Effect of Lactobacillus reuteri NCIMB 30351 drops on symptoms of infantile functional gastrointestinal disorders and gut microbiota in early infants: Results from a randomized, placebo-controlled clinical trial.

Infantile functional gastrointestinal disorders, such as colic, constipation, diarrhea, and gastroesophageal reflux (regurgitation), often occur in early infancy and, representing one of the causes of significant parental anxiety, lead to a significant strain on the healthcare resources. In this study, we aimed to evaluate the effects of Lactobacillus reuteri drops (L. reuteri NCIMB 30351) on the symptoms of infantile colic, constipation, diarrhea, and gastroesophageal reflux, as well as on the levels of intestinal microbiota in full-term newborns during the first months of life. A randomized, placebo-controlled, single-masked (blinded), post-marketing clinical study was conducted in two clinical units-Children's City Clinical Hospital of Moscow and Medical Center "St. Andrew's Hospitals-NEBOLIT" from March 2020 to May 2022 in 90 infants aged from 1 to 4 months (mean age (± SD) 12.3 ± 5.09 weeks; 53.3% females, 46.7% males). Patients with colic, regurgitation (single symptom or combination of several symptoms), and constipation or diarrhea were randomly allocated in two parallel arms to receive either 5 drops (2 × 108 colony forming unit) of L. reuteri NCIMB 30351 (n = 60) or masked placebo (n = 30) for 25 consecutive days. Two treatment arms had equal numbers of patients with constipation and diarrhea (n = 30 each). Daily crying times and their duration, evacuations, and regurgitations were recorded in a structured diary. The levels of gut microbiota were analyzed by deep sequencing of bacterial 16S rRNA gene. Infants with colic receiving supplementary L. reuteri NCIMB 30351 for 25 days had significant reduction in the numbers of colic (change from baseline - 6.3 (7.34) vs - 3.0 (7.29) in placebo, P < 0.05) and numbers of crying cases and mean duration of crying (decrease from baseline - 144 (70.7) minutes, lower in the diarrhea subgroup than in constipation infants, compared with - 80 (58.9) in placebo, P < 0.0001), as well as regurgitation numbers (decreased by - 4.8 (2.49) with L. reuteri vs - 3 (7.74) with placebo). We also observed increased numbers of evacuations in infants with constipation (L. reuteri 2.2 (2.4) vs 0.9 (1.06) in placebo, P < 0.05). There was a remarkable reduction of evacuations in infants with diarrhea, while not statistically significant. The analysis of bacterial 16S rRNA gene in the collected samples showed that L. reuteri positively influences the proportions of prevalent species, while it negatively affects both conditionally pathogenic and commensal microbes. Additional in vitro test for formation of Clostridium colonies in the presence of the probiotic demonstrated that L. reuteri effectively inhibits the growth of pathogenic Clostridium species. No adverse events were reported in this study.   Conclusion: The uptake of L. reuteri NCIMB 30351 leads to a significant reduction in the number of regurgitations, feeding-induced constipations, and diarrhea as well as mean daily numbers of crying and crying duration in infants during the first months of life. Our results suggest that L. reuteri NCIMB 30351 represents a safe and effective treatment for colic in newborns.  Trial registration: ClinicalTrials.gov : NCT04262648. What is Known: • Infantile functional gastrointestinal disorders, such as colic, constipation, diarrhea, and gastroesophageal reflux (regurgitation), often occur in early infancy and, represent one of the causes of significant parental anxiety. • A number of studies have shown that both the composition and diversity of the intestinal microbiota play important roles in the development and function of the gastrointestinal tract. What is New: • The uptake of L. reuteri NCIMB 30351 leads to a significant reduction in the number of regurgitations, feeding-induced constipations, and diarrhea as well as mean daily numbers of crying and crying duration in infants during the first months of life. • L. reuteri positively influences the proportions of prevalent species, while it negatively affects both conditionally pathogenic and commensal microbes in gut microbiota.

