Xiaoer Huanglong pellets remodels the periphery microenvironment to improve attention deficit hyperactivity disorder based on the microbiota-gut-brain axis

Longtai You; Hulinyue Peng; Jing Liu; Na Sai; Wenwen Zhao; Xiao Li; Chunjing Yang; Peng Guo; Jian Ni

doi:10.1016/j.phymed.2025.157007

Xiaoer Huanglong pellets remodels the periphery microenvironment to improve attention deficit hyperactivity disorder based on the microbiota-gut-brain axis

Phytomedicine. 2025 Jun 18:145:157007. doi: 10.1016/j.phymed.2025.157007. Online ahead of print.

Authors

Longtai You¹, Hulinyue Peng², Jing Liu³, Na Sai⁴, Wenwen Zhao¹, Xiao Li¹, Chunjing Yang⁵, Peng Guo⁶, Jian Ni⁷

Affiliations

¹ Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, PR China.
² School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, PR China.
³ Department of lnfectious Diseases, Nanjing Research Center for Infectious Diseases of Integrated Traditional Chinese and Western Medicine, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, PR China.
⁴ School of Pharmacy, Inner Mongolia Medical University, 010110 Hohhot, PR China.
⁵ Dept. of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China. Electronic address: yangchunjing3671@bjsjth.cn.
⁶ Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, PR China; Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, PR China. Electronic address: guopeng@bch.com.cn.
⁷ School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, PR China. Electronic address: njtcm@263.net.

PMID: 40554893
DOI: 10.1016/j.phymed.2025.157007

Abstract

Background: Recently, research interest in attention deficit hyperactivity disorder (ADHD) has grown significantly, driven by its increasing incidence and substantial societal impact. Among the various pathogenic mechanisms under investigation, the microbiota-gut-brain axis has emerged as a crucial area of focus. In the context of ADHD treatment, Xiaoer Huanglong Pellets (XRHLP), a traditional Chinese herbal formulation, have demonstrated therapeutic efficacy, although the underlying mechanisms remain partially understood.

Purpose: This study aimed to analyze and compare the therapeutic effects and underlying mechanisms of XRHLP, including gastric release (WR_HL), enteric release (CR_HL), and colon release (JCR_HL) pellets, for ADHD treatment.

Methods: This study employed a multi-modal approach to investigate the effects of XRHLP on ADHD. Behavioral assessments combined with Enzyme-linked immunosorbent assay and Western-blot analyses were conducted to evaluate the therapeutic outcomes in model rats with ADHD. Comprehensive profiling of the gut-brain axis was performed using 16S ribosomal RNA sequencing and untargeted and targeted metabolomic analyses. The causal role of the gut microbiota was further validated using fecal microbiota transplantation (FMT).

Results: WR_HL, CR_HL, and JCR_HL improved ADHD-like behaviors and neurotransmission dysfunction, with JCR_HL exhibiting superior intervention effects compared to WR_HL and CR_HL. These therapeutic effects are mediated through multiple pathways, including the restoration of gut microbial homeostasis, attenuation of inflammatory cascades, and repair of compromised intestinal and blood-brain barrier. The intervention also corrected systemic metabolic imbalances by specifically addressing the abnormalities in amino acid metabolism, neurotransmitter regulation, and short-chain fatty acid production. FMT experiments further confirmed the critical role of microbial modulation in mediating the behavioral and microbial regulatory effects of XRHLP.

Conclusion: In summary, XRHLP exerts anti-ADHD effects by improving the microbiota-gut-brain axis and correcting amino acid metabolic disorders, providing new insights into the molecular mechanisms by which traditional Chinese medicine influences ADHD and offers potential avenues for drug development.

Keywords: Attention deficit hyperactivity disorder (ADHD); Gut microbiota; Host metabolism; Neuroinflammation; Xiaoer Huanglong pellets (XRHLP).