Colic causes significant stress to 10% to 25% of infants and their parents, yet it has no recognized etiology (Dubois & Gregory, 2016; Garcia Marques et al., 2017). The significant stress of colic is associated with recurrent periods of prolonged, inconsolable crying or fussiness that cannot be prevented in infants less than 5 months of age without signs of failure to thrive, fever, or illness (Benninga et al., 2016). Although colic self-resolves, parental stress over crying has been implicated in delayed bonding and in cases of child abuse and shaken baby syndrome (Dubois & Gregory, 2016; Liu et al., 2018).

Figure. No caption available.

The suspected etiology of colic is likely multifactorial, involving gastrointestinal (GI) system health, parenting style, and infant temperament (Banks & Chee, 2020; Mai et al., 2018; Savino et al., 2009). Specifically, an imbalance or dysbiosis within the GI microbial landscape has been implicated (Fatheree et al., 2017; Mai et al., 2018; Nation et al., 2017; Ong et al., 2019). Colic and increased crying time are associated with increased GI colonization of gas-producing coliforms like the Proteobacteria, Escherichia coli, and Klebsiella (Dubois & Gregory, 2016; Fatheree et al., 2017). Colic and crying time are also associated with lower GI colonization of Bacteroidetes, Actinobacteria, like Bifidobacterium, and Firmicutes, like Lactobacilli (Dubois & Gregory, 2016; Nocerino et al., 2020; Savino et al., 2004).

Colic typically self-resolves by 3 to 4 months of age, yet its resolution is as undefined as its etiology. Although evidence supports microbiome differences at colic onset, there is little evidence of microbiome changes at colic resolution. Existing studies have evaluated effectiveness of probiotics on colic resolution (Simonson et al., 2021), but there is limited evidence about how the microbiome changes at colic resolution without probiotics. The purpose of this scoping review is to evaluate the state of the evidence on what is known about the GI microbiome of infants at colic onset and resolution.

The Colic Experience

The impact of colic on the infant and their family has been explored to better understand the lived parental experience of colic. These qualitative studies identified themes of overwhelming parental emotions and feelings of survival, loss, shame, suffering, guilt, frustration, and hopelessness (Cirgin Ellet & Swenson, 2005; Landgren & Hallstrom, 2011). In both studies, the family was described as being in a state of crisis and everyone was crying, infants and parents, due to the stress of colic. Landgren and Hallstrom (2011) note that parents used a variety of strategies to stop the crying associated with colic. Cirgin Ellet and Swenson (2005) report parental frustration at the lack of remedies and ambiguous understanding of colic's origin. This frustration, desperation for relief, and the themes of stress highlight the importance of studies to identify colic's etiology and develop effective strategies for prevention and treatments.

The Role of Gastrointestinal Microbiome

Colic's emotional impact has been explored, yet the etiology of colic remains unclear. Colic most likely has a multifactorial origin, involving the interaction of the GI system, parenting style, infant temperament, and infant neurologic immaturity. Gastrointestinal system involvement is the subject of this review, but it is important to consider how other factors may influence colic.

Early descriptions of colic include excessive crying, gassy tendencies, and abdominal distension that point to GI involvement (Wessel et al., 1954). The GI microbiome, consisting of all microorganisms living within the human GI system, plays an important role in processing nutrients, preventing colonization by potentially pathogenic organisms, and developing the intestinal immune system and inflammatory responses (Human Microbiome Project Consortium, 2012; Partty et al., 2017; Savino et al., 2009). As sequencing technology has advanced, the understanding of how humans relate to their microbial flora has grown. Having a commensal, or healthy, microbiome results in a eubiotic state.

Dysbiotic microbes communicate with the host through inflammatory markers thus promoting GI inflammation (Dubois & Gregory, 2016; Partty et al., 2017; Rhoads et al., 2018). The microbes primarily colonizing the infant with colic's microbiome tend to be coliforms, gas producers (Dubois & Gregory, 2016; Ong et al., 2019; Savino et al., 2009). Coliforms link to the crying, gas, and distension often identified with colic (Mai et al., 2018).

