The goal of this clinical trial is to evaluate whether daily probiotic supplementation with Bifidobacterium bifidum (Bifipral® drops) can reduce crying time in formula-fed infants aged 5 months or younger diagnosed with infant colic (according to Rome IV criteria), with or without concomitant atopic dermatitis. The main questions it aims to answer are: * Does daily administration of B. bifidum for 8 weeks achieve at least a 50% reduction in average daily crying duration compared to placebo? * Does B. bifidum supplementation improve secondary outcomes, including crying frequency, sleep quality, bowel movement frequency, stool consistency, fecal microbiota composition, short-chain fatty acid (SCFA) levels, and SCORAD score in infants with atopic dermatitis? Researchers will compare formula-fed infants receiving Bifipral® drops (containing B. bifidum strains BFP19® and BFP29®) to a comparison group receiving an indistinguishable placebo to see if the probiotic safely improves colic symptoms and gut microbiota balance. Participants will be asked to: * Complete a 7-day observational run-in period to confirm eligibility and record baseline symptoms in a daily diary. * Administer 5 drops daily of the study product (probiotic or placebo) for 8 weeks. * Complete daily diaries tracking crying duration/frequency, sleep parameters, and bowel habits. * Attend 3 clinical visits (Baseline, Week 8, and a Safety Follow-up 2-4 weeks post-treatment). * Provide fecal samples at Baseline (Visit 1) and Week 8 (Visit 2) for microbiota profiling and SCFA analysis.
BACKGROUND AND SCIENTIFIC RATIONALE: Bifidobacterium bifidum is a primary commensal of the human intestinal microbiota, exhibiting a pronounced tropism for the early stages of life. It is highly adapted to the neonatal ecosystem due to its ability to efficiently utilize both host glycans-specifically human milk oligosaccharides (HMOs)-and intestinal mucin. This capability is enabled by a rich repertoire of extracellular glycosidases and the presence of structures such as sortase-dependent pili, which promote adhesion to the epithelium, mucosal colonization, and interaction with the immune system. The degradation of HMOs present in breast milk by B. bifidum confers a crucial role in modulating the gut microbiota: the released degradation products, such as fucose, sialic acid, and LNB (Lacto-N-Biose), serve as substrates for other beneficial species, promoting cross-feeding mechanisms and ensuring the establishment of a healthy microbial community. While in breastfed infants the growth of B. bifidum is sustained by HMOs, non-breastfed infants exhibit a dramatic deficiency of this key species. However, the ability of B. bifidum to stably adhere to the mucosa via pili and metabolize endogenous mucin suggests that it can successfully colonize the intestine even in the absence of breastfeeding, acting as a functional surrogate to restore cross-feeding mechanisms and immune tolerance typical of healthy neonates. This positions B. bifidum among the primary intestinal colonizers capable of significantly modulating the infant's immunological trajectory. A reduction in bifidobacteria has been associated with both infant colic, defined according to Rome IV criteria, and atopic manifestations, including atopic dermatitis. Both conditions share a background of immuno-enteric immaturity and a higher prevalence of dysbiosis characterized by a decrease in Bifidobacterium and an increase in gas-producing species. In light of this evidence, B. bifidum emerges as a key species whose decline is associated with adverse outcomes along a continuum that includes colic and atopic dermatitis. STUDY HYPOTHESIS AND OBJECTIVES: Despite the strong biological rationale, to date there are no randomized controlled trials specifically evaluating the efficacy of B. bifidum in non-breastfed infants with infant colic, nor are structured data available on its potential impact on symptoms associated with atopy. The primary goal of this study is to evaluate whether daily administration of a probiotic blend consisting of Bifidobacterium bifidum BFP19® and Bifidobacterium bifidum BFP29® (Bifipral® drops) reduces crying duration in non-breastfed infants diagnosed with infant colic according to Rome IV criteria. Additionally, the study explores the impact of this intervention on sleep parameters, bowel habits, fecal microbiota composition (via shotgun metagenomics), short-chain fatty acids (SCFAs) levels, and, in subjects with concomitant atopic dermatitis, changes in the SCORAD score. PROCEDURAL SUMMARY: Following a 7-day observational run-in period to confirm diagnosis and collect baseline data, eligible infants are randomized (1:1 ratio, block randomization stratified by age) to receive either Bifipral® drops (5 drops/day, supplying 4 x 10\^9 CFU/day total) or an indistinguishable placebo for 8 weeks. Daily diaries are maintained by parents to record behavioral and gastrointestinal outcomes. Clinical assessments and biological sampling occur at baseline (Visit 1), end of treatment at Week 8 (Visit 2), and a final safety follow-up visit scheduled 2 to 4 weeks post-treatment. Fecal samples are processed for metagenomic profiling and SCFA analysis.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
64
Oral drops containing a combination of Bifidobacterium bifidum BFP19® and Bifidobacterium bifidum BFP29®. Administered at a dose of 5 drops once daily (providing a total of 4 x 10⁹ CFU/day, 2 x 10⁹ CFU per strain), preferably in the morning before feeding, for 8 weeks.
