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Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13 Page 223

influence and improve neuroinflammation through different mechanisms. Butyrate is a known inhibitor
of histone deacetylases (HDACs) [108,109] , which control the innate inflammatory system by regulating the
number of microglia cells and astrocytes [110] . Histone acetylation is a post-translational modification
through epigenetic process and causes the chromatin structure to loosen by weakening electrostatic
attraction between the histone proteins and DNA backbone. Activation of microglia are suppressed by this
process. Therefore, increased HDACs have been shown to be involved in neurodegenerative disorders, such
as Alzheimer’s and Parkinson’s diseases [110,111] .

Butyrate is one of the most important microbial end-products of the human colon fermentation process
which displays several physiological effects via different mechanisms. One function is mentioned
above: butyrate is a well-established HDAC inhibitor. In addition to having a significant impact on the
transcriptional system, butyrate also serves as the energy substrate. Butyrate is the primary source of
energy in the colon and microbiome, which accounts for nearly 70% of ATP produced. It may appear that
metabolic events in the colon are disconnected with that of the brain. However, it is impossible to ignore
the immense energy demand of the brain. In this regard, energy imbalance in the brain has been noted at
early stages of neurodegenerative disease such as Alzheimer’s disease [112] . Another function of butyrate is its
ability to activate GPCRs, as described in detail above, within the vagus nerve system section [113] . Butyrate
can signal through GPR109a, which is widely expressed in colonocytes, T cells and has also been found in
microglia. Butyrate is sensed by FFA2 (previously GPR43) and FFA3 (previously GPR41), which modulate
the relationship between SCFAs and gut, as well as the whole body energy use [114,115] .

Many studies have shown that butyrate can serve as an anti-inflammatory agent, improving gut barrier
function, protecting against colon cancer and neurodegenerative diseases, such as Alzheimer’s disease [116-118] .
These studies demonstrate that treatment with butyrate inhibited pro-inflammatory cytokines (IFN-γ,
TNF-α, IL-1β, IL-6, and IL-8) and upregulated anti-inflammatory cytokines (IL-10 and TGF-β). This effect
may be partly due to the inhibition of transcription factor NF-κB that controls the transcription of DNA,
cytokine production, and cell survival. Aguilar et al. [119] demonstrated that butyrate suppressed the NF-
κB signaling pathway by rescuing the redox machinery and controlling ROS, which also regulate NF-κB
activation. In addition, butyrate is known to enhance and repair barrier function of intestinal epithelial
cells. In vitro experiments have illustrated that butyrate plays an important role in the maintenance of gut-
barrier integrity in order to block the translocation of LPS, which can cause immune activation [120] . For
instance, butyrate leads to the upregulation of mucin 2, the most prominent mucin protein, and enhances
[121]
the protection of the mucosal layer . These effects of butyrate were demonstrated in Caco-2 cell cultures,
which are human epithelial colorectal adenocarcinoma cells, and can form confluent monolayers in vitro that
both structurally and functionally resemble the small intestinal epithelium. For instance, butyrate leads to
the upregulation of mucin 2, the most prominent mucin protein, and enhances the protection of the mucosal
[121]
layer .

Gut dysbiosis and reduced levels of SCFAs have been observed within neurological disease, including
Pelizaeus–Merzbacher disease [122] . Unger et al. [123] found changes in gut microbiota and SCFAs in patients
diagnosed with Parkinson’s disease. Fecal SCFA concentrations were significantly reduced in Parkinson’s
patients compared to controls. This was associated with reduced microbiota populations of Bacteroidetes
and Prevotellaceae [123] . Furthermore, some studies have demonstrated beneficial effects of SCFAs during
neuronal pathologies, such as against formation of neurotoxic Aβ aggregation, which occurs during the
pathogenesis of Alzheimer’s disease [124] . SCFAs have been reported to increase the expression level of
retinotic acid in the GI tract, which inhibits Th17 cell differentiation and promotes Treg proliferation,
limiting prolonged neuroinflammation [125] . SCFAs, especially butyrate, are able to modulate immune
cells and influence cell proliferation and apoptosis. For example, high concentration of butyrate induces
[126]
cell apoptosis while low concentration will enhance cell proliferation . Collectively, these observations
support the ability of SCFAs to have a therapeutic effect on many neurodegenerative disorders.