30563
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
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.