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Page 226 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13
[156]
anti-inflammatory cytokines (IL-4 and IL-10) . In another study of a randomized, double-blind trial, patients
diagnosed with Alzheimer’s disease given a probiotic mixture for 12 weeks, exhibited a significant score
[157]
improvement on the mini-mental state examination compared to controls .
High fiber prebiotic with or without probiotic supplementation can be a non-invasive strategy to treat
neurological conditions. High fiber diets can affect gut microbiota abundance. For example, inulin is a
prebiotic fiber and inulin-type fructan supplementation on the fecal microbiota is able to selectively change
abundance of specific colon bacteria strains, such as Anaerostipes, Bilophila, and Bifidobacterium [158] . As
such, high fiber supplementation has been shown to counter age-related microbiota dysbiosis [159] . Feeding
mice with inulin has been shown to beneficially alter gut microbiome resulting in improved neurological
outcomes through affecting gut microbiota-produced SCFAs. In support, high fiber diets, in which SCFAs
can be derived, have numerous reported health benefits in reducing risk of type 2 diabetes, obesity, stroke,
and cardiovascular disease. High fiber diets have been shown to increase circulating levels of butyrate,
which may affect CNS function directly [160] . Collectively, these studies provide exciting evidence and
demonstrate the need for further investigations into the ability of live bacteria with or without prebiotic
supplementation to treat inflammation and neurological pathologies.

Diet
The microbiota composition and diversity are sensitive to host dietary habits [23,161] . Dietary factors may have
pro-inflammatory or anti-inflammatory effects [162] , which can indirectly affect gut microbiota by providing
multiple nutrients and specific compounds. For example, data suggest that the modified Mediterranean-
ketogenic diet can modulate the gut microbiome and metabolites in association with improved Alzheimer’s
disease biomarkers in cerebrospinal fluid [163] . The abundance of Enterobacteriaceae, Akkermansia, Slackia,
Christensenellaceae, and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium
reduces after modified Mediterranean-ketogenic diet treatment in subjects. A bad dietary habit, such as
chronic alcohol intake, can induce neuroinflammation and neurodegeneration. Reduction of intestinal
bacterial load was able to attenuate alcohol-associated CNS and gut inflammation [164] . Alcohol activated
microglia and modified its cell morphology, taking on an amoeboid shape with enlarged soma and
shortened peripheral processes [164] .

Exercise
Exercise is considered as a protective treatment for neurodegenerative diseases [165] . Both voluntary and
controlled exercise can alter the gut microbiota [166] . The microbiota composition of exercised rats was
notably different from the sedentary rats with a significantly higher butyrate concentration [167] . Voluntary
running has neuroprotective effects in an α-synuclein rat model of Parkinson’s disease [168] . It can protect
rats against neuronal loss, increase enteric glial expression, and modify gut microbiome composition in
the Parkinson’s disease model [169] . Exercise is also considered to enhance immune system. The vagus nerve
regulates gastrointestinal inflammatory tone. Parasympathetic neuroimmune reflex depends on vagal
afferent neurons for the local release of intestinal inflammatory mediators in response to pathogenic gut
bacteria. For this reason, elevated vagal tone and parasympathetic influence in the resting state of athletes
foster a preferential anti-inflammatory milieu through conditionally influencing microbial composition [170] .

CONCLUSION AND FUTURE DIRECTIONS
Recent discoveries link the GBM and neurological disorders through the microbiota-gut-brain axis. It
is also increasingly recognized that disruptions in the GBM ecosystem and its function may directly or
indirectly impact CNS disease states, implicating the involvement of microglial-induced neuroinflammation
and neurodegeneration. In this respect, there is bidirectional communication between the GBM and the
brain, which is achieved through several pathways [Figure 1]. This communication involves the immune
system, which not only supports the tolerance towards the microbiome ecosystem residing in the GI