Deprivation of dietary fiber promotes low-grade neuroinflammation and anxiety-like behavior in mice

Background: Intestinal health is an important determinant of brain function in that an array of gut perturbants, especially those targeting microbiota, influence behavior. Fermentable dietary fiber nourishes gut microbiota and, consequently, promotes gut health. We hypothesized that depriving mice of fermentable dietary fiber would impact their brain and behavior. Methods: Male C57BL/6J mice were fed standard grain-based chow (GBC), a compositionally defined diet (CDD) which mimics macronutrient content of GBC but lacks fermentable fiber, or CDD supplemented with the fermentable fiber inulin (CDD+INU). Mice were subjected to behavioral testing 6-8 weeks later followed by analysis of the gut brain axis. Results: Relative to GBC-fed mice, CDD-fed mice exhibited low-grade gut inflammation and a reduction in open-field center exploration, signaling heightened anxiety-like behavior. CDD+INU fully reversed these abnormalities arguing they were a consequence of fiber deprivation. Analysis of the gut microbiome and serum metabolome showed that CDD+INU increased oxidative phosphorylation and immune suppressive metabolites. Flow cytometric and transcriptomic analyses of the brain revealed an array of pro-inflammatory alterations in myeloid cells, CD4+ T-cells, microglia and astrocytes in mice fed CDD but not CDD+INU. Most notably, microglia and astrocytes from mice fed CDD, but not CDD+INU, displayed reduced mitochondrial respiration and greater glycolytic activity. CDD, but not CDD+INU consumption also reduced the abundance of oligodendrocytes and neurons, and increased hippocampal pro-inflammatory gene expression. Conclusions: Deprivation of fermentable fiber results in coordinated changes in brain immune composition and glial metabolic state that is associated with increased anxiety-like behavior.