Methods

The objectives for this scoping literature review were to identify what is known about the microbiome at colic onset and resolution. In July 2021, searches of SCOUT, PubMed, and CINAHL returned 935 articles using the search terms "infant colic" AND "microbiome" NOT "equine." After removing duplicates, a total of 637 articles were reviewed by title and abstract (Figure 1). Reference lists of the final literature were reviewed. Two sources were extracted and included in the scoping review. Articles were selected if they included infants less than 5 months of age with colic and sequenced the GI microbiome at either colic onset or resolution. This review includes interventional studies with probiotics if they also sequenced the microbiome and assessed for colic onset or resolution. Articles were not excluded based on infant feeding method. Some studies included only breastfed infants, whereas others were inclusive of all feeding methods. Savino et al. (2017) is the only study of exclusively formula-fed infants in this review, and Partty and Isolauri (2012) did not address feeding methods in their report. Articles were excluded if they did not study humans, if they did not study infants less than 5 months of age with colic, and if they did not sequence the GI microbiome. Thus, studies of skin, oral, vaginal, and maternal microbiome studies were excluded. Articles that focused on other outcomes of colic such as reduced crying time or focused on etiological theories of colic without also including the GI microbiome were excluded. Reviews and clinical guidelines were excluded from the scoping review to focus on original, primary evidence. Thirty-eight articles met criteria for full-text review.

FIGURE 1. PRISMA DIAGRAM

Results

After full-text review, 21 meeting inclusion criteria comprise this scoping review, including 2 articles identified from the references. See Table 1. The primary evidence in this review includes randomized control trials (n = 12), prospective cohort studies (n = 4), case-control studies (n = 4), and cross-sectional studies (n = 1). Dates of publication were not limited, to cover the evolution of knowledge relating to the infant GI microbiome in colic. Articles' publication dates ranged from 2004 to 2021.

Table 1. Studies Included in the Review

Methods of Microbiome Detection

Microbiome technologies have advanced in specificity over the 18 years of literature from this scoping review. Earlier studies with less advanced technologies, such as fluorescence in situ hybridization and stool cultures, were included to show the evolution and scope of knowledge about the GI microbiome and colic (Mentula et al., 2008; Partty et al., 2012; Savino et al., 2004). The more recent studies in this review used 16s rRNA sequencing and real-time quantitative polymerase chain reaction (Korpela et al., 2020; Nocerino et al., 2020; Savino et al., 2020). Level of bacterial taxa reported varied from phylum to species level, which may relate to the specificity capabilities of the technology used in each study. The genus Bifidobacterium is known for anti-inflammatory effects, but some studies indicate the species B. breve to increase crying and inflammation (Partty & Isolauri, 2012; Partty et al., 2012; Partty et al., 2017). This example demonstrates how greater taxonomic specificity may explain discrepancies between study findings and may lead to better evidence for identifying the etiology and treatment of colic.

Gastrointestinal Microbiome Composition at Colic Onset

The GI microbiome of infants at colic onset must be compared with infants without colic to understand the relationship between the microbiome and colic. Many studies identified higher colonization of Proteobacteria, like Klebsiella and Escherichia, beginning as early as 2 weeks of age and continuing through colic diagnosis in infants with colic when compared with their counterparts (de Weerth, Fuentes, Puylaert, et al., 2013; Nocerino et al., 2020; Savino et al., 2018). First-pass meconium in infants who later developed colic was found to have lower abundance of the phylum Firmicutes and the genus Lactobacillus demonstrating that colonization patterns leading to colic may be present at birth (Korpela et al., 2020). Reductions in crying and fuss time have been associated with increased colonization of Bacteroidetes, Actinobacteria, like Bifidobacterium, and Firmicutes, like Lactobacillus (de Weerth, Fuentes, Puylaert, et al., 2013; Nocerino et al., 2020; Partty & Isolauri, 2012; Rhoads et al., 2018; Roos et al., 2013). B. breve has been associated with increased crying and fussiness in colic, and elevated proinflammatory marker levels (Partty & Isolauri, 2012; Partty et al., 2012; Partty et al., 2017).

