Using an in silico
approach based on the integration of publicly available gene expression data, we inferred that the anticonvulsant topiramate could serve as a novel therapeutic for IBD, and performed an experimental validation which demonstrated topiramate’s efficacy in ameliorating a TNBS-induced rodent model of IBD. The precise mechanism of action for topiramate is unknown, but it is known to enhance GABA-activated chloride channels, shows activity on kainate and AMPA receptors, and inhibits the activity of some carbonic anhydrase enzymes (7
). Topiramate is administrated orally and is often used to treat seizures and migraines, and has some antidepressant activity. Although topiramate has not previously been suggested as a therapy for IBD, it has been investigated for off-label use in treating obesity and type II diabetes (8
), and was recently shown to have efficacy against multiple sclerosis (10
). Although elucidation of the precise mechanism of action by which topiramate acts to ameliorate the induced IBD phenotype in our study requires follow-up investigations that exceed the scope of this pilot investigation, functional enrichment analysis of reveals that sets of genes related to NF-kB signaling
, inflammatory response
, antigen presentation
, and other functional processes relevant to the pathophysiology of IBD are oppositionally expressed between the disease and drug expression profiles ().
Using a TNBS-induced rodent model of IBD, we demonstrated that induced animals treated with topiramate (TNBS+topiramate) showed improvements in both gross and microscopic measures of disease pathology relative to the relevant vehicle treated group (TNBS+vehicle), with endpoints exceeding even the prednisolone treated positive control group. Both topiramate and predinisolone reduced the severity of diharrhea over the course of treatment relative to the vehicle treated group (TNBS+vehicle) (), however only the topiramate treated group exhibited significantly reduced gross pathology and microscopic damage scores (). Although prednisolone is an established treatment for IBD in humans and was correctly identified as such by our method, previous studies have reported limited efficacy of prednisolone in chemically induced rodent models of IBD (11
). Prednisolone does prevent the complete loss of the mucosal layer observed in the induced vehicle treated animals (TNBS+vehicle); however, it’s likely that the potent immunosuppressive effects or prednisolone are such that it substantially slows healing from the initial chemical insult, and possibly renders damaged tissues more susceptible to secondary bacterial infections.
Although the experimental results from the rodent model of IBD corroborate our computational predictions derived from gene expression measurements of human disease, there are several caveats that could potentially limit the interpretation of the results. Foremost, we have only demonstrated the efficacy of topiramate for IBD in a TNBS-induced animal model, which we acknowledge may not be entirely representative of IBD pathology in humans. Secondly, the nature of the model is such that it is more representative an acute IBD flare-up, and therefore additional studies are needed to determine if topiramate could serve as an effective long-term therapeutic solution for chronic IBD in humans. We also note that only two of the eight genes chosen for PCR validation showed statistical significance between the induced untreated (TNBS+Vehicle) and topiramate treated groups (TNBS+topiramate), however this may be explained by species differences in gene expression between human intestinal tissue, which was used to select the genes, and rat intestinal tissue. Also, the experiment reflected an acute treatment scenario, and it’s possible that several of these genes may only reach distinguishing expression levels after a longer period of treatment. Finally, we note that our study evaluated only a single, albeit relatively conservative dose of topiramate, and therefore additional studies are needed to evaluate the possible optimal dose ranges for use of topirmate in treating both acute and chronic IBD in humans.
In this study, we demonstrate that computational approaches leveraging public gene expression microarray data can be used to infer novel drug therapies for IBD, and offer experimental evidence that the anticonvulsant topiramate is capable of ameliorating disease pathophysiology in a TNBS-induced rodent model of IBD. Because topiramate is already established as a safe and effective drug for treating neurological diseases in humans, and the side effect profile is generally more favorable than most drugs typically used to treat IBD(2
), these results support the need for additional clinical investigation into the use of topiramate for treating IBD in human subjects. Additionally, these findings support and motivate the need for future studies by which computational approaches for leveraging publicly available molecular data for drug repurposing are further developed and applied towards additional diseases contributing significantly to the morbidity and mortality of modern human populations.