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

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 a search of the literature in Pubmed and Medline 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 reductions in colic episodes and crying time were 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 a placebo, in children with functional abdominal pain or irritable bowel syndrome, a significant reduction in pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, and in one study on corn fiber cookies, partial hydrolyzed guar gum, a specific multiple herbal extract (STW-5), or vitamin D supplementation. To date, there is moderate-certainty evidence with a weak grade of recommendation on Lactobacillus reuteri DSM 17938 (108 CFU/day) in reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 × 109 CFU twice daily) in reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove the 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.

Microbiota intestinal y cólicos infantiles: ¿hay lugar para los prebióticos, probióticos y posbióticos? / Gut Microbiota and Infant Colic: is there a Place for Prebiotics, Probiotics, and Postbiotics?

El consumo de probióticos, prebióticos y posbióticos, o su combinación, puede contribuir a mantener una microbiota intestinal saludable ya que permite la regulación de su disbiosis en el caso de algunas enfermedades o trastornos, principalmente en los trastornos gastrointestinales funcionales (TGIF). El microbioma intestinal es protagonista esencial en la fisiopatología de los TGIF a través de sus funciones metabólicas y nutricionales, el mantenimiento de la integridad de la mucosa intestinal y la regulación de la respuesta inmunitaria. Las investigaciones realizadas hasta la fecha indican que los probióticos, prebióticos y posbióticos pueden tener efectos inmunomoduladores directos y clínicamente relevantes. Existen pruebas del uso de esta familia de bióticos en individuos sanos para mejorar la salud general y aliviar los síntomas en una serie de enfermedades como los cólicos infantiles. La colonización y establecimiento de la microbiota comienza en el momento del nacimiento; los primeros 2-3 años de vida son fundamentales para el desarrollo de una comunidad microbiana abundante y diversa. Diversos estudios científicos realizados mediante técnicas tradicionales dependientes de cultivo y más recientemente por técnicas moleculares han observado diferencias en las poblaciones bacterianas de bebés sanos y aquellos que sufren TGIF, estos últimos caracterizados por un aumento de especies patógenas y una menor población de bifidobacterias y lactobacilos, en comparación con los primeros. En tal contexto, se considera que la microbiota intestinal como protagonista en el desarrollo de esos trastornos, entre ellos los cólicos infantiles, a través de sus funciones metabólicas, nutricionales, de mantenimiento de la integridad de la mucosa intestinal y regulación de la respuesta inmunitaria. Esto ha abierto la puerta al estudio de la utilización de prebióticos, probióticos y posbióticos en el tratamiento y/o prevención de los TGIF infantiles. El parto vaginal y de término así como la lactancia son fundamentales en la constitución de una microbiota saludable. Como herramientas de apoyo, existen estudios de eficacia que sustentan la administración de esta familia de bióticos, principalmente en los casos en que la lactancia no sea posible o esté limitada. (AU)

The consumption of probiotics, prebiotics, and postbiotics, or a combination of them, can contribute to maintaining a healthy intestinal microbiota as it allows the regulation of its dysbiosis in the case of some diseases or disorders, mainly in functional gastrointestinal disorders (FGIDs). The gut microbiome is an essential player in the pathophysiology of FGIDs through its metabolic and nutritional functions, the maintenance of intestinal mucosal integrity, and the regulation of the immune response. Research results thus far indicate that probiotics, prebiotics, and postbiotics may have direct and clinically relevant immunomodulatory effects. There is evidence regarding the prescription of this family of biotics in healthy individuals to improve overall health and alleviate symptoms in many conditions like infantile colic. The colonization and microbiota establishment begins at birth; the first 2-3 years of life are critical for developing an abundant and diverse microbial community. Several scientific studies performed by traditional culture-dependent techniques and more recently by molecular techniques have observed differences in the bacterial populations of healthy infants and those suffering from FGIDs, the latter characterized by an increase in pathogenic species and a lower population of bifidobacteria and lactobacilli, compared to the former. In this context, the intestinal microbiota plays a leading role in the onset of these disorders, including infantile colic, through its metabolic and nutritional functions, maintenance of the integrity of the intestinal mucosa, and regulation of the immune response. That has opened the door to the study of prebiotics, probiotics, and postbiotics usage in the treatment and or prevention of infantile FGIDs. Vaginal and term delivery and breastfeeding are fundamental in the constitution of a healthy microbiota. As supportive tools, there are efficacy studies that support the administration of this family of biotics, mainly in cases where lactation is not possible or is limited.

