People living with obesity have a higher risk of late-life cognitive decline and developing dementia. In women, the risk of cognitive decline may further raise during the menopausal transition, a period of substantial hormonal and metabolic changes.

Recent studies suggest that a healthy diet could help to prevent neurocognitive disorders by reducing inflammatory processes in the body and brain. Emerging evidence further indicates that the gut-brain axis and the intestinal microbiome play a crucial role in mediating this effect, through metabolic, immune, neuronal and vascular routes. Modifying the gut microbiota may thus counteract the heightened systemic inflammation seen in obesity and during menopausal transition to eventually benefit brain health.

Specifically, plant-based nutirents, such as fibre and polyphenols, have microbiome-changing, anti-inflammatory and neuroprotective properties that may slow brain aging and neuro-inflammation. However, evidence from human interventional studies and knowledge on the underlying mechanisms remain scarce.

This randomized controlled trial will therefore test whether altering gut bacteria through six months of daily intake of a personalized "polybiotic" dietary formula, compared to placebo, improves markers of brain health in women during the perimenopausal transition that are living with overweight or obesity. We plan to enroll 120 women aged 35-60 with overweight/obesity and elevated inflammatory blood markers, randomized to: intervention (7.5 or 15 g inulin, plus 200 mg resveratrol and 320 mg quercetin per day in powder form with main meals) or control (isocaloric maltodextrin). Exclusions include type 1 diabetes, current psychiatric/gastrointestinal disorders, and magentic resonance imaging (MRI) contraindications.

Before and after 26 weeks, participants will undergo brain MRI to assess inflammation-related brain markers, neuropsychological testing, anthropometric measurements, they will fill in a set of questionnaires and donate stool and blood. Gut bacteria will be profiled by next-generation sequencing; metabolites will be measured in blood and stool. The primary outcome is a proxy of neuroinflammation in the white matter assessed using diffusion-weighted MRI. Secondary analyses will examine blood-brain-barrier permeability and other functional and structural MRI measures, including MR spectoscropy. Mechanistic links among changes in inflammatory markers, microbiota composition, and short-chain fatty acids will be explored using path and network models.

This study may help to develop novel prevention and treatment strategies to mitigate obesity-related cognitive decline via the gut-brain axis.

Inclusion Criteria:

• STRAW+10 -1 or -2
• BMI > 25 or WHR >= 0.85
• hsCRP > 1 mg/l
• no MRI contra-indication
• written informed consent

Exclusion Criteria:

• occurrence of a clinically relevant psychiatric disease in the last 12 months (e.g., depression, substance abuse, eating disorder, schizophrenia)
• type 1 diabetes
• previous bariatric/gastric surgery
• pregnancy or breastfeeding woman
• severe untreated disease, cancer treatment last 12 months, any chronic gastric tract disease (IBS, Morbus Crohn, Heliobacter pylori Infection etc.) or any chronic inflammatory disease
• Polycystic ovary syndrome, total ovarectomy
• Intake of antibiotics in past 3 months, intake of inulin (>5g/day) or polyphenol supplementation (>50mg/day) in past 3 months