Izzy Saef, Yahya Taha, Albastaki Omar, Cao Tian, Schwerdtfeger Luke A, Abou-El-Hassan Hadi, Chopra Kusha, Ekwudo Millicent N, Kurdeikaite Ugne, Verissimo Isabelly M, LeServe Danielle S, Lanser Toby B, Aronchik Michael, Oliveira Marilia G, Moreira Thais, Rezende Rafael Machado, El Khoury Joseph, Cox Laura M, Weiner Howard L, Zafonte Ross, Whalen Michael J
Divisions of Stroke, Cerebrovascular, and Critical Care Neurology, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Brain Commun. 2024 May 3;6(4):fcae147. doi: 10.1093/braincomms/fcae147. eCollection 2024.
The associations between human concussions and subsequent sequelae of chronic neuropsychiatric and cardiovascular diseases such as hypertension have been reported; however, little is known about the underlying biological processes. We hypothesized that dietary changes, including a high-salt diet, disrupt the bidirectional gut-brain axis, resulting in worsening neuroinflammation and emergence of cardiovascular and behavioural phenotypes in the chronic period after repetitive closed head injury in adolescent mice. Adolescent mice were subjected to three daily closed head injuries, recovered for 12 weeks and then maintained on a high-salt diet or a normal diet for an additional 12 weeks. Experimental endpoints were haemodynamics, behaviour, microglial gene expression (bulk RNA sequencing), brain inflammation (brain tissue quantitative PCR) and microbiome diversity (16S RNA sequencing). High-salt diet did not affect systemic blood pressure or heart rate in sham or injured mice. High-salt diet increased anxiety-like behaviour in injured mice compared to sham mice fed with high-salt diet and injured mice fed with normal diet. Increased anxiety in injured mice that received a high-salt diet was associated with microgliosis and a proinflammatory microglial transcriptomic signature, including upregulation in interferon-gamma, interferon-beta and oxidative stress-related pathways. Accordingly, we found upregulation of tumour necrosis factor-alpha and interferon-gamma mRNA in the brain tissue of high salt diet-fed injured mice. High-salt diet had a larger effect on the gut microbiome composition than repetitive closed head injury. Increases in gut microbes in the families , and were positively correlated with anxiety-like behaviours. In contrast, Muribaculaceae, Acholeplasmataceae and were negatively correlated with anxiety in injured mice that received a high-salt diet, a time-dependent effect. The findings suggest that high-salt diet, administered after a recovery period, may affect neurologic outcomes following mild repetitive head injury, including the development of anxiety. This effect was linked to microbiome dysregulation and an exacerbation of microglial inflammation, which may be physiological targets to prevent behavioural sequelae in the chronic period after mild repetitive head injury. The data suggest an important contribution of diet in determining long-term outcomes after mild repetitive head injury.
人类脑震荡与慢性神经精神疾病和心血管疾病（如高血压）的后续后遗症之间的关联已有报道；然而，对于潜在的生物学过程却知之甚少。我们推测，饮食变化，包括高盐饮食，会破坏双向肠-脑轴，导致青少年小鼠重复性闭合性头部损伤后慢性期神经炎症恶化以及心血管和行为表型的出现。将青春期小鼠每天进行三次闭合性头部损伤，恢复12周，然后再分别给予高盐饮食或正常饮食12周。实验终点包括血流动力学、行为、小胶质细胞基因表达（批量RNA测序）、脑炎症（脑组织定量PCR）和微生物群多样性（16S RNA测序）。高盐饮食对假手术组或受伤小鼠的全身血压或心率没有影响。与高盐饮食喂养的假手术小鼠和正常饮食喂养的受伤小鼠相比，高盐饮食增加了受伤小鼠的焦虑样行为。接受高盐饮食的受伤小鼠焦虑增加与小胶质细胞增生和促炎性小胶质细胞转录组特征有关，包括干扰素-γ、干扰素-β和氧化应激相关途径的上调。因此，我们发现高盐饮食喂养的受伤小鼠脑组织中肿瘤坏死因子-α和干扰素-γ mRNA上调。高盐饮食对肠道微生物群组成的影响大于重复性闭合性头部损伤。、和科肠道微生物的增加与焦虑样行为呈正相关。相比之下，Muribaculaceae、无胆甾原体科和与接受高盐饮食的受伤小鼠的焦虑呈负相关，这是一种时间依赖性效应。研究结果表明，恢复期后给予高盐饮食可能会影响轻度重复性头部损伤后的神经学结局，包括焦虑的发展。这种效应与微生物群失调和小胶质细胞炎症加剧有关，这可能是预防轻度重复性头部损伤后慢性期行为后遗症的生理靶点。数据表明饮食在决定轻度重复性头部损伤后的长期结局方面具有重要作用。