Infant microbiota in colic: predictive associations with problem crying and subsequent child behavior.

Infant colic is a condition of unknown cause which can result in carer distress and attachment difficulties. Recent studies have implicated the gut microbiota in infant colic, and certain probiotics have demonstrated possible efficacy. We aim to investigate whether the intestinal microbiota composition in infants with colic is associated with cry/fuss time at baseline, persistence of cry/fuss at 4-week follow-up, or child behavior at 2 years of age. Fecal samples from infants with colic (n = 118, 53% male) were analyzed using 16S rRNA sequencing. After examining the alpha and beta diversity of the clinical samples, we performed a differential abundance analysis of the 16S data to look for taxa that associate with baseline and future behavior, while adjusting for potential confounding variables. In addition, we used random forest classifiers to evaluate how well baseline gut microbiota can predict future crying time. Alpha diversity of the fecal microbiota was strongly influenced by birth mode, feed type, and child gender, but did not significantly associate with crying or behavioral outcomes. Several taxa within the microbiota (including Bifidobacterium, Clostridium, Lactobacillus, and Klebsiella) associate with colic severity, and the baseline microbiota composition can predict further crying at 4 weeks with up to 65% accuracy. The combination of machine learning findings with associative relationships demonstrates the potential prognostic utility of the infant fecal microbiota in predicting subsequent infant crying problems.

Efficacy of a partially hydrolysed formula, with reduced lactose content and with Lactobacillus reuteri DSM 17938 in infant colic: A double blind, randomised clinical trial.

BACKGROUND & AIMS: We aimed to compare the efficacy of a partially hydrolysed formula (pHF) with reduced lactose content and Lactobacillus reuteri DSM 17938 (L. reuteri) with a standard formula in infant colic (IC). METHODS: We performed a double blind, parallel-group randomized active-controlled. Inclusion criteria were: exclusively formula fed, full term infants, aged <4 months, diagnosis of IC. All the enrolled infants were randomized to receive either pHF with reduced lactose content and L. reuteri (Group A) or standard formula (Group B). The treatment duration was 4 weeks and children were followed-up to 8 weeks. The primary outcome was the mean infant crying duration at 28 days. RESULTS: Two-hundred-forty-one children were randomized to the treatments' group (Group A = 124; Group B = 117). Mean daily crying time at 28th day was significantly lower in Group B when compared to Group A [104.7 (87-122.4) versus 146.4 min (129.2-163.7), treatment effect -41.8 (95% C.I.: -66.5 to -17.1), p = 0.001]. No significant adverse event was reported in both groups. CONCLUSIONS: Standard formula showed a lower overall crying time respect to the intervention formula (ClinicalTrials.govNCT02813772).

Efficacy of Bifidobacterium breve CECT7263 for infantile colic treatment: an open-label, parallel, randomised, controlled trial.

Infantile colic is a prevalent condition characterised by excessive crying with no effective treatment available. We aimed to evaluate the efficacy of Bifidobacterium breve CECT7263 and a combination of this and Lactobacillus fermentum CECT5716 versus simethicone in reducing the daily time spent crying in colicky infants. A multicentre randomised, open-label, parallel, controlled trial of 28 days was performed in 150 infants who were diagnosed with colic according to the Rome III criteria and who randomly received simethicone (80 mg/day; Simethicone group), B. breve CECT7263 (2×108 cfu/day, Bb group), or a combination of L. fermentum CECT5716 and B. breve CECT7263 (1×108 cfu/day per strain, Bb+Lf group). The main outcomes were minutes of crying per day and the percentage of reduction in daily crying from baseline. Data were analysed per intention to treat. All treatments significantly decreased the daily crying time at the end of the intervention (P-time <0.001). However, the infants in the Bb group had significantly decreased crying time from the first week of the study (P<0.05), whereas the Bb+Lf group and the simethicone group had significantly decreased crying time from the second week (P<0.05). The percentage of reduction in the minutes of crying from baseline in the Bb group was significantly higher than that in the Simethicone group every week of the intervention (-40.3 vs -27.6% at 1-week; -59.2 vs -43.2% at 2-weeks; -64.5 vs -53.5% at 3-week and -68.5 vs -59.5% at 4-weeks, P<0.05). Additionally, in the Bb group, infants had better night sleep, and parents reported a more positive mood at the end of the intervention. All the products used in the study were safe and well tolerated. In conclusion, the breastmilk-isolated probiotic strain B. breve CECT7263 is a safe and effective treatment for infantile colic, presenting an earlier and more robust effect than the reference prescribed drug, simethicone.