Matching placebo oral drops, indistinguishable from the active intervention in packaging, color, odor, taste, consistency, and labeling. Administered at a dose of 5 drops once daily, preferably in the morning before feeding, for 8 weeks.
AOU Sant'Andrea
Roma, RM, Italy
RECRUITINGTreatment Response Rate Based on Daily Crying Duration
Proportion of infants achieving a clinical response, defined as a \>/=50% reduction in the mean daily crying duration compared to baseline. Crying duration is recorded by parents in a structured daily diary. Baseline crying duration is calculated as the average of the values recorded during the 3 consecutive days preceding the baseline visit., in accordance with methodological standards of probiotic studies and Rome IV recommendations.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Daily Crying Episode Frequency
Change in the average number of crying episodes per 24-hour period, as recorded by parents in the structured daily behavioral diary.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Total 24-Hour Sleep Duration
Change in total sleep duration over a 24-hour period (expressed in hours per day), calculated as the average of 3 consecutive days recorded by parents in the daily diary.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Number of Nocturnal Awakenings
Change in the mean number of nocturnal awakenings per night, calculated as the average of 3 consecutive nights recorded by parents in the daily diary.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Longest Uninterrupted Nighttime Sleep Episode
Change in the duration (expressed in hours) of the longest continuous nighttime sleep episode per night, calculated as the average of 3 consecutive nights recorded by parents in the daily diary.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Daily Bowel Movement Frequency
Change in the mean number of bowel movements per day, as recorded by parents in the daily diary.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Stool Consistency Score
Change in stool consistency assessed using the modified Bristol Stool Form Scale for infants. The scale ranges from Type 1 (hard lumps) to Type 7 (watery/liquid). Minimum score is 1, maximum score is 7; lower scores indicate harder stool consistency and higher scores indicate looser/more liquid stool consistency.
Time frame: Baseline (3-day run-in average) to Week 8 (end of treatment)
Change from Baseline in Fecal Microbiota Composition (Alpha Diversity)
Change in gut microbial community alpha diversity (Shannon Diversity Index) determined by shotgun metagenomic sequencing of collected fecal samples.
Time frame: Baseline (Visit 1) to Week 8 (Visit 2)
Change from Baseline in Fecal Short-Chain Fatty Acid (SCFA) Concentrations
Change in absolute concentrations (expressed in micromoles per gram of dry stool) of key fecal short-chain fatty acids (acetate, propionate, and butyrate) measured via gas chromatography/mass spectrometry.
Time frame: Baseline (Visit 1) to Week 8 (Visit 2)
Change from Baseline in SCORing Atopic Dermatitis (SCORAD) Index Total Score
Change in the SCORing Atopic Dermatitis (SCORAD) index total score evaluated in the subgroup of participants with concomitant atopic dermatitis. The SCORAD total score evaluates disease extent, clinical severity of 6 parameters, and subjective symptoms (pruritus and sleep loss). The total score ranges from 0 to 103, where 0 indicates absence of disease and higher scores represent greater disease severity (worse outcome).
Time frame: Baseline (Visit 1) to Week 8 (Visit 2)
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