Maternal gestational diabetes mellitus leads to adverse growth patterns and disease risk in offspring in vivo: evidence from cross-generational effects on gut microbiota

Gestational diabetes mellitus (GDM) is an important risk factor for metabolic diseases such as obesity in its offspring, and this effect may be mediated by altering the infant’s gut microbiota. Fecal samples from offspring born to mothers with GDM (G-O, n = 29) and non-GDM mothers (C-O, n = 30) was collected and analyzed by 16 S rRNA gene sequencing. Subsequently, two types of infant fecal microbiota were transplanted into pseudo-sterile mouse models maintained on normal diet (ND) and high-fat diet (HFD) for 16 weeks, to investigate the relationship between the fecal microbiota of offspring of GDM and the risk of diseases such as obesity and dysglycemia in their later life. Significant differences in gut microbial composition between G-O and C-O (p < 0.05). Fecal microbiota transplantation (FMT) from G-O resulted in obesity, hypertrophy of adipocytes in white adipose tissue (WAT), and abnormal glucose tolerance compared to mice that received FMT from C-O. The 16 S rRNA sequencing results showed that under ND, the abundance of the potentially pathogenic bacteria Eubacterium_nodatum_group and Lachnoclostridium was significantly increased in the FMT from G-O group, while the abundance of the beneficial bacteria Acetatifactor, Muribaculum, and Lactobacillus was significantly decreased (all p < 0.05). Further analysis showed that fecal isobutyrate levels were significantly lower in the FMT from G-O group compared to the FMT from C-O group (p < 0.05). In addition, under HFD, the FMT from G-O group enriched the abundance of Alistipes, Rikenellaceae_RC9_gut_group, Rikenella, and Bilophila, while the abundance of Akkermansia, Faecalibaculum, and Lactobacillus showed a decrease (all p < 0.05). Meanwhile, the fecal acetate content in the FMT from G-O group was significantly higher than that in the FMT from C-O group (p < 0.05). Mothers with GDM are associated with significant gut microbiota dysbiosis in G-O, and transplantation of G-O fecal microbiota is associated with increased fat accumulation and impaired glucose tolerance in mice Therefore, the gut microbiota dysbiosis in G-O is associated with later-life growth abnormalities and increased disease risk, suggesting a potential role in this association. This study focused on the impact of gestational diabetes mellitus (GDM) on offspring’s long-term health, especially the role of the gut microbiota in infant feces. Fecal samples were collected from offspring born to mothers with (G-O) and without GDM(C-O) and analysed changes in the gut microbiota in infant feces using 16 S rRNA sequencing; A pseudo-sterile mouse model was established by administering water containing antibiotics; FMT of the gut microbiota in infant feces from C-O and G-O was given by gavage to pseudo-sterile male C57BL/6 mice, which were fed either ND or HFD daily for 16 weeks. The results demonstrated significant differences in gut microbiota between mice receiving FMT from C-O and G-O, regardless of whether they were maintained on ND or HFD. Under ND, FMT from G-O results in increased body weight, hypertrophy of adipocytes in both iWAT and eWAT, and impaired glucose tolerance compared to those FMT with C-O. 16 S rRNA sequencing revealed a significant increase in the abundance of potentially pathogenic bacteria, including Eubacterium_nodatum_group and Lachnoclostridium, in mice receiving FMT from G-O. Conversely, the abundance of beneficial bacteria such as Acetatifactor, Muribaculum, and Lactobacillus was significantly reduced. Further analyses indicated that isobutyrate levels were markedly lower in the feces of mice receiving FMT from G-O transplants compared to those receiving FMT from C-O. Under HFD, mice receiving FMT of the gut microbiota in infant feces from G-O exhibited increased body weight and eWAT, hypertrophy of iWAT adipocytes, and impaired glucose tolerance. In addition, these mice showed an increased abundance of Alistipes, Rikenellaceae_RC9_gut_group, Rikenella and Bilophila in their feces compared to those transplanted with feces from C-O; conversely, the abundance of Akkermansia, Faecalibaculum and Lactobacillus was significantly reduced, while the concentration of acetate in the feces was significantly increased. This study provides a scientific basis for exploring the association between gut microbiota and the intergenerational effects of GDM, with further mechanistic studies needed to clarify the underlying pathways.