The influence of the gastrointestinal microbiome on infant colic.

INTRODUCTION: Although infantile colic is relatively frequent, its pathophysiology is not yet understood. The aim of this paper is to provide a better understanding of the link between infantile colic and the gastrointestinal microbiome. AREAS COVERED: The gastro-intestinal microbiome may already start to develop in the womb and grows exponentially immediately after birth. Factors influencing the microbiome can cause dysbiosis and precipitate symptoms of colic through several mechanisms such as increased gas production and low grade gut inflammation. Other possible factors are immaturity of the enterohepatic bile acid cycle and administration of antibiotics and other medications during the perinatal period. An effective treatment for all colicky infants has yet to be discovered, but the probiotic Lactobacillus reuteri DSM17938 was shown to be effective in breastfed infants with colic. The scientific databases 'Pubmed' and 'Google scholar' were searched from inception until 02/2020. Relevant articles were selected based on the abstract. EXPERT OPINION: Recent literature confirmed that the composition of the gastrointestinal microbiome is associated with the development of infantile colic. It can be speculated that full sequencing and bioinformatics analysis to identify the microbiome down to the species level may provide answers to the etiology and management of infantile colic.

Microbiome of the first stool after birth and infantile colic.

BACKGROUND: Recent studies have shown a diverse microbiome in the first stool after birth. The clinical significance of the microbiome of the first stool is not known. Infantile colic has earlier been associated with the composition of the intestinal microbiome. METHODS: We set out to test whether the microbiome of the first stool is associated with subsequent infantile colic in a prospective, population-based cohort study of 212 consecutive newborn infants. We used next-generation sequencing of the bacterial 16S rRNA gene. RESULTS: The newborns who later developed infantile colic (n = 19) had a lower relative abundance of the genus Lactobacillus and the phylum Firmicutes in the first stool than those who remained healthy (n = 139). By using all microbiome data, random forest algorithm classified newborn with subsequent colic and those who remained healthy with area under the curve of 0.66 (SD 0.03) as compared to that of shuffled samples (P value <0.001). CONCLUSIONS: In this prospective, population-based study, the microbiome of the first-pass meconium was associated with subsequent infantile colic. Our results suggest that the pathogenesis of infantile colic is closely related to the intestinal microbiome at birth.

Microvesicles from Lactobacillus reuteri (DSM-17938) completely reproduce modulation of gut motility by bacteria in mice.

Microvesicles are small lipid, bilayer structures (20-400 nm in diameter) secreted by bacteria, fungi, archaea and parasites involved in inter-bacterial communication and host-pathogen interactions. Lactobacillus reuteri DSM-17938 (DSM) has been shown to have clinical efficacy in the treatment of infantile colic, diarrhea and constipation. We have shown previously that luminal administration to the mouse gut promotes reduction of jejunal motility but increases that in the colon. The production of microvesicles by DSM has been characterized, but the effect of these microvesicles on gastrointestinal motility has yet to be evaluated. To investigate a potential mechanism for the effects of DSM on the intestine, the bacteria and its products have here been tested for changes in velocity, frequency, and amplitude of contractions in intact segments of jejunum and colon excised from mice. The effect of the parent bacteria (DSM) was compared to the conditioned media in which it was grown, and the microvesicles it produced. The media used to culture the bacteria (broth) was tested as a negative control and the conditioned medium was tested after the microvesicles had been removed. DSM, conditioned medium, and the microvesicles all produced comparable effects in both the jejunum and the colon. The treatments individually decreased the velocity and frequency of propagating contractile cluster contractions in the jejunum and increased them in the colon to a similar degree. The broth control had little effect in both tissues. Removal of the microvesicles from the conditioned medium almost completely eradicated their effect on motility in both tissues. These results show that the microvesicles from DSM alone can completely reproduce the effects of the whole bacteria on gut motility. Furthermore, they suggest a new approach to the formulation of orally active bacterial therapeutics and offer a novel way to begin to identify the active bacterial components.

