Butyrate deficiency due to microbial dysbiosis promotes anxiety

for this association remains incompletely understood. Diabetes-associated genes have been implicated in the control of central nervous system (CNS) disorders. In the current study, we observed a significant downregulation of secretagogin (SCGN) across multiple organs in diabetic mouse models. Consequently, SCGN knockout (Scgn-/-) mice developed diabetes, confirming SCGN as a diabetes-associated gene. Behavioral analyses revealed that Scgn-/- mice exhibited anxiety-like phenotypes compared to wild-type (WT) mice. Notably, germ-free (GF) Scgn-/- mice did not manifest these behavioral abnormalities, demonstrating that SCGN influences anxiety through gut microbiota-dependent mechanisms. Subsequent 16S rRNA sequencing confirmed gut microbiota dysbiosis in Scgn-/- mice. Fecal microbiota transplantation (FMT) from Scgn-/- donors into GF mice recapitulated the anxiety-like phenotypes. Given the established roles of microbial metabolites in gut-brain axis signaling, we quantified short-chain fatty acids (SCFAs), identifying marked depletion of a key neuroactive metabolite, butyrate, in the Scgn-/- fecal and plasma samples. Immunohistochemical analysis revealed neural overactivation via c-Fos expression in the medial prefrontal cortex (mPFC) of Scgn-/- mice, which was corroborated by metabolomic profiling indicating dysregulated tryptophan metabolism in this region. Mechanistically, the upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) and kynureninase (KYNU) promoted excessive quinolinic acid production. This NMDA receptor agonist enhanced pyramidal neuron excitability in the mPFC, driving anxiety-like behaviors in Scgn-/- mice. Critically, butyrate administration reversed this pathological cascade in vivo and in vitro, as validated by electrophysiological recordings. Taken together, our findings demonstrate that SCGN deficiency induces gut dysbiosis, reduces butyrate bioavailability, and promotes mPFC excitotoxicity through disrupted tryptophan metabolism, ultimately culminating in anxiety. This SCGN-modulated gut-brain axis identifies novel therapeutic targets for diabetes-associated anxiety.

二者的关联目前仍未完全阐明。糖尿病相关基因已被证实参与中枢神经系统（CNS）疾病的调控。本研究中，我们在糖尿病小鼠模型的多个器官中均观察到分泌粒蛋白（secretagogin, SCGN）的显著下调。由此，SCGN基因敲除（knockout, Scgn⁻/⁻）小鼠可自发出现糖尿病表型，证实SCGN为糖尿病相关基因。行为学分析显示，与野生型（wild-type, WT）小鼠相比，Scgn⁻/⁻小鼠表现出焦虑样行为表型。值得注意的是，无菌（germ-free, GF）饲养的Scgn⁻/⁻小鼠并未出现上述行为异常，表明SCGN通过肠道菌群依赖的机制调控焦虑行为。后续的16S核糖体RNA（16S rRNA）测序证实，Scgn⁻/⁻小鼠存在肠道菌群失调。采用粪便菌群移植（fecal microbiota transplantation, FMT）技术，将Scgn⁻/⁻供体小鼠的粪便菌群移植到无菌小鼠体内，可重现其焦虑样行为表型。鉴于微生物代谢产物在肠-脑轴信号传导中的既定作用，我们对短链脂肪酸（short-chain fatty acids, SCFAs）进行了定量检测，发现Scgn⁻/⁻小鼠的粪便及血浆样本中关键神经活性代谢产物丁酸（butyrate）的含量显著降低。免疫组织化学分析显示，Scgn⁻/⁻小鼠的内侧前额叶皮层（medial prefrontal cortex, mPFC）内c-Fos表达升高，提示神经元过度激活；代谢组学分析进一步证实该脑区存在色氨酸代谢紊乱，与上述结果一致。机制层面，吲哚胺2,3-双加氧酶1（indoleamine 2,3-dioxygenase 1, IDO1）与犬尿氨酸酶（kynureninase, KYNU）的表达上调促进了过量喹啉酸的生成。作为N-甲基-D-天冬氨酸（NMDA）受体激动剂，喹啉酸可增强内侧前额叶皮层内锥体神经元的兴奋性，进而诱发Scgn⁻/⁻小鼠的焦虑样行为。至关重要的是，丁酸给药可在体内及体外逆转这一病理级联反应，该结果经电生理记录得到验证。综上，我们的研究结果表明，SCGN缺乏可诱导肠道菌群失调、降低丁酸生物利用度，并通过紊乱色氨酸代谢增强内侧前额叶皮层的兴奋性毒性，最终导致焦虑行为。这一受SCGN调控的肠-脑轴通路为糖尿病相关焦虑提供了全新的治疗靶点。