Melatonin Alleviates High Temperature Exposure-Induced Fetal Growth Restriction via the Gut-Placenta-Fetus Axis

Research Background

Global climate warming has become a significant threat to human health, particularly affecting pregnant women and fetuses. Studies have shown that high-temperature exposure increases the risk of adverse pregnancy outcomes such as preterm birth, stillbirth, placental insufficiency, and fetal growth restriction. Although previous research has explored the direct impact of heat stress (HS) on reproductive functions, the potential role of gut microbiota in this process remains underexplored. The gut-placenta axis plays a crucial role in fetal development and growth through gut microbiota. Research has found that gut microbial dysbiosis is closely related to pregnancy-related conditions (e.g., preeclampsia) and fetal growth restriction. Additionally, inflammation plays a significant role in adverse pregnancy outcomes, and melatonin (MEL), an endogenous hormone with antioxidant and anti-inflammatory properties, has been shown to have potential effects in alleviating inflammation and oxidative stress during pregnancy.

This study is the first to explore the mechanism by which melatonin alleviates heat stress-induced fetal growth restriction through the regulation of gut microbiota, aiming to provide new intervention targets for the adverse effects of rising global temperatures on vulnerable populations.

Source of the Paper

The research was conducted by a team of authors including Jia-Jin Wu, Xiaoyu Zheng, and Caichi Wu, from institutions such as the College of Animal Science at South China Agricultural University, the Henry Fok School of Biology and Agriculture at Shaoguan University, and the Lingnan Modern Agriculture Laboratory. The paper was published in February 2024 in the Journal of Advanced Research, titled Melatonin alleviates high temperature exposure induced fetal growth restriction via the gut-placenta-fetus axis in pregnant mice.

Research Process and Results

1. Research Design and Animal Model

Researchers first established a heat stress-induced pregnant mouse model, dividing the mice into three groups: control (CON), heat stress (HS), and heat stress + melatonin (HS+MEL). The HS and HS+MEL groups were exposed to 38°C from 12:00 to 14:00 daily, while the rest of the time was maintained at 25±2°C. The HS+MEL group was also supplemented with 10 mg/L melatonin orally.

2. Evaluation of Fetal Growth Restriction

The study found that heat stress significantly reduced the body weight of pregnant mice, as well as fetal weight and placental weight. However, melatonin supplementation significantly alleviated these adverse effects, restoring fetal weight and placental function. This indicates that melatonin can effectively mitigate heat stress-induced fetal growth restriction.

3. Evaluation of Intestinal Barrier Function

Heat stress significantly increased the expression of oxidative stress and inflammatory markers in the intestines of pregnant mice and reduced the expression of tight junction proteins (e.g., Occludin and Claudin-1), indicating impaired intestinal barrier function. Melatonin supplementation significantly improved these indicators, restoring intestinal barrier function.

4. Gut Microbiota Analysis

Through 16S rRNA gene sequencing, researchers found that heat stress caused gut microbial dysbiosis, primarily characterized by a reduction in beneficial bacteria (e.g., Butyricimonas) and an increase in LPS (Lipopolysaccharide)-producing bacteria (e.g., Aliivibrio). Melatonin supplementation significantly restored the balance of these microbial communities, reducing LPS production.

5. LPS-Induced Damage to the Placenta and Fetus

The study found that heat stress significantly increased LPS levels in the serum, placenta, and fetus, activating the TLR4/MAPK/VEGF signaling pathway in the placenta, leading to impaired placental barrier function and nutrient transport dysfunction. Melatonin supplementation significantly reduced LPS levels, inhibited inflammatory signaling pathways, and restored placental function.

6. Microbiota Dependency Verification

Using a pseudo-sterile mouse model and fecal microbiota transplantation experiments, researchers confirmed that the protective effect of melatonin partially depends on gut microbiota. Transplanting fecal microbiota from the HS and HS+MEL groups into antibiotic-treated mice showed that mice receiving HS microbiota exhibited more severe fetal growth restriction and placental dysfunction.

7. LPS Challenge Experiment

To further verify the role of LPS, researchers established an LPS-challenged pregnant mouse model. LPS exposure significantly reduced fetal and placental weight and increased the expression of inflammatory markers in the intestines and placenta. Melatonin supplementation significantly alleviated these adverse effects, confirming its role in mitigating LPS-induced fetal growth restriction.

Research Conclusion

This study is the first to reveal the mechanism by which melatonin alleviates heat stress-induced fetal growth restriction through the regulation of gut microbiota and the gut-placenta-fetus axis. Specifically, melatonin restores beneficial bacteria and inhibits LPS-producing bacteria, reducing LPS production and systemic inflammation, thereby restoring placental function and fetal growth. This discovery provides new intervention strategies for the adverse effects of global warming on vulnerable populations.

Research Highlights

1. First to reveal the role of gut microbiota in heat stress-induced fetal growth restriction.
   
2. Discovered that melatonin alleviates fetal growth restriction by regulating gut microbiota and inhibiting LPS-producing bacteria.
   
3. Verified the microbiota dependency of melatonin through pseudo-sterile mice and fecal microbiota transplantation experiments.
   
4. Provides potential nutritional or pharmaceutical intervention strategies for pregnant women and fetuses in high-temperature environments.
   

Application Value and Future Directions

This study not only provides new scientific insights into the impact of high temperatures on pregnancy outcomes but also offers theoretical support for developing melatonin-based interventions. Future research could further explore the protective effects of melatonin under other environmental stressors (e.g., pollution, infection) and assess its safety and efficacy in human pregnancy. Additionally, interventions targeting gut microbiota (e.g., probiotics or prebiotics) may also become potential strategies for alleviating fetal growth restriction.

Through this in-depth exploration, we have not only uncovered the potential threats of high-temperature environments to maternal and fetal health but also provided scientific evidence for future targeted interventions. As global climate change continues to intensify, the importance of this research will become increasingly prominent.