The therapeutic efficacy of Bifidobacterium animalis subsp. lactis BB-12® in infant colic: A randomised, double blind, placebo-controlled trial.

BACKGROUND: The pathogenesis of infant colic is poorly defined. Gut microbiota seems to be involved, supporting the potential therapeutic role of probiotics. AIMS: To assess the rate of infants with a reduction of ≥50% of mean daily crying duration after 28 days of intervention with the probiotic Bifidobacterium animalis subsp. lactis BB-12® (BB-12). Secondary outcomes were daily number of crying episodes, sleeping time, number of bowel movements and stool consistency. METHODS: Randomized controlled trial (RCT) on otherwise healthy exclusively breastfed infants with infant colic randomly allocated to receive BB-12 (1 × 109  CFU/day) or placebo for 28 days. Gut microbiota structure and butyrate, beta-defensin-2 (HBD-2), cathelicidin (LL-37), secretory IgA (sIgA) and faecal calprotectin levels were assessed. RESULTS: Eighty infants were randomised, 40/group. The rate of infants with reduction of ≥50% of mean daily crying duration was higher in infants treated with BB-12, starting from the end of 2nd week. No infant relapsed when treatment was stopped. The mean number of crying episodes decreased in both groups, but with a higher effect in BB-12 group (-4.7 ± 3.4 vs -2.3 ± 2.2, P < 0.05). Mean daily stool frequency decreased in both groups but the effect was significantly higher in the BB-12 group; stool consistency was similar between the two groups. An increase in Bifidobacterium abundance (with significant correlation with crying time reduction), butyrate and HBD-2, LL-37, sIgA levels associated with a decrease in faecal calprotectin level were observed in the BB-12 group. CONCLUSIONS: Supplementation with BB-12 is effective in managing infant colic. The effect could derive from immune and non-immune mechanisms associated with a modulation of gut microbiota structure and function.

Acute changes in the colonic microbiota are associated with large intestinal forms of surgical colic.

BACKGROUND: Horses that undergo surgery for treatment of primary large colon disease have been reported to be at increased risk of developing recurrent colic episodes postoperatively. The reasons for this are currently unknown. The aim of the current study was to characterise the faecal microbiota of horses with colic signs associated with primary large colon lesions treated surgically and to compare the composition of their faecal microbiota to that of a control group of horses undergoing emergency orthopaedic treatment. Faecal samples were collected from horses in both groups on admission to hospital, during hospitalisation and following discharge from hospital for a total duration of 12 weeks. Additionally, colonic content samples were collected from surgical colic patients if pelvic flexure enterotomy was performed during laparotomy. A total of 12 samples were collected per horse. DNA was extracted from samples using a commercial kit. Amplicon mixtures were created by PCR amplification of the V1 - V2 regions of the bacterial 16S rRNA genes and submitted for sequencing using the Ion Torrent PGM next-generation sequencing system. Multivariate data analysis was used to characterise the faecal microbiota and to investigate differences between groups. RESULTS: Reduced species richness was evident in the colonic samples of the colic group compared to concurrent sampling of the faeces. Alpha and beta diversity differed significantly between the faecal and colonic microbiota with 304 significantly differentially abundant OTUs identified. Only 46 OTUs varied significantly between the colic and control group. There were no significant differences in alpha and beta diversity of faecal microbiota between colic and control horses at admission. However, this lack of significant differences between groups should be interpreted with caution due to a small sample size. CONCLUSIONS: The results of the current study suggest that faecal samples collected at hospital admission in colic cases may not accurately represent changes in upper gut microbiota in horses with colic due to large colon disease.

Gastrointestinal Tolerance, Growth and Safety of a Partly Fermented Formula with Specific Prebiotics in Healthy Infants: A Double-Blind, Randomized, Controlled Trial.

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed infants.

Probiotics to prevent infantile colic.

