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Characterization of GI Barrier Integrity and Gut Microbiome-Derived Metabolites in BTBR, Shank3 and Cntnap2 Mouse Models of ASD, and Demonstration of AB-2004 As a Potential Mitigating Therapeutic

Poster Presentation
Thursday, May 2, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
R. Graf1, S. Campbell1, D. Donabedian1, G. Preston1, T. Hanania2, L. Thiede3, B. Perley4, S. Wiltshire4 and K. Tang1, (1)Axial Biotherapeutics, Inc., Boston, MA, (2)Behavioral Pharamcology, PsychoGenics, Inc., Paramus, NJ, (3)PsychoGenics, Inc., Paramus, NJ, (4)Charles River Laboratories, Worcester, MA
Background: Autism spectrum disorder (ASD) is a complex developmental disability that affects an already large and still increasing proportion of the world population. ASD is predominantly characterized by behavioral abnormalities; however, there is growing evidence that patients also suffer from comorbid symptoms including gastrointestinal dysfunction (Chaidez et al., 2014). Microbiome dysbiosis could play a role in increased intestinal permeability (leaky gut) which is a common condition found in ASD. Dysregulation of bacterial metabolites, such as those generated from metabolism of tyrosine and tryptophan, has been implicated as a pathological driver contributing to the disease symptomology. Specifically, 4-ethylphenylsulfate (4-EPS), a gut microbiota-derived metabolite, is elevated in a pediatric ASD population (Needham, et al., 2018 INSAR #28205).

Objectives: The purpose of the present study was to characterize intestinal permeability as well as microbiota-derived metabolites in three relevant and commonly used animal models of ASD: BTBR, Shank3 and Cntnap2-/- mice.

Methods: Serum FITC-dextran amounts were measured via fluorescence intensity in samples from BTBR, Shank3 and Cntnap2-/- mice. 4-EPS was extracted from urine from Cntnap2-/- mice and measured using LC-MS/MS. To determine the effects of AB-2004, this compound was formulated into chow to a final concentration of either 0, 1 or 5 % and was available ad libitum for the duration of 4 weeks. The same methods were used to evaluate the impact on leaky gut and 4-EPS in Cntnap2-/- mice.

Results: Based on the results, intestinal permeability, as measured by serum FITC-dextran intensity, was significantly increased in Shank3 and Cntnap2-/- mice but not in the BTBR cohort. Similarly, the levels of urinary 4-EPS were significantly elevated in Cntnap2-/- mice compared to control animals. This data aligns with previously published work in the maternal immune activation (MIA) mouse paradigm of ASD in which elevated 4-EPS levels and increased intestinal permeability were observed (Hsiao, et al., 2013). To further investigate whether intestinal permeability and increased 4-EPS levels could be ameliorated, the effects of AB-2004, an oral gut-restricted experimental therapeutic, were assessed in the Cntnap2-/- model. AB-2004 treatment effectively restored GI barrier integrity and reduced 4-EPS levels in a gut-restrictive manner.

Conclusions: In conclusion, the Cntnap2-/- mouse model recapitulated the leaky gut phenotype and elevated levels of the gut microbiome-derived metabolite 4-EPS that have been reported in ASD patients. Interestingly, treatment with AB-2004 restored GI integrity and normalized elevated 4-EPS. Taken together, these findings identify the Cntnap2-/- model as a promising platform for the development of microbiome-inspired therapies for the effective treatment of GI and behavioral dysfunctions in ASD.

See more of: Gastrointestinal (GI)
See more of: Gastrointestinal (GI)