Arnold Amanda R, Chassaing Benoit, Lakhani Kiran, Bergeron Coralie, Shaughnessy Emma K, Rosenhauer Anna M, Stoehr Maura C, Horne Benjamin, Wilkinson Tyler, Huhman Kim L
Neuroscience Institute, Georgia State University, United States of America; Department of Psychiatry and Behavioral Sciences, Emory University, United States of America.
Neuroscience Institute, Georgia State University, United States of America; Microbiome-Host Interactions, INSERM U1306, CNRS UMR6047, Institut Pasteur, Université Paris Cité, Paris, France; Mucosal microbiota in chronic inflammatory diseases, INSERM U1016, CNRS UMR8104, Université de Paris, Paris, France.
Horm Behav. 2025 Jun;172:105750. doi: 10.1016/j.yhbeh.2025.105750. Epub 2025 Apr 30.
Chronic low-grade inflammation and exposure to stress are key contributing factors in the etiology and progression of many neuropsychiatric disorders. Dietary emulsifiers, such as carboxymethylcellulose (CMC) and polysorbate-80 (P80), are commonly added to processed foods and drinks and are classified by the Food and Drug Administration (FDA) as generally recognized as safe (GRAS). Recently, however, we and others have reported that these additives at translationally relevant doses cause low-grade intestinal inflammation, microbiota dysbiosis, and alterations in gene expression in brain areas that mediate behavioral and neuroendocrine responses to stress-provoking stimuli.
To test whether emulsifier exposure sensitizes behavioral, hormonal, and neuronal responses to stress, C57BL/6 J male mice were given water +1 % emulsifier (CMC or P80) or water alone for 12 weeks after which they were exposed to social defeat stress. We previously found increased PTGS2 (COX-2) gene expression in the amygdala following emulsifier consumption. To determine whether inflammation, potentially through the COX pathway, is a potential mechanism driving emulsifier-induced increases in stress sensitivity, we administered the COX inhibitor aspirin (25 mg/kg/day) in conjunction with emulsifiers for the last six weeks of treatment.
In defeated mice, CMC increased circulating corticosterone, while both emulsifiers increased social avoidance behavior and altered defeat-induced c-Fos immunofluorescence in various brain regions. Moreover, behavioral and hormonal alterations were attenuated by aspirin.
These data demonstrate that ingestion of at least some dietary emulsifiers at concentrations analogous to those ingested by humans increases sensitivity to social stress in mice and that the COX pathway may be a mechanistic candidate by which emulsifier-induced increases in sensitivity to social stress occur.
慢性低度炎症和应激暴露是许多神经精神疾病病因及进展的关键促成因素。膳食乳化剂，如羧甲基纤维素（CMC）和聚山梨酯80（P80），通常添加到加工食品和饮料中，美国食品药品监督管理局（FDA）将其归类为一般认为安全（GRAS）。然而，最近我们和其他人报告称，这些添加剂在与翻译相关的剂量下会导致低度肠道炎症、微生物群失调，以及在介导对应激刺激的行为和神经内分泌反应的脑区中基因表达的改变。
为了测试乳化剂暴露是否会使对应激的行为、激素和神经元反应敏感化，给C57BL/6 J雄性小鼠饮用含1%乳化剂（CMC或P80）的水或仅饮用普通水12周，之后使其遭受社会挫败应激。我们之前发现食用乳化剂后杏仁核中PTGS2（COX - 2）基因表达增加。为了确定炎症（可能通过COX途径）是否是驱动乳化剂诱导应激敏感性增加的潜在机制，在治疗的最后六周，我们将COX抑制剂阿司匹林（25毫克/千克/天）与乳化剂联合给药。
在遭受挫败的小鼠中，CMC增加了循环皮质酮水平，而两种乳化剂都增加了社会回避行为，并改变了在各个脑区中挫败诱导的c - Fos免疫荧光。此外，阿司匹林减轻了行为和激素改变。
这些数据表明，摄入至少某些与人类摄入浓度相当的膳食乳化剂会增加小鼠对社会应激的敏感性，并且COX途径可能是乳化剂诱导社会应激敏感性增加的一种潜在机制。
