Early‐life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides

Xi Zhang; Darren Chak Lun Chan; Jie Zhu; Daniel Zhen Ye Sin; Ye Peng; Matthew Kwok Leong Wong; Wenyi Zhu; Yee Tsui; Andrea M. Haqq; Joseph Y. Ting; Anita Kozyrskyj; Francis Ka Leung Chan; Siew Chien Ng; Hein Min Tun

doi:10.1002/mco2.70104

journal article Open Access Feb 17, 2025

Early‐life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides

Xi Zhang

Darren Chak Lun Chan Jie Zhu

Daniel Zhen Ye Sin Ye Peng Matthew Kwok Leong Wong Wenyi Zhu

Yee Tsui Andrea M. Haqq Joseph Y. Ting Anita Kozyrskyj Francis Ka Leung Chan Siew Chien Ng Hein Min Tun

MedComm Vol. 6 No. 3 · Wiley

View at Publisher Save 10.1002/mco2.70104

Abstract

AbstractCompelling evidence supports a link between early‐life gut microbiota and the metabolic outcomes in later life. Using an early‐life antibiotic exposure model in BALB/c mice, we investigated the life‐course impact of prenatal and/or postnatal antibiotic exposures on the gut microbiome of offspring and the development of metabolic dysfunction‐associated steatotic liver disease (MASLD). Compared to prenatal antibiotic exposure alone, postnatal antibiotic exposure more profoundly affected gut microbiota development and succession, which led to aggravated endotoxemia and metabolic dysfunctions. This was primarily resulted from the overblooming of gut Parabacteroides and hepatic accumulation of cytotoxic lysophosphatidyl cholines (LPCs), which acted in conjunction with LPS derived from Parabacteroides distasonis (LPS_PA) to induce cholesterol metabolic dysregulations, endoplasmic reticulum (ER) stress and apoptosis. Integrated serum metabolomics, hepatic lipidomics and transcriptomics revealed enhanced glycerophospholipid hydrolysis and LPC production in association with the upregulation of PLA2G10, the gene controlling the expression of the group X secretory Phospholipase A2s (sPLA2‐X). Taken together, our results show microbial modulations on the systemic MASLD pathogenesis and hepatocellular lipotoxicity pathways following early‐life antibiotic exposure, hence help inform refined clinical practices to avoid any prolonged maternal antibiotic administration in early life and potential gut microbiota‐targeted intervention strategies.

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Published: Feb 17, 2025
Vol/Issue: 6(3)
License: View

Authors

X

Xi Zhang

Microbiota I‐Center (MagIC) Hong Kong SAR China; Jockey Club School of Public Health and Primary Care Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; HKU‐Pasteur Research Pole, School of Public Health LKS Faculty of Medicine, The University of Hong Kong Hong Kong SAR China

D

Darren Chak Lun Chan

HKU‐Pasteur Research Pole, School of Public Health LKS Faculty of Medicine, The University of Hong Kong Hong Kong SAR China

J

Jie Zhu

Microbiota I‐Center (MagIC) Hong Kong SAR China

D

Daniel Zhen Ye Sin

Jockey Club School of Public Health and Primary Care Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China

Y

Ye Peng

Microbiota I‐Center (MagIC) Hong Kong SAR China; Jockey Club School of Public Health and Primary Care Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China

M

Matthew Kwok Leong Wong

Microbiota I‐Center (MagIC) Hong Kong SAR China

W

Wenyi Zhu

Microbiota I‐Center (MagIC) Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Department of Medicine and Therapeutics Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China

Y

Yee Tsui

HKU‐Pasteur Research Pole, School of Public Health LKS Faculty of Medicine, The University of Hong Kong Hong Kong SAR China

A

Andrea M. Haqq

Department of Pediatrics University of Alberta Edmonton Canada

J

Joseph Y. Ting

Department of Pediatrics University of Alberta Edmonton Canada

A

Anita Kozyrskyj

Department of Pediatrics University of Alberta Edmonton Canada

F

Francis Ka Leung Chan

Microbiota I‐Center (MagIC) Hong Kong SAR China; Centre for Gut Microbiota Research The Chinese University of Hong Kong Hong Kong SAR China

S

Siew Chien Ng

Microbiota I‐Center (MagIC) Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Department of Medicine and Therapeutics Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China

H

Hein Min Tun

Microbiota I‐Center (MagIC) Hong Kong SAR China; Jockey Club School of Public Health and Primary Care Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China; Li Ka Shing Institute of Health Sciences Faculty of Medicine, The Chinese University of Hong Kong Hong Kong SAR China

Cite This Article

Xi Zhang, Darren Chak Lun Chan, Jie Zhu, et al. (2025). Early‐life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides. MedComm, 6(3). https://doi.org/10.1002/mco2.70104

Early‐life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides

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