This dysbiosis may lead to increased GI inflammation and affect future immune system function (Dubois & Gregory, 2016; Partty et al., 2017; Rhoads et al., 2018; Savino et al., 2020). More research is needed with higher taxonomic specificity to better define the microbiome of infants with and without colic and better understand its influence on colic development and symptoms.

Gastrointestinal Microbiome Composition at Colic Resolution

Infants with colic have a different microbiome at onset than infants without colic. To better describe the evolution of colic, it is important to understand the microbiome as colic resolves. De Weerth, Fuentes, Puylaert, et al. (2013) investigated the microbiome at colic resolution without probiotic intervention during the first 100 days of life and found that Proteobacteria were significantly increased, and Bifidobacterium and Lactobacillus were significantly decreased in infants with colic compared with noncolic infants. These differences were no longer detectable at age of colic resolution. However, these researchers do not state whether the change in microbiome composition correlated with the reduced crying of colic resolution.

Studies using probiotic interventions used different probiotic strains and mixtures, including species from Lactobacilli, Bifidobacteria, Streptococcus, and Propionibacterium (Baldassarre et al., 2018; Fatheree et al., 2017; Mentula et al., 2008; Nation et al., 2017; Nocerino et al., 2020; Partty & Isolauri, 2012; Partty et al., 2012; Roos et al., 2013; Savino et al., 2010; Savino et al., 2018; Savino et al., 2020). Safety, effects on colic symptoms, and the microbiome were assessed. Although adding bacteria to the GI system through probiotics may have affected microbiome colonization, the crying and colic symptom reductions associated with these microbiome changes may be important to understand how the microbiome affects colic onset and resolution.

Probiotic studies found that reductions in crying with colic were associated with an increase in Lactobacillus and Bifidobacterium (Nocerino et al., 2020; Savino et al., 2018; Savino et al., 2020). Baldassarre et al. (2018) found that though Lactobacillus and Bifidobacterium remained relatively the same in the probiotic and placebo groups of breastfed babies with colic, there was a higher rate of crying reduction in the probiotic group. Partty et al. (2012) investigated crying and fuss time rather than colic specifically but noted that over the first 3 months of life, as Bifidobacterium increased, crying and fuss time decreased. Approximately half of the participants received the probiotic intervention during the study, but the researchers noted no difference in total crying in these infants (Partty et al., 2012). Bacteroidetes produced conflicting results; Roos et al. (2013) found that increased relative abundance correlated with a reduction in crying, whereas Fatheree et al. (2017) found that Bacteroides decreased as colic resolved. These different results may be due to sample size, as Fatheree et al. noted their small sample size may have affected results but may derive from the differences between the phylum and genus taxa. Savino et al. (2010) also found a reduction in E. coli that correlated with reduced crying time in the probiotic arm of their study of breastfed infants with colic. Overall, these findings suggest the microbiome at colic resolution resembles the noncolic microbiome by increased Bifidobacterium and Lactobacillus and decreased E. coli. However, more research is needed to understand the microbiome at colic self-resolution and the involvement of Proteobacteria at resolution.

Probiotic studies demonstrated safety of use; however, only a few revealed an improvement in clinical symptoms. If the probiotic did not demonstrate an effect, the researchers often noted that crying reduced in all groups throughout the study (Fatheree et al., 2017; Mentula et al., 2008; Nation et al., 2017).

Geography and feeding methods likely influence microbiome colonization. Nation et al. (2017), in a study conducted in Australia, confirmed this notion and noted different results from multiple studies in other countries, including Savino et al. (2010). Savino et al. (2018) conducted another Italian probiotic study that further supported their earlier (Savino et al., 2010) findings. Variations in feeding type and method are associated with variations in GI microbiome colonization (Dubois & Gregory, 2016). Breastfed infants receive bacteria through the breastmilk microbiome and human milk oligosaccharides that nourish the bacteria in the human gut (de Weerth, Fuentes, & de Vos, 2013). Formula-fed infants have different GI microbiomes than their exclusively breastfed peers (Forbes et al., 2018; Mueller et al., 2015). Geography and feeding methods may explain the discrepancies between studies of different probiotics in infants with colic.