BACKGROUND: Infantile colic is typically defined as full-force crying for at least three hours per day, on at least three days per week, for at least three weeks. Infantile colic affects a large number of infants and their families worldwide. Its symptoms are broad and general, and while not indicative of disease, may represent a serious underlying condition in a small percentage of infants who may need a medical assessment. Probiotics are live microorganisms that alter the microflora of the host and provide beneficial health effects. The most common probiotics used are of Lactobacillus, Bifidobacterium and Streptococcus. There is growing evidence to suggest that intestinal flora in colicky infants differ from those in healthy infants, and it is suggested that probiotics can redress this balance and provide a healthier intestinal microbiota landscape. The low cost and easy availability of probiotics makes them a potential prophylactic solution to reduce the incidence and prevalence of infantile colic. OBJECTIVES: To evaluate the efficacy and safety of prophylactic probiotics in preventing or reducing severity of infantile colic. SEARCH METHODS: In January 2018 we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 10 other databases and two trials registers. In addition, we handsearched the abstracts of relevant meetings, searched reference lists, ran citation searches of included studies, and contacted authors and experts in the field, including the manufacturers of probiotics, to identify unpublished trials. SELECTION CRITERIA: Randomised control trials (RCTs) of newborn infants less than one month of age without the diagnosis of infantile colic at recruitment. We included any probiotic, alone or in combination with a prebiotic (also known as synbiotics), versus no intervention, another intervention(s) or placebo, where the focus of the study was the effect of the intervention on infantile colic. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures of Cochrane. MAIN RESULTS: Our search yielded 3284 records, and of these, we selected 21 reports for full-text review. Six studies with 1886 participants met our inclusion criteria, comparing probiotics with placebo. Two studies examined Lactobacillus reuteri DSM, two examined multi-strain probiotics, one examined Lactobacillus rhamnosus, and one examined Lactobacillus paracasei and Bifidobacterium animalis. Two studies began probiotics during pregnancy and continued administering them to the baby after birth.We considered the risk of bias for randomisation as low for all six trials; for allocation concealment as low in two studies and unclear in four others. All studies were blinded, and at low risk of attrition and reporting bias.A random-effects meta-analysis of three studies (1148 participants) found no difference between the groups in relation to occurrence of new cases of colic: risk ratio (RR) 0.46, 95% confidence interval (CI) 0.18 to 1.19; low-certainty evidence; I2 = 72%.A random-effects meta-analysis of all six studies (1851 participants) found no difference between the groups in relation to serious adverse effects (RR 1.02, 95% CI 0.14 to 7.21; low-certainty evidence; I2 not calculable (only four serious events for one comparison, two in each group: meconium plug obstruction, patent ductus arteriosus and neonatal hepatitis).A random-effects meta-analysis of three studies (707 participants) found a mean difference (MD) of -32.57 minutes per day (95% CI -55.60 to -9.54; low-certainty evidence; I2 = 93%) in crying time at study end in favour of probiotics.A subgroup analysis of the most studied agent, Lactobacillus reuteri, showed a reduction of 44.26 minutes in daily crying with a random-effects model (95% CI -66.6 to -21.9; I2 = 92%), in favour of probiotics. AUTHORS' CONCLUSIONS: There is no clear evidence that probiotics are more effective than placebo at preventing infantile colic; however, daily crying time appeared to reduce with probiotic use compared to placebo. There were no clear differences in adverse effects.We are limited in our ability to draw conclusions by the certainty of the evidence, which we assessed as being low across all three outcomes, meaning that we are not confident that these results would not change with the addition of further research.

Pilot Analysis of Early Lactobacillus rhamnosus GG for Infant Colic Prevention.

We conducted a secondary analysis of data from a trial of Lactobacillus rhamnosus GG (LGG) supplementation as a pilot study to assess whether LGG prevents infant colic. For the first 6 months of life, infants received a daily dose of 10 billion colony-forming units of LGG or a control (n = 184). We compared the likelihood of a diagnosis of colic before 4 months of age, based on parent-reported symptoms or a physician diagnosis of colic. Out of the 184 infants, 18 (9.8%) had colic. There were no differences between the 2 groups in the percentage of infants with colic based on symptoms (control 5.4% vs LGG 9.8%; P = 0.19); physician diagnosis (control 3.2% vs LGG 7.6%; P = 0.26); or either symptoms or diagnosis combined (control 6.5% vs LGG 13.0%; P = 0.13). In this pilot study, early infant LGG supplementation does not appear to prevent the later development of colic.

