T, Jo JH, Perkin MR, et al. Gut microbiota development during infancy: Impact of introducing allergenic foods. J Allergy Clin Immunol, 202
6.  Laursen MF. Gut Microbiota Development: Influence of Diet from Infancy to Toddlerhood. Ann Nutr Metab, 2021.
7.  Colome MTG, Mazo JE and Espadaler J. Gut Microbiota Dysbiosis and Role of Probiotics in Infant Colic. Archives of Clinical Microbiology, 2017.
8.  Ellwood J, Rodi JD. Comparison of common interventions for the treatment of infantile colic: a systematic review of reviews and guidelines. Paediatrics, 2020.  

9.  Pereira AR, Rodrigues J, Albergaria M. Effectiveness of probiotics for the treatment of infantile colic. AJGP, 2022.
10.  Francavilla R, Cristofori F, Indrio Indications and recommendations by societies and institutions for the use of probiotics and prebiotics in paediatric functional intestinal disorders. J Pediatr Gastroenterol Nutr, 2016.
11.  Abrahamsson TR, Wu RY, Sherman PM. Microbiota in functional gastrointestinal disorders in infancy: Implications for management. Nestle Nutr Inst Workshop Ser, 2017.
12.  Nation ML, Dunne EM, Joseph SJ, et al. Impact of Lactobacillus reuteri colonization on gut microbiota, inflammation, and crying time in infant colic. Sci Rep, 2017.
13.  Daelemans S, Peeters L, Hauser B, Vandenplas Y. Recent advances in understanding and managing infantile colic. F1000Res, 2018.
14.  Savino F, Galliano I, Garro M, et al. Regulatory T cells and toll-like receptor 2 and 4 mRNA expression in infants with colic treated with Lactobacillus reuteri Benef Microbes, 2018.
15.  Tatari M, Yazdani-Charati J, Karami H, Rouhanizade Effects of probiotics on infantile colic using quadratic inference functions method. Iran J Neonatol, 2017.
16.  Hjern A, Lindblom K, Reuter A, Silfverdal A systematic review of prevention and treatment of infantile colic. Acta Paediatr, 2020.
17.  Mi GL, Zhao L, Qiao DD, et al. Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial. Antonie Van Leeuwenhoek, 2015.
18. Chau K, Lau E, Greenberg S, Jacobson S, et al. Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938. J Pediatr, 2015. 
19. Sung V, D'Amico F, Cabana MD, et al. Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis. Pediatrics, 2018.