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Randomized Controlled Trial
. 2024 Dec 27;24(1):840.
doi: 10.1186/s12887-024-05289-7.

Assessment of the safety and gut microbiota modulation ability of an infant formula containing Bifidobacterium animalis ssp. lactis CP-9 or Lactobacillus salivarius AP-32 and the effects of the formula on infant growth outcomes: insights from a four-month clinical study in infants under two months old

Shang-Po Shen #  1 , Hung-Chih Lin #  1   2   3 , Jui-Fen Chen  4 , Hui-Shan Wang  5 , Yen-Yu Huang  4 , Ko-Chiang Hsia  4 , Jia-Hung Lin  5 , Yi-Wei Kuo  5 , Ching-Min Li  4 , Yu-Chieh Hsu  4 , Shin-Yu Tsai  4 , Hsieh-Hsun Ho  6   7
Affiliations
Randomized Controlled Trial

Assessment of the safety and gut microbiota modulation ability of an infant formula containing Bifidobacterium animalis ssp. lactis CP-9 or Lactobacillus salivarius AP-32 and the effects of the formula on infant growth outcomes: insights from a four-month clinical study in infants under two months old

Shang-Po Shen et al. BMC Pediatr. .

Abstract

Background: Breast milk is a natural treasure for infants, and its microbiota contains a rich array of bacterial species. When breastfeeding is not possible, infant formula with probiotics can be used as a sole source or as a breast milk supplement. The main aim of this study was to evaluate the growth outcomes and tolerance of infants consuming an infant formula containing Bifidobacterium animalis ssp. lactis CP-9 (B. animalis CP-9) or Lactobacillus salivarius AP-32 (L. salivarius AP-32), which were isolated from breast milk and the guts of healthy infants. The safety of these strains in terms of antibiotic resistance and their ability to modulate the gut microbiota were also evaluated.

Methods: One hundred eighty healthy infants were included in this study and separated into three groups: the control group, the L. salivarius AP-32 group, and the B. animalis CP-9 group. In this clinical study, adverse events, growth effects, and the incidence of allergies and gastrointestinal disorders in infants consuming infant formula containing B. animalis CP-9 or L. salivarius AP-32 were evaluated. Finally, the impact of the probiotic infant formula on the gut microbiota was elucidated via next-generation sequencing (NGS) analysis.

Results: The 4-month interventional study revealed that body weight, recumbent length, and head circumference were similar among the three groups. No adverse events related to the intervention were observed. The microbiota composition was more diverse on day 0 and became more uniform by month 4. B. animalis CP-9 and L. salivarius AP-32 were found to be susceptible to streptomycin, tetracycline, erythromycin, clindamycin, chloramphenicol, and ampicillin.

Conclusions: The use of infant formula containing B. animalis CP-9 and L. salivarius AP-32 was considered safe and well tolerated, with no adverse events observed during the study. While these strains showed low antibiotic resistance and no immediate concerns related to antibiotic resistance genes, further research is needed to comprehensively assess their long-term safety and efficacy and the potential risk of horizontal gene transfer in broader contexts.

Trial registration: The trial was registered with the US Library of Medicine (clinicaltrials.gov) with the number NCT03993301 on 20/06/2019.

Keywords: Gastrointestinal disorders; Infant formula; Infant growth; Probiotics.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study adhered to the guidelines of the Declaration of Helsinki, was approved by the China Medical University & Hospital Research Ethics Committee (IRB No. CMUH108-REC2-005), and was registered with the US Library of Medicine ( www.clinicaltrial.gov ) with the identifier NCT03993301. Written informed consent was obtained from the parents or legal guardians of all participants. Consent for publication: Not applicable. Competing interests: Glac Biotech Co., Ltd. provided financial support in the form of salaries for J. F. Chen, H.S. Wang, Y.Y. Huang, K.C. Hsia, J.H. Lin, Y.W. Kuo, C.M. Li, Y.C. Hsu, S.Y. Tsai, and H.H. Ho but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. S.P. Shen and H.C. Lin declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow chart of the study design and subjects. A It was requested that the study infants consume at least 2 scoops (17.2 g) of infant formula per day for 4 months. B One hundred eight (180) healthy, full-term infants were enrolled and randomized to the CP-9 (n = 60), AP-32 (n = 60), or placebo (n = 60) groups. All randomized subjects received allocated treatment. One hundred eighteen (118) subjects completed the 4-month treatment
Fig. 2
Fig. 2
Body weight, recumbent length, and head circumference were measured. The (A) body weight, (C) recumbent length, and (E) head circumference were measured on day 0 and month 4. Growth was converted to the daily rate of (B) body weight gain, (D) recumbent length gain, and (F) head circumference gain
Fig. 3
Fig. 3
Distribution of antibiotic resistance genes and mobile element genes. A B. animalis CP-9 contained only one circular chromosome (1,944,145 bp) and no plasmid. B L. salivarius AP-32 contained one circular chromosome (1,727,032 bp) and two plasmids (269,712 bp and 17,451 bp). Drug resistance genes are indicated in red, and mobile element genes are indicated in blue
Fig. 4
Fig. 4
Modulation of the microbiota in faecal samples collected on day 0 and month 4. A Alpha diversity, (B) beta diversity, (C) proportions of the 10 most abundant phyla, and (D) proportions of the 10 most abundant genera
Fig. 5
Fig. 5
The genera and species involved in the modulation of the microbiota in faecal samples collected on day 0 and at month 4. A Phyla: Actinobacteria, Firmicutes, and Proteobacteria; (B) genera: Bifidobacterium, Lactobacillus, and Klebsiella; (C) species: Bifidobacterium longum, Bifidobacterium animalis, and Lactobacillus salivarius. The q value was the p value adjusted using the false discovery rate (FDR) with Benjamini‒Hochberg (BH) correction
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