Early-Life Antibiotic Exposure Aggravates Hepatic Steatosis Through Perturbations in Gut Microbiota Succession and Development

Abstract

Background: Despite compelling evidence for the imprinting effect of early-life gut microbiota on the development of metabolic dysfunction-associated steatotic liver disease (MASLD), the long-term impact and mechanistic insights of maternal antibiotic exposure-induced gut microbiota perturbations on metabolic dysfunctions have yet to be clarified.

Methods: Using an early-life antibiotic exposure model in BALB/c mice, we characterized the impact of prenatal and/or postnatal antibiotic exposures on the gut microbiome of offspring through maternal administration of penicillin V. Serological and histological examinations, alongside an integrated transcriptomic and lipidomic analysis, were conducted to comprehensively investigate the systemic and hepatocellular pathogenic responses in high-fat-diet-fed mice following antibiotic exposure in early life.

Findings: Early-life antibiotic exposure tremendously impacted the diversity, community structure, and intergenerational transfer of the gut microbiota in offspring. Microbiome-driven effects reduced the expression of hepatic cholesterol 7α-hydroxylase (CYP7A1), an enzyme naturally irresponsive to high-fat diet (HFD), in wild-type BALB/c mice. Compared to prenatal antibiotic exposure alone, postnatal antibiotic exposure had a more profound effect on HFD intervention by aggravating endotoxemia and metabolic dysfunctions. This was primarily resulted from the enrichment of gut Parabacteroides and hepatic accumulation of cytotoxic lipids, such as lysophosphatidyl cholines (LPCs), which enhanced endoplasmic reticulum stress response and apoptosis.

Interpretation: Early-life antibiotic exposure substantially perturbed gut microbiota succession and development in offspring and aggravated metabolic dysfunction in later life, despite genetically determined resistance to HFD.

Funding: This project was partially supported by a start-up research grant of The Chinese University of Hong Kong (CUHK) and a grand under Early Career Scheme from the Research Grants Council of the Hong Kong Special Administrative Region, China (RGC/ECS Project No. 27117022) to HMT. This study was also supported by InnoHK, The Government of Hong Kong, Special Administrative Region of the People’s Republic of China. FKLC, SCN, HMT are named inventors of patent applications held by The CUHK and MagIC that cover the therapeutic and diagnostic use of microbiome.

Declaration of Interest: FKLC is Board Member of CUHK Medical Centre. He is a co-founder, non-executive Board Chairman and shareholder of GenieBiome Ltd. He receives patent royalties through his affiliated institutions. He has received fees as an advisor and honoraria as a speaker for Eisai Co. Ltd., AstraZeneca, Pfizer Inc., Takeda Pharmaceutical Co., and Takeda (China) Holdings Co. Ltd. SCN has served as an advisory board member for Pfizer, Ferring, Janssen, and Abbvie and received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, Abbvie, and Takeda. SCN has received research grants through her affiliated institutions from Olympus, Ferring, and Abbvie. SCN is a scientific co-founder and shareholder of GenieBiome Ltd. SCN receives patent royalties through her affiliated institutions.

Ethical Approval: Ethical approval for animal experiments were obtained from the Committee on the Use of Live Animals in Teaching and Research.

Keywords: Early life, gut microbiota, antibiotics, metabolic dysfunction-associated steatotic liver disease, multiomics