Reversible aberrancies in gut microbiome of moderate and late preterm infants: results from a randomized, controlled trial.

The aim of this study was to obtain insight into the composition and function of the deviant gut microbiome throughout infancy in children born moderately and late preterm and their response to microbiome modulation. We characterized the longitudinal development of the gut microbiome from birth to the age of 12 months by metagenomic sequencing in 43 moderate and late preterm children participating in a randomized, controlled trial (ClinicalTrials.gov/no.NCT00167700) assessing the impact of a probiotic (Lactobacillus rhamnosus GG, ATCC 53,103, currently Lacticaseibacillus rhamnosus GG) and a prebiotic (galacto-oligosaccharide and polydextrose mixture, 1:1) intervention as compared to a placebo administered from 3 to 60 days of life. In addition, 9 full-term, vaginally delivered, breast-fed infants, who remained healthy long-term were included as references. Significant differences in taxonomy, but not in functional potential, were found when comparing the gut microbiome composition of preterm and full-term infants during the first month of life. However, the gut microbiome of preterm infants resembled that of full-term infants by 6 months age. Probiotic and prebiotic treatments were found to mitigate the shift in the microbiome of preterm infants by accelerating Bifidobacteria-dominated gut microbiome in beta diversity analysis. This study provides intriguing information regarding the establishment of the gut microbiome in children born moderately and late preterm, representing the majority of children born preterm. Specific pro- and prebiotics may reverse the proinflammatory gut microbiome composition during the vulnerable period, when the microbiome is low in resilience and susceptible to environmental exposure and simultaneously promotes immunological and metabolic maturation.

Probiotics on Pediatric Functional Gastrointestinal Disorders.

The potential association between gut microbiota perturbations and childhood functional gastrointestinal disturbances opens interesting therapeutic and preventive possibilities with probiotics. The aim of this review was to evaluate current evidence on the efficacy of probiotics for the management of pediatric functional abdominal pain disorders, functional constipation and infantile colic. Thus far, no single strain, combination of strains or synbiotics can be recommended for the management of irritable bowel syndrome, functional abdominal pain or functional constipation in children. However, Lactobacillus reuteri DSM 17938 may be considered for the management of breastfed colic infants, while data on other probiotic strains, probiotic mixtures or synbiotics are limited in infantile colic.

Maternal Intrapartum Antibiotic Administration and Infantile Colic: Is there a Connection?

BACKGROUND: The aetiology of infantile colic remains unknown. However, altered gut microbiota composition has been reported in children with the disorder. OBJECTIVE: The objective of this study was to determine the associations between perinatal factors potentially affecting gut colonization and infantile colic. METHODS: Altogether 48 infants with colic and 29 controls were selected from 2 ongoing clinical studies. Infants with and without colic were comparable with regard to their background characteristics. RESULTS: A significant difference was detected in intrapartum antibiotic use and breastfeeding rates between infants with and without colic. The association between exposure to intrapartum antibiotics and infantile colic remained statistically significant after adjusting for potential confounding factors. CONCLUSIONS: Since intrapartum antibiotic exposure may have an effect on early gut colonization, our finding is consistent with the association between aberrant early gut microbiota composition and development of colic. Antibiotic-exposed neonates may represent a novel target group for preventive intervention studies.

Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis.

CONTEXT: Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective. OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type. DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries. STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days. DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models. RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] -25.4 [95% confidence interval (CI): -47.3 to -3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants. LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic. CONCLUSIONS: L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.

Infantile Colic Is Associated With Low-grade Systemic Inflammation.

OBJECTIVES: Dysbiosis, an imbalance in the taxonomic composition of the gut bacteria occurring during the critical stages of development, induces lasting shifts in the immunological and metabolic phenotype if accompanied by an inflammatory response. Because altered gut microbiota and successful treatment with probiotics have both been demonstrated in cases of colic, we hypothesized here that infants with colic might have low-grade inflammation. METHODS: In 28 infants with colic and in 12 healthy controls at the age of 1 month, we measured the following serum immunological biomarkers: cytokines interleukin 1ß (IL-1ß); IL-6; IL-10; tumor necrosis factor α; interferon γ (IFN-γ); chemokines IL-8; monocyte chemotactic protein-1 (MCP-1); macrophage inflammatory protein 1ß (MIP-1ß) and chemokine (C-X-C motif) ligand 16; and intestinal fatty acid-binding protein, a biomarker of enterocyte damage and zonulin, a biomarker of intestinal permeability. In addition, intestinal microbiota composition was correlated with immunological biomarkers. RESULTS: Infants with colic had increased concentrations of IL-8, MCP-1, and MIP-1ß in serum as compared with healthy children. All the other immunological biomarkers were comparable between the groups. Fecal levels of Clostridium leptum correlated negatively with the proinflammatory markers MCP-1 (r = -0.44, P = 0.02), MIP-1ß (r = -0.43, P = 0.02), and tumor necrosis factor α (r = -0.38, P = 0.04). In addition, C coccoides group levels correlated negatively with MCP-1 (r = -0.43, P = 0.02) and Bifidobacterium breve levels positively with chemokine (C-X-C motif) ligand 16 (r = 0.38, P = 0.04). CONCLUSIONS: In addition to gut microbiota alterations, colic in infants is associated with low-grade systemic inflammation. Specific bacterial species beyond conventional probiotics may have anti-inflammatory properties that may help to modulate microbiota and alleviate colic-related inflammation.

Probiotic Lactobacillus rhamnosus GG therapy and microbiological programming in infantile colic: a randomized, controlled trial.

