Gut microbiome moderates the association between metabolic syndrome and the cerebrospinal fluid concentration of YKL‐40 in a cognitively unimpaired cohort
Darby Peter, Margo B. Heston, Gilda E. Ennis, Rob Knight, Rima F. Kaddurah‐Daouk, Sterling C Johnson, Sanjay Asthana, Cynthia M. Carlsson, Nathaniel A. Chin, Gwendlyn Kollmorgen, Margherita Carboni, Kaj Blennow, Henrik Zetterberg, Tyler K. Ulland, Federico E. Rey, Barbara B Bendlin- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Type 2 diabetes (T2D) and metabolic syndrome (MetS) are associated with increased risk of dementia, as well as altered gut microbiome composition (Ott et al., 1999; Ley et al., 2006). However, the extent to which gut microbiome alterations moderate brain pathology in these conditions remains unclear. Here, we examined the extent to which MetS associates with altered cerebrospinal fluid (CSF) biomarkers of Alzheimer’s Disease (AD), glial activation, and neurodegeneration, and whether MetS interacts with gut microbiome composition to impact brain pathology.
Method
Cognitively unimpaired adults (n = 88, Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center; Table 1) underwent fasting blood collection and lumbar puncture, and provided a stool sample. Twenty‐six percent (n = 23) of participants met MetS criteria. Fecal microbiota composition was characterized using 16S rRNA sequencing. QIIME2 was used to denoise and classify features, followed by Phyloseq to filter rare taxa, agglomerate taxa at the phylum rank, and compute relative abundances. Analyses centered on Firmicutes:Bacteroidetes, given its previously observed alterations in T2D and MetS (Stadlbauer et al., 2015). CSF biomarkers were quantified using a robust prototype assay as part of the Roche NeuroToolKit research platform. Multiple regression models were used to determine associations between MetS and CSF biomarkers in addition to Firmicutes:Bacteroidetes, and any MetS by Firmicutes:Bacteroidetes effects on CSF biomarkers. Results are reported as significant when p < 0.05, uncorrected.
Result
A significant negative association between MetS and CSF YKL‐40 was observed (Figs. 1a, 1b), but no significant association between MetS and Firmicutes:Bacteroidetes (Fig 1c), nor associations with other CSF biomarkers (Table 2). MetS showed a significant interaction with Firmicutes:Bacteroidetes on YKL‐40 (Fig. 1d), as control participants with a higher ratio showed increased YKL‐40.
Conclusion
In a cognitively unimpaired cohort, MetS was associated with lower CSF YKL‐40 (a marker of astrocytic activation) and moderated the relationship between Firmicutes:Bacteroidetes and CSF YKL‐40. While the direction of the findings was unexpected, T2D is associated with inhibition of astrocyte activation (Jing et al., 2013), and astroglial function is modulated by gut microbiota. Follow‐up studies are currently testing how gut microbiome modulates neuroimmune function in the context of AD.