Differences in the equine faecal microbiota between horses presenting to a tertiary referral hospital for colic compared with an elective surgical procedure.

BACKGROUND: The faecal microbiota is emerging as potentially important in intestinal disease. More research is needed to characterise the faecal microbiota from horses with colic. OBJECTIVES: To compare the relative abundance of bacterial populations comprising the faecal microbiota in horses presenting for colic compared with an elective surgical procedure. STUDY DESIGN: Prospective observational clinical study. METHODS: Admission faecal samples were collected from horses presenting for colic and elective surgical procedures. Faecal samples were extracted for genomic DNA, PCR- amplified, sequenced and analysed using QIIME. Species richness and Shannon diversity were estimated for each faecal sample. The extent of the relationship between bacterial communities (beta diversity) was quantified using pairwise UniFrac distances, visualised using principal coordinate analysis (PCoA) and statistically analysed using PERMANOVA. The relative abundance of bacterial populations between the two treatment groups were compared using ANCOM. RESULTS: Faecal bacterial communities in horses presenting for colic had fewer species (P<0.001) and lower diversity (P<0.001) compared with horses presenting for elective surgical procedures. Based on the PERMANOVA analysis, there was a significant difference in the bacterial community composition between horses admitted for colic vs. elective procedures (P = 0.001). Based on ANCOM test, at the genus level, 14 bacterial lineages differed between the two groups. The relative abundance of known commensal bacteria including Prevotella, Clostridia, Lachnospiraceae were reduced whereas Christenellaceae, Streptococcus and Sphaerochaeta were increased in horses with colic when compared with elective cases. MAIN LIMITATIONS: Relative low numbers and a diverse population of horses. CONCLUSIONS: Changes in bacterial populations in the faecal microbiota of horses presenting for colic observed in this study concurs with previous studies in veterinary and human patients with gastrointestinal disease. Future studies focusing on different causes of colic, chronic or recurrent disease, and the association with histological changes within the intestine are needed. The Summary is available in Portuguese - see Supporting Information.

Neonatal Antibiotic Treatment Is Associated With an Altered Circulating Immune Marker Profile at 1 Year of Age.

Background: Neonatal antibiotics disturb the developing gut microbiome and are therefore thought to influence the developing immune system, but exact mechanisms and health consequences in later life still need to be elucidated. Therefore, we investigated whether neonatal antibiotics influence inflammatory markers at 1 year of age. In addition, we determined whether health problems during the first year of life, e.g., allergic disorders (eczema and wheezing) or infantile colics, were associated with changes in the circulating immune marker profile at 1 year of age. Methods: In a subgroup (N = 149) of the INCA-study, a prospective birth-cohort study, a blood sample was drawn from term born infants at 1 year of age and analyzed for 84 immune related markers using Luminex. Associations of antibiotic treatment, eczema, wheezing, and infantile colics with immune marker concentrations were investigated using a linear regression model. The trial is registered as NCT02536560. Results: The use of broad-spectrum antibiotics in the first week of life, was significantly associated with different levels of inflammatory markers including sVCAM-1, sCD14, sCD19, sCD27, IL-1RII, sVEGF-R1, and HSP70 at 1 year of age. Eczema was associated with decreased concentrations of IFNα, IFNγ, TSLP, CXCL9, and CXCL13, but increased concentrations of CCL18 and Galectin-3. Wheezing, independent of antibiotic treatment, was positively associated to TNF-R2 and resistin. Infantile colics were positively associated to IL-31, LIGHT, YKL-40, CXCL13, sPD1, IL1RI, sIL-7Ra, Gal-1, Gal-9, and S100A8 at 1 year of age, independent of early life antibiotic treatment. Conclusion: In this explorative study, we identified that neonatal antibiotics are associated with immunological alterations at 1 year of age and that, independent of the antibiotic treatment, infantile colics were associated with alterations within gut associated markers. These findings support the importance of the first host microbe interaction in early life immune development.

