Butyrate and Dietary Soluble Fiber Improve Neuroinflammation Associated With Aging in Mice.

Stephanie M Matt,Marcus A Lawson,Jacob M Allen,Lucy J Mailing,Jeffrey A Woods,Rodney W Johnson

doi:10.3389/fimmu.2018.01832

Stephanie M Matt, Marcus A Lawson + Show 4 more

Open Access

https://doi.org/10.3389/fimmu.2018.01832

Copy DOI

Abstract

Aging results in chronic systemic inflammation that can alter neuroinflammation of the brain. Specifically, microglia shift to a pro-inflammatory phenotype predisposing them to hyperactivation upon stimulation by peripheral immune signals. It is proposed that certain nutrients can delay brain aging by preventing or reversing microglial hyperactivation. Butyrate, a short-chain fatty acid (SCFA) produced primarily by bacterial fermentation of fiber in the colon, has been extensively studied pharmacologically as a histone deacetylase inhibitor and serves as an attractive therapeutic candidate, as butyrate has also been shown to be anti-inflammatory and improve memory in animal models. In this study, we demonstrate that butyrate can attenuate pro-inflammatory cytokine expression in microglia in aged mice. It is still not fully understood, however, if an increase in butyrate-producing bacteria in the gut as a consequence of a diet high in soluble fiber could affect microglial activation during aging. Adult and aged mice were fed either a 1% cellulose (low fiber) or 5% inulin (high fiber) diet for 4 weeks. Findings indicate that mice fed inulin had an altered gut microbiome and increased butyrate, acetate, and total SCFA production. In addition, histological scoring of the distal colon demonstrated that aged animals on the low fiber diet had increased inflammatory infiltrate that was significantly reduced in animals consuming the high fiber diet. Furthermore, gene expression of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were altered by both diet and age, with aged animals exhibiting a more anti-inflammatory microglial profile on the high fiber diet. Taken together, high fiber supplementation in aging is a non-invasive strategy to increase butyrate levels, and these data suggest that an increase in butyrate through added soluble fiber such as inulin could counterbalance the age-related microbiota dysbiosis, potentially leading to neurological benefits.

Highlights

IntroductionThere is a disruption in the communication and balance between the brain and immune system
During healthy aging, there is a disruption in the communication and balance between the brain and immune system
There were no differences in LPS Binding Protein (LBP) (Figure S3 in Supplementary Material). These studies tested the hypotheses that [1] peripheral administration of NaB attenuates basal inflammation and immune reactivity in aged microglia, [2] a high soluble fiber diet, through production of butyrate, attenuates peripheral and central inflammation associated with aging, and that [3] a high soluble fiber diet attenuates aging-induced microglial hyperactivity observed in response to an immune challenge

Summary

Introduction

There is a disruption in the communication and balance between the brain and immune system. We demonstrated that aged mice had decreased methylation of the IL-1β gene promoter in primary microglia basally or following systemic lipopolysaccharide (LPS) that is associated with increased IL-1β mRNA [3]. This is critical because overproduction of IL-1β can cause cognitive dysfunction in rodent models [4] and increased IL-1β in aged individuals is associated with risk of neurodegenerative diseases such as Alzheimer’s [5]. HDAC inhibitors have become an attractive therapeutic candidate due to the ability to increase histone acetylation and promote the expression of neurotrophic and anti-inflammatory genes [7, 8]. Most studies using butyrate have focused on its effects on histone acetylation, there is evidence that butyrate can affect DNA methylation [9,10,11]

Methods

Results

Conclusion