The enhancing therapeutic effect of neonatal jaundice by bifidobacterium through regulating inflammation and gut microbiota in combination with phototherapy-a randomized controlled trial

Feng Zhang; Jiayi Chen; Yanhan Yuan; Juanjuan Chen; Wei Jiang; Weiwei Xiang; Na Wang; Zhimin Wu; Sainan Fan; Kun Zhang; Yanan Ma; Tianyu Liu; Jiahui Zhang; Qinghua Yu; Jinping Zhang

doi:10.3389/fmicb.2026.1761245

The enhancing therapeutic effect of neonatal jaundice by bifidobacterium through regulating inflammation and gut microbiota in combination with phototherapy-a randomized controlled trial

Front Microbiol. 2026 Apr 1:17:1761245. doi: 10.3389/fmicb.2026.1761245. eCollection 2026.

Authors

Feng Zhang^#¹, Jiayi Chen^#², Yanhan Yuan², Juanjuan Chen², Wei Jiang³, Weiwei Xiang³, Na Wang², Zhimin Wu², Sainan Fan², Kun Zhang², Yanan Ma², Tianyu Liu¹, Jiahui Zhang², Qinghua Yu³, Jinping Zhang²

Affiliations

¹ College of Food Science and Technology, Shanghai Ocean University, Shanghai, China.
² Department of Pediatrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, DiproX Medical Research Center, Shanghai, China.
³ Laboratory of Microbiology, Immunology, and Metabolism, Diprobio (Shanghai) Co, Limited, Shanghai, China.

^# Contributed equally.

Abstract

Background: Hyperbilirubinemia is among the most common conditions in neonates, and phototherapy is currently the most widely used treatment. However, it can induce side effects such as skin rashes, diarrhea, and gut microbiota dysbiosis, particularly affecting Bifidobacterium levels. This study aimed to investigate whether the supplementation of Bifidobacterium can alleviate dysbiosis and improve clinical outcomes in jaundiced neonates.

Methods: A total of 79 jaundiced neonates were enrolled and divided into four groups: Phototherapy Control, M-16V, Bb-12, and the combined M-16V+Bb-12 group. Probiotics were administered until 30 days post-discharge, and neurodevelopment was assessed at 1.5-2 years using the Griffith Development Scales. Fecal samples collected before, during, and after treatment were analyzed using metagenomic sequencing and non-targeted metabolomics.

Results: Probiotic supplementation significantly increased daily defecation frequency, accelerated the reduction rate of transcutaneous bilirubin, and shortened hospital stays. Griffith scores indicated that Bb-12 supplementation improved scores in personal-social and performance domains. Metagenomic analysis revealed significant differences in beta diversity between the control and probiotic groups; specifically, M-16V and combined supplementation increased the abundance of Bifidobacterium breve. Pathway enrichment analysis showed up-regulation of pyrimidine-containing compound metabolic processes, intramolecular transferase activity, and DNA conformation change. Metabolomics further demonstrated that combined supplementation elevated levels of 5-methyltetrahydrofolate (linked to DNA synthesis), benzoic acid and indoleacetic acid (linked to growth and development), and the anti-inflammatory metabolite indole-3-lactic acid.

Discussion: For neonates receiving phototherapy, the addition of M-16 V + Bb-12 probiotics can improve the diversity of microflora, reduce the fixed value of harmful bacteria in the intestine, and enhance the excretion of bilirubin from the intestine, to improve the inflammatory damage and microbiota disorder caused by phototherapy, and achieve the effect of clinically improving jaundice, reducing bilirubin, shortening the length of hospitalization, and promoting neurodevelopment. It provides a safer and more effective treatment for neonatal jaundice.

Keywords: bilirubin metabolism; gut microbiota; neonatal jaundice; probiotics; repair of inflammatory injury.