Use of Bifidobacterium Bifidum in Formula-Fed Infants With Colic, With or Without Atopic Dermatitis

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.

Inclusion criteria

• Non-breastfed infants aged ≤ 5 months diagnosed with infant colic according to Rome IV criteria, with or without atopic dermatitis.
• Written informed consent from parents or legal guardians.

Exclusion criteria

• Age > 5 months.
• Exclusive breastfeeding or mixed feeding.
• Absence of infant colic diagnosis.
• Presence of chronic diseases, neoplasms, immunodeficiencies, chronic infections, autoimmune diseases, IBD, celiac disease, genetic-metabolic disorders, cystic fibrosis or other chronic pulmonary diseases, cardiovascular/respiratory/GI malformations, neuropsychiatric disorders, neurological conditions, or vegetarian/vegan diet.