福赛坦菌激活舌背黏膜上皮细胞ERK通路导致脂味觉减退和成年“追赶肥”的机制研究

Rapid nutritional promotion after undernutrition in adults motivates catch-up fat, which is considered to be an important causative factor in the high incidence of obesity-related diseases in China. We found that the Tannerella forsythia in dorsal tongue surface induced fat taste perception impairment and adult catch-up fat, but the mechanism is unclear. Our further research revealed that activation of the ERK pathway in epithelial cells of dorsal tongue and increases in lingual keratosis were likely to play a crucial role in reducing perception of fat taste. Thus, we hypothesize that Tannerella forsythia induces fat taste perception impairment and adult catch-up fat by activating ERK pathway in epithelial cells of dorsal tongue and taste bud cells. The detailed mechanism is that the ERK pathway upregulation in epithelial cells of dorsal tongue results in lingual hyperkeratosis, consequently blocking the binding of lipids to their receptors, and the upregulation of ERK pathway in taste bud cells competitively inhibits fatty acid stimulated ERK pathway activation. We intend to investigate the dynamic changes of Tannerella forsythia colonization, activation of ERK pathway in epithelial cells of dorsal tongue and fat taste perception. We also plan to explore the effects of the Tannerella forsythia colonization on ERK pathway activation in epithelial cells of dorsal tongue, fat taste perception and metabolic profiles, as well as the mechanism of Tannerella forsythia inducing fat taste perception impairment and adult catch-up fat. This study will shed new light on the strategy for the precise prevention and intervention of obesity-related diseases in China.

成年低营养水平者若营养快速大幅提升可导致“追赶肥”，这是肥胖相关疾病高发的重要原因之一。我们研究了舌背福赛坦菌定植可诱导脂味觉减退和成年“追赶肥”，但其机制尚待探究。进一步研究提示舌背黏膜上皮细胞ERK通路激活和角化增加，可能在脂味觉减退中起关键作用。本研究提出：福赛坦菌激活舌背黏膜上皮细胞ERK通路，诱导上皮过度角化，阻碍脂质与其受体结合；激活味蕾细胞ERK通路，竞争性抑制脂肪酸激活该通路，导致脂味觉减退和成年“追赶肥”。我们拟动态观察成年“追赶肥”大鼠舌背福赛坦菌定植、黏膜上皮细胞ERK通路和脂味觉改变；以福赛坦菌感染和甲硝唑干预大鼠福赛坦菌舌背定植，确证其对上述变化和代谢特征的影响；进而对舌背黏膜上皮细胞在体内以ERK通路抑制剂、体外以福赛坦菌等干预，验证福赛坦菌经激活舌背黏膜上皮细胞ERK通路导致脂味觉减退和成年“追赶肥”，并初步阐明其机制，为我国肥胖相关疾病精准防控提供新思路。

低营养水平者若营养快速大幅提升可导致成年“追赶肥”，这是我国肥胖相关疾病高发的.重要原因之一。脂味觉减退在成年“追赶肥”形成中起重要作用，其机制研究极具重要意义。.本研究通过人群及动物研究，探究脂味觉减退与口腔舌背细菌的关系，观察成年“追赶肥”动物模型舌背细菌组成、舌背黏膜味蕾数量和脂味觉敏感性的改变；初步揭示口腔细菌在成年“追赶肥”脂味觉减退和代谢异常形成中作用及潜在的分子机制。研究结果如下：（1）人群相关性分析提示脂味觉减退与代谢异常密切相关；（2）不同脂味觉敏感人群其口腔细菌组成存在显著差异；（3）确定了不同脂味觉敏感人群的标志细菌；（4）“追赶肥”大鼠内脏脂肪堆积和胰岛素抵抗明显；（5）“追赶肥”大鼠脂味觉减退；（6）“追赶肥”大鼠和正常组口腔细菌组成有显著差异；（7）“追赶肥”大鼠口腔Hh信号通路减低、味蕾增殖水平减退、味蕾数量减少；（8）抗生素处理减菌鼠口腔Hh信号通路激活、味蕾增殖水平增加。上述研究结果得出如下结论：口腔菌群可能是脂味觉减退的重要原因；口腔细菌可能经Hh信号通路介导味蕾细胞增殖减少进而导致“追赶肥”大鼠脂味觉减退和代谢异常。本课题初步阐明了“追赶肥”大鼠脂味觉减退及其机制，为我国肥胖相关疾病精准防控提供新思路。