Maternal melatonin supplementation shapes gut microbiota and protects against inflammation in early life.

BACKGROUND: Gut microbiota colonization is critical for immune education and nutrient metabolism. Research shows that melatonin has beneficial effects as a therapy for many diseases via modulating gut dysbiosis. However, it is unclear whether melatonin alters gut microbiota colonization in early life. METHODS: In the experimental group (Mel), mice were intraperitoneally injected with melatonin at 10 mg/kg body weight for embryonic days 14-16 and received drinking water containing 0.4 mg/mL melatonin until 28 days postpartum. In the control group (Ctrl), mice were injected with the same volume of 2.5% ethanol in saline and provided with standard water. Two more groups were created by treating neonatal mice with 20 mg/kg lipopolysaccharide (LPS) to induce inflammation, resulting in the groups Ctrl + LPS and Mel + LPS, respectively. We examined the gut microbiota of the neonatal mice in the Ctrl and Mel group on Days 7, 14, 21, and 28 post-birth. On Day 14, melatonin and short-chain fatty acids (SCFAs) concentrations were measured in the Ctrl and Mel group and the mice were treated with LPS to be evaluated for intestinal injury and inflammatory response 15 h post treatment. According to the result of the SCFAs concentrations, some neonatal mice were intraperitoneally injected with 500 mg/kg sodium butyrate (SB) from Days 11-13, intraperitoneally injected with 20 mg/kg LPS on Day 14, and then euthanized by carbon dioxide inhalation the next morning. Intestinal injury and inflammatory responses were evaluated in the Ctrl + LPS and SB + LPS groups, respectively. RESULTS: By Day 14, it was evident that maternal melatonin supplementation significantly increased the relative abundance of Firmicutes in the ileal [61.03 (35.35 - 76.18) % vs. 98.02 (86.61 - 99.01) %, P = 0.003] and colonic [73.88 (69.77 - 85.99) % vs. 96.16 (94.57 - 96.34) %, P = 0.04] microbiota, the concentration of melatonin (0.79 ± 0.49 ng/ml vs. 6.11 ± 3.48 ng/ml, P = 0.008) in the gut lumen, and the fecal butyric acid (12.91 ± 5.74 µg/g vs. 23.58 ± 10.71 µg/g, P = 0.026) concentration of neonatal mice. Melatonin supplementation, and sodium butyrate treatment markedly alleviated intestinal injury and decreased inflammatory factors in neonatal mice. CONCLUSION: This study suggests that maternal melatonin supplementation can shape the gut microbiota and metabolism of offspring under normal physiological conditions and protect them against LPS-induced inflammation in early life.

Hashimoto's thyroiditis induces neuroinflammation and emotional alterations in euthyroid mice.

BACKGROUND: Although studies have reported an increased risk for mood disorders in Hashimoto's thyroiditis (HT) patients even in the euthyroid state, the mechanisms involved remain unclear. Neuroinflammation may play a key role in the etiology of mood disorders in humans and behavioral disturbances in rodents. Therefore, this study established a euthyroid HT model in mice and investigated whether HT itself was capable of triggering neuroinflammation accompanied by emotional alterations. METHODS: Experimental HT was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Four weeks after the last challenge, mice were tested for anxiety-like behavior in the open field and elevated plus maze tests and depression-like behavior in the forced swimming and tail suspension tests. Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with neuroinflammation. The changes in components of central serotonin signaling were also investigated. RESULTS: HT mice showed intrathyroidal monocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function, which defines euthyroid HT in humans. These mice displayed more anxiety- and depressive-like behaviors than controls. HT mice further showed microglia and astrocyte activation in the frontal cortex detected by immunohistochemistry, real-time RT-PCR, and transmission electron microscopy (TEM). These observations were also accompanied by enhanced gene expression of proinflammatory cytokines IL-1ß and TNF-α in the frontal cortex. Despite this inflammatory response, no signs of neuronal apoptosis were visible by the TUNEL staining and TEM in the frontal cortex of HT mice. Additionally, IDO1 and SERT, key serotonin-system-related genes activated by proinflammatory cytokines, were upregulated in HT mice, accompanied by reduced frontal cortex serotonin levels. CONCLUSIONS: Our results are the first to suggest that HT induces neuroinflammation and alters related serotonin signaling in the euthyroid state, which may underlie the deleterious effects of HT itself on emotional function.