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Background <p>The rising prevalence of metabolic diseases represents a global health challenge, with metabolically unhealthy normal-weight (MUHNW) individuals remaining largely overlooked. In addition to direct fine particulate matter (PM<sub>2.5</sub>) inhalation, there is growing recognition that maternal PM<sub>2.5</sub> exposure may be a contributing environmental factor for metabolic disorders. However, the mechanisms by which maternal PM<sub>2.5</sub> exposure induced metabolic disorders in the offspring remain unknown.</p> Methods <p>Eight-week-old pregnant C57BL/6N mice were exposed to either filtered air (FA) or ambient PM<sub>2.5</sub> throughout gestation, from gestational day 0 to 18, using a whole-body inhalation exposure system. Eight-week-old male C57BL/6N mice were treated once daily for three consecutive days with an antibiotic cocktail containing 1&#xa0;g/L ampicillin, 0.5&#xa0;g/L neomycin, 0.5&#xa0;g/L vancomycin, and 1&#xa0;g/L metronidazole to generate pseudo-germ-free mice. Subsequently, fecal microbiota from maternal PM<sub>2.5</sub>-exposed three-week-old male mouse offspring (donor) were transplanted to pseudo-germ-free mice (recipient) via oral gavage twice weekly for five weeks. After fecal microbiota transplantation (FMT), fecal samples from donor and recipient mice were collected for full-length 16S rRNA sequencing. Liver tissue from donor mice was analyzed by 5R 16S rRNA sequencing.</p> Results <p>Maternal PM<sub>2.5</sub> exposure induced non-obese insulin resistance in adult male mouse offspring, with the liver identified as a susceptible organ characterized by suppressed AKT phosphorylation. Subsequently, systemic and hepatic insulin resistance were recapitulated in pseudo-germ-free mice, which received gut microbiota from maternal PM<sub>2.5</sub>-exposed mouse offspring via FMT. Mechanistically, the increased abundance of <i>Helicobacter hepaticus</i> contributed to DNA damage-mediated colonic barrier injury. This impaired colonic barrier facilitated gut-to-liver translocation of bacteria and lipopolysaccharide (LPS), which triggered hepatic inflammation via activation of TLR4 signaling pathway, ultimately leading to insulin resistance.</p> Conclusions <p>These findings indicated a causal role for gut microbiota dysbiosis in maternal PM<sub>2.5</sub> exposure-induced non-obese insulin resistance in the offspring, providing potential insights into the developmental origins of MUHNW from the perspective of maternal exposure to air pollution.</p>

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Maternal PM2.5 exposure induces insulin resistance in adult male mouse offspring via gut–liver axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Renjie Hu,
  • Wenbin Zhao,
  • Wenjun Fan,
  • Ran Li,
  • Lu Zhang,
  • Li Qin,
  • Huanhuan Zhu,
  • Xuan Zhu,
  • Qinghua Sun,
  • Guifen Qiang,
  • Cuiqing Liu

摘要

Background

The rising prevalence of metabolic diseases represents a global health challenge, with metabolically unhealthy normal-weight (MUHNW) individuals remaining largely overlooked. In addition to direct fine particulate matter (PM2.5) inhalation, there is growing recognition that maternal PM2.5 exposure may be a contributing environmental factor for metabolic disorders. However, the mechanisms by which maternal PM2.5 exposure induced metabolic disorders in the offspring remain unknown.

Methods

Eight-week-old pregnant C57BL/6N mice were exposed to either filtered air (FA) or ambient PM2.5 throughout gestation, from gestational day 0 to 18, using a whole-body inhalation exposure system. Eight-week-old male C57BL/6N mice were treated once daily for three consecutive days with an antibiotic cocktail containing 1 g/L ampicillin, 0.5 g/L neomycin, 0.5 g/L vancomycin, and 1 g/L metronidazole to generate pseudo-germ-free mice. Subsequently, fecal microbiota from maternal PM2.5-exposed three-week-old male mouse offspring (donor) were transplanted to pseudo-germ-free mice (recipient) via oral gavage twice weekly for five weeks. After fecal microbiota transplantation (FMT), fecal samples from donor and recipient mice were collected for full-length 16S rRNA sequencing. Liver tissue from donor mice was analyzed by 5R 16S rRNA sequencing.

Results

Maternal PM2.5 exposure induced non-obese insulin resistance in adult male mouse offspring, with the liver identified as a susceptible organ characterized by suppressed AKT phosphorylation. Subsequently, systemic and hepatic insulin resistance were recapitulated in pseudo-germ-free mice, which received gut microbiota from maternal PM2.5-exposed mouse offspring via FMT. Mechanistically, the increased abundance of Helicobacter hepaticus contributed to DNA damage-mediated colonic barrier injury. This impaired colonic barrier facilitated gut-to-liver translocation of bacteria and lipopolysaccharide (LPS), which triggered hepatic inflammation via activation of TLR4 signaling pathway, ultimately leading to insulin resistance.

Conclusions

These findings indicated a causal role for gut microbiota dysbiosis in maternal PM2.5 exposure-induced non-obese insulin resistance in the offspring, providing potential insights into the developmental origins of MUHNW from the perspective of maternal exposure to air pollution.