Determining the role of novel metabolic pathways in driving intracranial pressure reduction after weight loss

Idiopathic intracranial hypertension, a disease classically occurring in women with obesity, is characterised by raised intracranial pressure. Weight loss leads to 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 was the focus for this study.

Meal stimulation tests (fasted plasma sample, then samples at 15, 30, 60, 90 and 120 minutes following a standardised 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.

18 idiopathic intracranial hypertension patients were included (Roux-En-Y gastric bypass n=7, gastric banding n=6, or sleeve gastrectomy n=5). At 2 weeks post-bariatric surgery, despite similar weight loss, Roux-En-Y gastric bypass had a two-fold (50%) greater reduction in intracranial pressure compared to sleeve. Increased meal stimulated glucagon-like peptide-1 secretion was observed after Roux-En-Y gastric bypass (+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 Roux-En-Y gastric bypass 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. Roux-En-Y gastric bypass 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 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.