Discussion and Future Implications

Colic is associated with microbiome changes. The dysbiosis associated with colic may lead to increased GI inflammatory biomarkers and GI inflammation. The connection between the microbiome, inflammatory biomarkers, and GI inflammation may help to explain GI system involvement in the etiology of colic. Fecal calprotectin and proinflammatory chemokines have been used to investigate the presence and role of GI inflammation in colic (Nocerino et al., 2020; Partty et al., 2017; Savino et al., 2020). Researchers are investigating connections between microbial colonization and the presence of inflammatory biomarkers. Lactobacillus and Bifidobacterium colonization has been associated with decreases in fecal calprotectin, indicating a protective effect against GI inflammation (Nocerino et al., 2020; Savino et al., 2020). Increased colonization with Proteobacteria may increase gas production due to fermentation of carbohydrates and proteins by the Proteobacteria. Increases in Bifidobacteria or Lactobacilli inhibit the growth of Proteobacteria that would inhibit the fermentation, gas production, and proinflammatory biomarker production associated with Proteobacteria colonization in colic (Nocerino et al., 2020; Rhoads et al., 2018). These studies highlight that the microbiome composition of infants with colic may affect GI inflammatory markers and GI inflammation. Possible connection between how the microbiome and GI inflammatory markers relate needs further investigation, but in the future, may provide a way to identify colic development. By understanding the connection between the microbiome and inflammatory biomarkers, pediatricians and nurse practitioners may be able to choose a targeted probiotic approach to preventing or treating colic.

Population Differences

Nutrition is known to affect the GI microbiome, and early infant feeding affects this early colonization. Colic dysbiosis was supported both in breastfed and formula-fed infants. In the nonintervention studies including breastfeeding and formula-feeding, infants with colic were found to have differing microbiomes than their noncolic counterparts regardless of feeding method (de Weerth, Fuentes, Puylaert, et al., 2013; Korpela et al., 2020; Rhoads et al., 2018; Savino et al., 2017). Australian probiotic studies of breastfed and formula-fed infants did not find a difference in microbiome colonization or improvement in crying time between intervention and control groups (Nation et al., 2017; Sung et al., 2014). The difference in findings may be due to geography or feeding methods when compared with the probiotic benefits seen in Italian probiotic studies of exclusively breastfed infants (Savino et al., 2010; Savino et al., 2018). These examples demonstrate how population differences involving feeding methods and geography may influence the choice of probiotic therapies.

Conclusions

The difference between the microbiome composition of infants with colic compared with their noncolic counterparts has been well established. The dysbiosis associated with colic is marked by increased colonization of proinflammatory Proteobacteria and decreased colonization of anti-inflammatory Firmicutes, especially Lactobacillus, and Actinobacteria, Bifidobacterium. Newer studies are beginning to associate proinflammatory Proteobacteria and anti-inflammatory Firmicutes and Actinobacteria with inflammatory biomarkers. These findings provide insights into how GI microbiome dysbiosis may manifest as symptoms of colic. More research into colic dysbiosis and GI inflammation may improve the understanding of colic's etiology and guide treatment development.

Data are limited on the microbiome composition at colic resolution. There is some indication that the infant microbiome at colic resolution resembles infants without colic, however, many of these studies used a probiotic intervention that likely influenced results. There is a gap in the literature concerning microbiome composition at colic self-resolution, especially without the influence of probiotic treatments. It is important to better understand how the microbiome contributes to colic resolution. Future research is needed to fill this gap without the influence of probiotic treatments. By better understanding how the microbiome affects colic onset and resolution, future researchers and clinicians can intervene to better prevent and treat colic. By preventing and treating colic, the stress caused by colic on the infant and their family can be reduced.

CLINICAL IMPLICATIONS

* Pediatricians and nurse practitioners may be able to choose a targeted probiotic approach to preventing or treating colic by understanding the connection between the microbiome and inflammatory biomarkers.

* The relationship between the GI microbiome and GI inflammatory markers needs further investigation and may provide a way for pediatricians and nurse practitioners to identify colic development.

* Increasing Lactobacillus or Bifidobacterium colonization through probiotics may have anti-inflammatory effects that reduce colic crying.

* Increased presence of coliforms, gas-producing bacteria, may relate to the gassy symptoms in colic.

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References