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Page 224 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13

MICROBIOME-TARGETED THERAPEUTICS ADDRESSING NEUROLOGICAL DISEASES
The conclusion of the 10-year NIH Human Microbiome Project has been integral in providing resources,
methods, and discoveries linking humans and their microbiomes to health and disease [127] . The study
utilized a combination of shotgun metagenomics, untargeted metabolomics, and immunoprofiling to
determine host-microbiota interactions manifest in largely diverse ways, and sampling large population
[127]
sizes is critical for accurately determining potential mechanisms of microbiome-linked diseases . They
demonstrated that microbiome composition alone was not always an accurate representation of host
phenotype, and necessitated the consideration of microbial functions of the microbiota ecosystem as
they interacted with host immunity, metabolism, and other interconnected activities [128] . Through this
accomplishment, microbiome-targeted strategies have begun to gain interest in both studying mechanistic
relationships within animal models and in the treatment of pathologies, including those related to the gut-
brain axis.

Antibiotics: non-absorbable “eubiotic” rifaximin
Beyond their bacteriostatic and bactericidal effects in treating GI infections, antibiotics have been shown
to negatively affect the intestinal flora, a phenomenon considered “collateral damage”. Antibiotic treatment
can have long-lasting negative effects on the GMB, which has been shown to decrease diversity and reduce
beneficial bacteria, leading to increased susceptibility to pathogens, such as Salmonella and Clostridium
difficile [129,130] . Alternatively, rifaximin, a broad-spectrum, non-absorbable antibiotic, prescribed to treat
irritable bowel syndrome and traveler’s diarrhea caused by E. coli, has shown unique qualities related to the
GMB and symptoms beyond the GI tract [131] . The mechanism of rifaximin action to reduce pathogens is
through binding the β-subunit of microbial RNA polymerase and inhibition of bacterial RNA synthesis [132] .
However, unlike other antibiotics which commonly reduce microbiota diversity and promote dysbiosis,
rifaximin exerts anti-inflammatory properties and has the “eubiotic” ability to enrich beneficial microbiota
populations [133] . For example, Maccaferri et al. [134] found that in vitro treatment with rifaximin increased
levels of Bifidobacteria, Atopobium, and Faecalibacterium prausnitzii cultured from colonic samples
of patients with Crohn’s disease. These changes were also accompanied by increases in SCFAs, microbial
[135]
metabolites known to be important in host health, metabolism, and immune homeostasis . In a rodent
model of ankylosing spondylitis spinal joint inflammation, rifaximin treatment was able to inhibit TLR-4/
NF-κβ signaling and decrease levels of pro-inflammatory cytokines, such as TNF-α, IL-6, IL-17A, and IL-
21 [136] . Another important commensal GMB population and producer of the SCFA lactate, Lactobacillus,
was increased in a rat model of visceral hyperalgesia with rifaximin treatment [137] . Furthermore, hepatic
encephalopathy is a common complication of patients with acute or chronic liver disease that is detected
through neuropsychological testing and presents as neurocognitive decline: forgetfulness, confusion,
irritability, and coma at its most severe forms [138] . These symptoms are mainly a result of elevated levels
of ammonia. Rifaximin was able to reduce levels of ammonia-producing intestinal bacteria without
decreasing GMB diversity, while also significantly reducing hospital stay, mortality rate, and improving
psychometric test performance in patients with mild and severe hepatic encephalopathy compared to other
treatments [139] . These observations support alternate uses for rifaximin which may be related to beneficial
changes in microbiota and SCFAs, including its indication for CNS-related disorders.

Microbial-derived metabolites: sodium butyrate
Beyond directly targeting and supplementing live bacteria in the GMB, the Human Microbiome Project
stressed the importance of microbiota functions in influencing host immunity and pathologies. As a HDAC
inhibitor, sodium butyrate can change the balance between two types of enzymes, histone acetylase and
HDACs [140] . These two enzymes control acetylation, which is an important process in chromatin structure
and gene expression associated with many diseases, such as diabetes, Alzheimer’s disease, and various
cancers [141-143] . Physiological doses of sodium butyrate (0.25-4.00 mM) were observed to inhibit glioblastoma
cell proliferation and induce cancer cell senescence in vitro [143] . Pharmacological treatment of sodium