Recent advances in understanding and managing infantile colic.

A newborn brings joy to the family. Crying belongs to the spectrum of normal behaviour of young infants. However, although it occurs in about 20% of all infants, unsoothable and persistent crying in young infants distresses the family, although it is usually benign. The aetiology of infantile colic remains unknown, although an unbalanced gastro-intestinal microbiome, increased intestinal permeability, and chronic inflammation are involved, as well as behavioural factors, including over- and under-stimulation. It is a challenge for healthcare professionals to decide when organic disease needs to be excluded. Parental stress is a reason for babies to cry more, inducing a vicious cycle. Therefore, parental reassurance with explanatory guidance is the cornerstone of management. The placebo effect is estimated to be as high as 50%. If an intervention is felt to be necessary to offer further support to the baby and family, it is important to choose the options for which there is some efficacy without adverse effects. There is evidence that some specific probiotic strains such as Lactobacillus reuteri DSM 19378, especially in breastfed infants, are effective. However, there are also promising data for some synbiotics and/or killed or tyndallized bacteria, as well as substances decreasing intestinal permeability. Formula management with extensive and/or partial hydrolysates may also bring relief. But, above all, offering parental support remains imperative.

Variation in faecal microbiota in a group of horses managed at pasture over a 12-month period.

Colic (abdominal pain) is a common cause of mortality in horses. Change in management of horses is associated with increased colic risk and seasonal patterns of increased risk have been identified. Shifts in gut microbiota composition in response to management change have been proposed as one potential underlying mechanism for colic. However, the intestinal microbiota in normal horses and how this varies over different seasons has not previously been investigated. In this study the faecal microbiota composition was studied over 12 months in a population of horses managed at pasture with minimal changes in management. We hypothesised that gut microbiota would be stable in this population over time. Faecal samples were collected every 14 days from 7 horses for 52 weeks and the faecal microbiota was characterised by next-generation sequencing of 16S rRNA genes. The faecal microbiota was dominated by members of the phylum Firmicutes and Bacteroidetes throughout. Season, supplementary forage and ambient weather conditions were significantly associated with change in the faecal microbiota composition. These results provide important baseline information demonstrating physiologic variation in the faecal microbiota of normal horses over a 12-month period without development of colic.

Crying Time and RORγ/FOXP3 Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial.

OBJECTIVES: To evaluate crying time, retinoid-related orphan receptor-γ (RORγ) and forkhead box P3 (FOXP3) messenger RNA levels (transcription factors that can modulate T cell responses to gut microbes), and to investigate gut microbiota and fecal calprotectin in infants treated with Lactobacillus reuteri for infantile colic. STUDY DESIGN: A double-blind, placebo-controlled randomized trial was conducted in primary care in Torino from August 1, 2015 to September 30, 2016. Patients suffering from infantile colic were randomly assigned to receive daily oral L reuteri (1 × 108 colony forming unit) or placebo for 1 month. Daily crying times were recorded in a structured diary. FOXP3 and RORγ messenger RNA in the peripheral blood was assessed with real-time TaqMan reverse transcription polymerase chain reaction. Gut microbiota and fecal calprotectin were evaluated. RESULTS: After infants with colic were supplemented with L reuteri DSM 17938 for 30 days, crying times were significantly shorter among infants with colic in the probiotic group compared with infants in the placebo group (74.67 ± 25.04 [IQR = 79] minutes /day vs 147.85 [IQR = 135] minutes /day [P = .001]). The FOXP3 concentration increased significantly (P = .009), resulting in decreased RORγ/FOXP3 ratios: 0.61 (IQR = 0.60) at day 0 and 0.48 (IQR = 0.28) at day 30 (P = .028). Furthermore, the probiotic increased the percentage of Lactobacillus (P = .049) and decreased fecal calprotectin (P = .0001). CONCLUSIONS: Infants with colic treated with L reuteri for 30 days had a significantly decreased crying time and an increased FOXP3 concentration, resulting in a decreased RORγ/FOXP3 ratio. The treatment reduced fecal calprotectin. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00893711.