2026 ECNP Congress

PS04-4080

Linking obesity to brain health through the gut–brain axis

Yee Teng Lee — D.E.A. Jensen, F. Beyer, M. Vartanian, I. Muller, S.B. Haange, M. Stumvoll, A. Villringer, V. Witte · University of Leipzig Medical Center, Clinic for Cognitive Neurology, Leipzig, Germany

2026 ECNP Congress

Aging is associated with progressive declines in brain structure and function, which may be further exacerbated by obesity. For instance, lower grey matter volume, hippocampal volume, and cortical thickness are associated with obesity, which could lead to poorer executive functions. Existing evidence also suggests the crucial role of gut-brain axis as a mechanistic driver in this association. For instance, an unfavourable obesity-associated Firmicutes/Bacteroidetes ratio may promote systemic inflammation in the gut, which triggers neuroinflammation in the hypothalamus, thereby negatively impacting brain health. However, the direct association between microbiome markers, obesity measures, and brain structural differences have yet to be fully elucidated. Our preregistered cross-sectional study (https://osf.io/de9ak) aimed to examine associations between brain markers and gut microbiome features among individuals with overweight and obesity using multimodal neuroimaging and microbiome data.

We analysed healthy adults with a BMI of 25 kg/m2 or higher, pooled from the Gut-Brain study (NCT03829189) [1] and the MIFOOD study (NCT05353504) [2]. Adiposity was assessed using BMI, waist-to-hip ratio (WHR), and body fat percentage. T1-weighted anatomical and diffusion-weighted MRI data was acquired on a 3T scanner and between study effects were harmonized using ComBat. Anatomical images were pre-processed using FreeSurfer 7.4.1 to obtain total grey matter and hippocampal volume, global cortical thickness, and hypothalamus masks. We used FSL 6.0.7.11 to preprocess diffusion-weighted images to measure white matter connectivity of global skeletonized fractional anisotropy (FA) and hypothalamic mean diffusivity (MD). We assessed stool samples using shotgun metagenomic sequencing to obtain gut microbiota diversity metrics (Shannon, Simpson indices) and bacterial abundance measures. Linear models implemented in R were used to assess the association of adiposity, brain structure, and microbiome diversity and abundance, adjusting for age and sex. We included a total of 150 adults (62 females) with overweight and obesity in this study (age=34.8 ± 10.2 SD years, BMI=30.3 ± 4.8 SD kg/m2). We found that higher BMI (β(SE)=-985.87 (476.89) mm3, 95% CI [-1928.49, -43.26], p=0.0405, pFDR= 0.304) and higher body fat (β(SE)=-4740.13 (2274.51) mm3, 95% CI [-9236.140, -244.125], p=0.0389, pFDR=0.304) were related to lower total grey matter volume. Analyses with gut microbiota revealed associations between lower alpha diversity, as indicated by Shannon index (β(SE)=-0.089 (0.036), 95% CI [-0.160, -0.019], p=0.0134, pFDR=0.0333) and Simpson’s D (dominance index) (β(SE)= 0.014 (0.006), 95%CI [0.002, 0.025], p=0.0222 pFDR=0.0333) and higher WHR. We did not find significant associations for obesity measures and hippocampal volume, hypothalamus MD or cortical thickness, and between microbiome markers and brain structures.

In this cohort of 150 adults with overweight and obesity, we found that higher BMI or body fat correlated with lower grey matter volume and lower gut alpha diversity. However, we could not establish significant links between microbiome measures and regional brain markers, which might stem from null effects or low variance in weight status, resulting in low statistical power. Data pooling in future analyses might help to clarify potential role of the gut–brain axis in obesity-related brain health, with both neuroimaging markers and microbial diversity representing complementary biomarkers and targets for future longitudinal and interventional studies.

References

  1. Medawar, E., Beyer, F., Thieleking, R., Haange, S.B., Rolle-Kampczyk, U., Reinicke, M., Chakaroun, R., von Bergen, M., Stumvoll, M., Villringer, A., Witte, A.V., 2024. Prebiotic diet changes neural correlates of food decision-making in overweight adults: a randomised controlled within-subject cross-over trial. Gut 73 (2), 298–310.
  2. Vartanian, M., Endres, K.J., Lee, Y.T., Friedrich, S., Meemken, M.T., Schamarek, I., Rohde-Zimmermann, K., Schürfeld, R., Eisenberg, L., Hilbert, A., Beyer, F., Stumvoll, M., Sacher, J., Villringer, A., Christensen, J.F., Witte, A.V., 2025. Investigating the impact of microbiome-changing interventions on food decision-making: MIFOOD study protocol. BMC Nutr. 11 (1), 8.