Infant colic is still a mysterious disorder of the microbiota–gut–brain axis

In 1954, Wessel et al. (1) introduced the most widely accepted definition of infant colic, and this was later modified to define colic as crying or fussing that lasted more than three hours a day for at least three days a week in an otherwise healthy and thriving infant. The Wessel rule of threes was, however, omitted from the 2016 clinical criteria for infant colic, published by the Rome IV consensus group (2). According to this criteria, the clinical diagnosis of infant colic must occur in a symptomatic infant of less than five months of age, whose caregivers report recurrent and prolonged periods of crying that have no obvious cause and that they cannot prevent or resolve and that there is no evidence of failure to thrive, fever or illness. In other words, the requirement for a certain duration of crying was omitted from the clinical criteria. However, for clinical research, the diagnosis of colic must also include both of the following, in addition to the preceding criteria. Firstly, the caregiver must report that the infant has cried or fussed for three or more hours per day for three or more days in a seven-day period. Secondly, a prospective behaviour diary should confirm that the total crying or fussing time was three hours or more in any 24-hour period. It is very important that these Rome IV diagnostic criteria are universally adopted, as a systematic review identified 39 trials where 20 different definitions were used (3). Despite years of research, the aetiology of colic crying remains unresolved and the treatment options are limited. The word colic originates from the Greek adjective ‘kolikos’, based on ‘kolon’, which suggests that an infant’s hard-to-soothe crying has been considered as a gastrointestinal disturbance for hundreds of years. Since the occurrence of infant colic coincides with the most remarkable changes in gut microbiota colonisation during the first weeks and months of life, it is not surprising that it has been suggested that gut microbiota, inflammation and, more recently, the microbiota-gut-brain axis play an important part in the pathophysiological mechanisms of colic (4,5). With regard to the microbiota-gut-brain axis, gut microbiota and its products have been considered to be affected by environmental factors, such as stress, diet and antibiotics. This results in an imbalance in mirobiota, dysbiosis, which, in turn, may ultimately bring about alterations in neuronal function, namely pain sensations (5). Infants with colic have decreased faecal-bacterial diversity and stability, compared with the infants without colic, and they also have higher faecal counts of gram-negative bacteria, especially coliform bacteria (4). The numbers of Lactobacilli and Bifidobacteria have also been reported to be reduced in colic in comparison with the healthy infants (4). It is important to note that all the studies have focused on the gut microbiota composition of breast-fed infants with colic, and there are no data on formula-fed infants. In this issue of Acta Paediatrica, a cross-sectional study by Savino et al. (6) aims to help fill this gap in the knowledge by comparing the gut microbiota composition of 77 formula-fed infants, with and without colic. Colic was diagnosed according to the Wessel criteria and using a validated parental diary. All the infants were born at fullterm and aged between two and 16 weeks during the study period. The authors analysed the primary outcomes of total bacteria, Bifidobacteria, the Lactobacillus-Enterococcus group and the Escherichia coli group, using fluorescent in situ hybridisation. The secondary outcomes were the faecal levels of ammonia, as an indicator of protein degradation, and faecal pH. This showed that the faeces of infants with colic contained a lower number of total bacteria than the infants without colic, together with a relative abundance of Escherichia coli group bacteria and higher levels of ammonia. However, there were no differences in the number of Bifidobacteria or LactobacillusEnterococcus group between the groups. These new data on formula-fed colic infants are in line with the earlier studies on breast-fed infants, except for the findings regarding Bifidobacteria and lactic acid bacteria. Bifidobacteria have been reported to dominate the gut microbiota of breast-fed infants, while the microbiota in the guts of formula-fed infants have been reported to be more diverse. These deviations might be due to the unique composition of maternal milk or the possible direct effects of microbes in breast milk. Therefore, a future study comparing the gut microbiota composition between breast-fed and formula-fed colic infants needs to be carried out in order to find out whether the type of feeding might hold the answer to why Savino et al. could not confirm the earlier findings concerning Bifidobacteria and lactic acid bacteria (4). In our opinion, this further research would be worth doing, despite the fact that breastfeeding has not been shown to provide a protective effect on the development of infantile colic and the incidence of infant colic is similar among formula-fed and breast-fed infants (7).