Abstract

Background Maternal high-fat diet (HFD) increases the risk of metabolic disorders in offspring. Placental inflammation acts as a critical mediator with poorly addressed etiology. Recently HFD-induced gut dysbiosis is demonstrated to be a key driver of systemic inflammation. Whether inflammatory signals triggered by HFD-induced gut dysbiosis are transmitted to the placenta via the maternal-fetal axis warrant further investigation. This study aims to elucidate the mechanistic connection between maternal gut dysbiosis and placental inflammation, thereby offering insights into microbiota-mediated developmental origins of metabolic diseases in offspring. Methods Female C57BL/6 mice were exposed to high fat diet (HFD) for 5 weeks prior to mating with male mice. Gut microbiota was profiled by using 16 S rRNA sequencing and fecal short-chain fatty acids (SCFAs) were quantified by GC-MS from HFD pregnant mice at gestational day 18.5 (G18.5). Mice were sacrificed at G18.5, and placenta histopathological analysis as well as inflammatory markers and lipopolysaccharide (LPS) level were analyzed. Anti-inflammatory effects of butyrate were evaluated in vitro by using HTR-8/Svneo cells and in vivo through gestational supplementation (0.3 mg/g body weight) in HFD-fed dams. Results Maternal HFD exposure induced significant placental inflammation as well as hepatic steatosis in the offspring. HFD-fed dams exhibited distinct gut dysbiosis with reduced fecal and serum SCFAs, which was accompanied by elevated placental LPS levels and exacerbated inflammatory responses. Butyrate treatment suppressed the expression of inflammatory cytokines in vitro through down-regulating the phosphorylation of NF-κB, ERK1/2 signaling pathways via G-protein-coupled receptor 41 (GPR41). Furthermore, gestational butyrate intervention effectively alleviated placental inflammation and mitigated fetal hepatic lipid deposition in HFD-exposed offspring. Conclusion Placental inflammation caused by maternal HFD i