Alimajstorovic Zerin, Mitchell James L, Yiangou Andreas, Hancox Thomas, Southam Andrew D, Grech Olivia, Ottridge Ryan, Winder Catherine L, Tahrani Abd A, Tan Tricia M, Mollan Susan P, Dunn Warwick B, Sinclair Alexandra J
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham B15 2GW, UK.
Brain Commun. 2023 Oct 18;5(5):fcad272. doi: 10.1093/braincomms/fcad272. eCollection 2023.
Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterized by raised intracranial pressure. Weight loss leads to the reduction in intracranial pressure. Additionally, pharmacological glucagon-like peptide-1 agonism reduces cerebrospinal fluid secretion and intracranial pressure. The potential mechanisms by which weight loss reduces intracranial pressure are unknown and were the focus of this study. Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 min following a standardized meal) were conducted pre- and post-bariatric surgery [early (2 weeks) and late (12 months)] in patients with active idiopathic intracranial hypertension. Dynamic changes in gut neuropeptides (glucagon-like peptide-1, gastric inhibitory polypeptide and ghrelin) and metabolites (untargeted ultra-high performance liquid chromatography-mass spectrometry) were evaluated. We determined the relationship between gut neuropeptides, metabolites and intracranial pressure. Eighteen idiopathic intracranial hypertension patients were included [Roux-en-Y gastric bypass (RYGB) = 7, gastric banding = 6 or sleeve gastrectomy = 5]. At 2 weeks post-bariatric surgery, despite similar weight loss, RYGB had a 2-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal-stimulated glucagon-like peptide-1 secretion was observed after RYGB (+600%) compared to sleeve (+319%). There was no change in gastric inhibitory polypeptide and ghrelin. Dynamic changes in meal-stimulated metabolites after bariatric surgery consistently identified changes in lipid metabolites, predominantly ceramides, glycerophospholipids and lysoglycerophospholipids, which correlated with intracranial pressure. A greater number of differential lipid metabolites were observed in the RYGB cohort at 2 weeks, and these also correlated with intracranial pressure. In idiopathic intracranial hypertension, we identified novel changes in lipid metabolites and meal-stimulated glucagon-like peptide-1 levels following bariatric surgery which were associated with changes in intracranial pressure. RYGB was most effective at reducing intracranial pressure despite analogous weight loss to gastric sleeve at 2 weeks post-surgery and was associated with more pronounced changes in these metabolite pathways. We suggest that these novel perturbations in lipid metabolism and glucagon-like peptide-1 secretion are mechanistically important in driving a reduction in intracranial pressure following weight loss in patients with idiopathic intracranial hypertension. Therapeutic targeting of these pathways, for example with glucagon-like peptide-1 agonist infusion, could represent a therapeutic strategy.
特发性颅内高压是一种典型发生于肥胖女性的疾病，其特征为颅内压升高。体重减轻可导致颅内压降低。此外，胰高血糖素样肽-1激动剂可减少脑脊液分泌和颅内压。体重减轻降低颅内压的潜在机制尚不清楚，这也是本研究的重点。对患有活动性特发性颅内高压的患者在减肥手术前及术后[早期（2周）和晚期（12个月）]进行进餐刺激试验（空腹血浆样本，然后在标准化进餐后15、30、60、90和120分钟采集样本）。评估肠道神经肽（胰高血糖素样肽-1、胃抑制多肽和胃饥饿素）和代谢物（非靶向超高效液相色谱-质谱法）的动态变化。我们确定了肠道神经肽、代谢物与颅内压之间的关系。纳入了18例特发性颅内高压患者[ Roux-en-Y胃旁路术（RYGB）= 7例，胃束带术= 6例或袖状胃切除术= 5例]。减肥手术后2周，尽管体重减轻程度相似，但RYGB术后颅内压降低幅度比袖状胃切除术大2倍（50%）。与袖状胃切除术（+319%）相比，RYGB术后进餐刺激后胰高血糖素样肽-1分泌增加（+600%）。胃抑制多肽和胃饥饿素无变化。减肥手术后进餐刺激代谢物的动态变化一致显示脂质代谢物发生变化，主要是神经酰胺、甘油磷脂和溶血甘油磷脂，这些与颅内压相关。在2周时，RYGB组观察到更多的差异脂质代谢物，这些也与颅内压相关。在特发性颅内高压中，我们发现减肥手术后脂质代谢物和进餐刺激的胰高血糖素样肽-1水平发生了新的变化，这些变化与颅内压变化有关。尽管术后2周RYGB与袖状胃切除术的体重减轻情况相似，但RYGB在降低颅内压方面最有效，且与这些代谢物途径中更明显的变化有关。我们认为，这些脂质代谢和胰高血糖素样肽-1分泌的新扰动在特发性颅内高血压患者体重减轻后降低颅内压的机制中具有重要意义。针对这些途径进行治疗，例如输注胰高血糖素样肽-1激动剂，可能代表一种治疗策略。
