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butyrate was also shown to significantly increase survival rate and delay the neuropathological sequelae in the
[106]
[144]
R6/2 transgenic mouse model of Huntington’s disease . The findings of Arnoldussen et al. demonstrated
the beneficial effect of dietary butyrate intervention on the detrimental effects of high fat diet, including
relieving high fat diet-induced cognitive impairment and dementia in humans. In addition to serving
as a therapeutic agent in some specific diseases, sodium butyrate can have complementary effects when
administered with other agents, such as metformin. Metformin is the most prescribed oral anti-diabetic
agent, whose potential benefit in many diseases has been investigated. Recent research demonstrates that
metformin is able to increase butyrate-producing populations within the gut microbiome [145,146] . Additional
data indicate metformin and butyrate have anti-inflammatory effects in relation to physiological functions,
including transcription, replication, and repair in the process of tumorigenesis [147] . Other SCFAs also have
therapeutic effects. For example, glatiramer acetate serves as immunomodulator to reverse detrimental
immune reactivity in two murine models of irritable bowel disorder. Collectively, these findings point to the
therapeutic potential of sodium butyrate and other SCFAs in the treatment of various pathologies including
neurological disorders.

Targeting the vagus nerve
Lewy body aggregates, constituted mainly by α-synuclein and ubiquitin, and GI dysfunctions are
physiopathological characteristics of early development of Parkinson’s disease [148] . Braak et al. [149]
hypothesized that these early biomarkers initiate within the gut and then progress to the CNS via the vagus
nerve and spinal cord. In support, vagus nerve-mediated brain migration of α-synuclein injected into
the intestinal wall has been found in a rodent model [150] . Sander and his colleagues further indicated the
correlation between the vagus nerve and cognitive fatigue in multiple sclerosis patients [151] . It is thought
to be the result of the vagus nerve stimulation due to the pro-inflammatory cytokines causing changes
in neural activity in brainstem and hypothalamus [152] . Furthermore, the stimulation of the vagus nerve is
used in the treatment of drug resistant depression, which is the major factor for developing Alzheimer’s
disease. Experiments in APP/PS1 (a murine model of Alzheimer’s disease) animals were performed to
induce morphological changes in microglia towards a neuroprotective phenotype, which was mediated
by vagus nerve activation [153] . Therefore, due to its important role in regulating the gut-brain axis through
transferring microbial metabolites and neurotransmitters, such as SCFAs and GABA, manipulation of vagus
nerve signaling may play a key role in modulation of some neurological conditions, including Parkinson’s
disease, Alzheimer’s disease, and multiple sclerosis.

LIFE-STYLE INTERVENTIONS
Lifestyle interventions can affect gut microbiome composition, which influence brain activity and immune
responses. Since neuroinflammation is strongly linked to neurodegenerative diseases, lifestyle alterations,
such as dietary supplement and exercise, are able to play an important role in improving disease states.

Pre-/probiotic supplementation
Probiotics are living beneficial microorganisms (bacteria and yeasts), and prebiotics are the indigestible
[154]
fibers which feed them . Probiotics have been widely marketed and consumed as dietary supplements or
[154]
as functional foods, such as “live” yogurts . Probiotic treatments with Lactobacillus acidophilus, L. casei,
and L. rhamnosus were able to affect transcription of host genes related to mucosal immunity in healthy
[26]
[155]
human volunteers, supporting the ability of live bacterial cultures to affect host activities . D’Mello et al.
demonstrated a probiotic mixture, VSL#3, was able to reduce “sickness behavior” by increasing novel social
investigation in a liver inflammation rodent model, which was related to an increase in circulating G-CSF,
reduction in TNF-α, and a decrease in activated microglia. In an in vitro study, peripheral blood mononuclear
cells isolated from patients with Parkinson’s disease were co-cultured with probiotic bacteria, Lactobacillus
and Bifidobacterium, to investigate changes in innate immune cell release of inflammatory signaling markers.
Probiotic strains were able to significantly reduce pro-inflammatory (TNF-α, IL-6, and IL-17A) and increase