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. 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. 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. 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.
Hu et al. (Tue,) studied this question.