BACKGROUND: Probiotic Lactobacillus reuteri and reduced allergen load may lessen the daily crying of colic infants, but the role of Lactobacillus rhamnosus GG (LGG) has remained obscure. METHODS: Infants with colic (n = 30) were enrolled during the first 6 wk of life. All families received behavioral support and allergen avoidance diet: breastfeeding mothers followed cow's milk elimination diet and formula-fed infants received extensively hydrolyzed casein formula. The randomized, double-blind intervention employed of LGG 4.5 × 10(9) cfu/d or placebo for a 4-wk study period. Daily crying was recorded by diaries and parental interviews. Fecal calprotectin and gut microbiota composition by quantitative PCR were evaluated before and after the intervention. RESULTS: Daily crying time was comparable between the probiotic (173 min) and the placebo group (174 min; P = 0.99) at the end of the intervention according to the parental diary. However, parents reported a decrease of 68% (95% confidence interval (CI): 58-78) in daily crying in the probiotic and 49% (95% CI: 32-66) in the placebo group (P = 0.05). CONCLUSION: LGG in infants treated in tandem with behavioral support and a cow's milk elimination diet did not provide additional treatment effect for diary-verified colic crying although parental report of crying suggested the probiotic intervention effective.

A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial.

BACKGROUND: Recent experimental evidence suggests that gut microbiota may alter function within the nervous system providing new insight on the mechanism of neuropsychiatric disorders. METHODS: Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria. RESULTS: At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03. CONCLUSION: Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.

Lactobacillus reuteri DSM 17938 for managing infant colic: protocol for an individual participant data meta-analysis.

INTRODUCTION: Infant colic, or excessive crying of unknown cause in infants less than 3 months old, is common and burdensome. Its aetiology is undetermined, and consensus on its management is still lacking. Recent studies suggest a possible link between infant colic and gut microbiota, indicating probiotics to be a promising treatment. However, only a few strains have been tested, and results from randomised controlled trials are conflicting. It is important to clarify whether probiotics are effective for treating infant colic in general, and to identify whether certain subgroups of infants with colic would benefit from particular strains of probiotics. METHODS AND ANALYSIS: Through an individual participant data meta-analysis (IPDMA), we aim to identify whether the probiotic Lactobacillus reuteri DSM 17938 is effective in the management of infant colic, and to clarify whether its effects differ according to feeding method (breast vs formula vs combined), proton pump inhibitor exposure, and antibiotic exposure. The primary outcomes are infant crying duration and treatment success (at least 50% reduction in crying time from baseline) at 21 days postintervention. Individual participant data from all studies will be modelled simultaneously in multilevel generalised linear mixed-effects regression models to account for the nesting of participants within studies. Subgroup analyses of participant-level and intervention-level characteristics will be undertaken on the primary outcomes to assess if the intervention effect differs between certain groups of infants. ETHICS AND DISSEMINATION: Approved by the Royal Children's Hospital Human Research Ethics Committee (HREC 34081). Results will be reported in a peer-reviewed journal in 2015. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014013210.

Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the impact of early prebiotic and probiotic intervention on preterm infants' well-being, crying, growth, and microbiological programming. STUDY DESIGN: Ninety-four preterm infants (gestational age 32-36 weeks and birth weight >1500 g) randomized to receive prebiotics (mixture of galacto-oligosaccharide and polydextrose 1:1), probiotics (Lactobacillus rhamnosus GG), or placebo during the first 2 months of life were followed up for 1 year. Infants were categorized based on the extent of crying and irritability during the first 2 months of life, and their gut microbiota was investigated by fluorescence in situ hybridization (n = 66) and quantitative polymerase chain reaction (n = 63). RESULTS: A total of 27 of 94 infants (29%) infants were classified as excessive criers, significantly less frequently in the prebiotic and the probiotic groups than in the placebo group (19% vs 19% vs 47%, respectively; P = .02). The placebo group had a higher percentage of Clostridium histolyticum group bacteria in their stools than did the probiotic group (13.9% vs 8.9%, respectively; P = .05). There were no adverse events related to either supplementation. CONCLUSIONS: Early prebiotic and probiotic supplementation may alleviate symptoms associated with crying and fussing in preterm infants. This original finding may offer new therapeutic and preventive measures for this common disturbance in early life.

Compositional development of Bifidobacterium and Lactobacillus microbiota is linked with crying and fussing in early infancy.

OBJECTIVES: Our aim was to establish whether there is an interconnection between the compositional development of the gut microbiota and the amount of fussing and crying in early infancy. METHODS: Behavioral patterns of 89 infants during the 7(th) and 12(th) week of life were recorded in parental diaries. Total distress was defined as the sum of daily amounts of crying and fussing. Infants' gut microbiota profiles were investigated by several molecular assays during the first six months of life. RESULTS: The median (range) duration of total distress among the infants was 106 (0-478) minutes a day during the 7(th) and 58 (0-448) minutes a day during the 12(th) week. The proportion of Bifidobacterium counts to total bacterial counts was inversely associated with the amount of crying and fussing during the first 3 months of life (p = 0.03), although the number of Bifidobacterium breve was positively associated with total distress (p = 0.02). The frequency of Lactobacillus spp. at the age of 3 weeks was inversely associated with total infant distress during the 7(th) week of life (p = 0.02). CONCLUSIONS: Bifidobacterium and Lactobacillus appear to protect against crying and fussing. Identification of specific strains with optimal protective properties would benefit at-risk infants.