Individuals with autism spectrum disorder (ASD; autism) are more susceptible to inflammatory disorders and gastrointestinal dysfunction, but the cause is unknown. We investigated gut permeability and the impact of acute inflammatory insult on gut function and behaviour in Nlgn3R451C mice expressing an autism-associated mutation in Neuroligin-3. Ex vivo intestinal permeability was assessed by measuring the passage of FITC across the mucosa from the lumen. To compare impacts of modulating the nervous system with immune pathway disruption, we bred Nlgn3R451C mice with mice lacking the interferon alpha/beta receptor subunit 1 (IFNAR1-/- mice) to produce Nlgn3R451CxIFNAR1-/- mice. Mice were treated with 3% DSS (Dextran-Sodium-Sulfate) for 7 days and ulcerative colitis symptoms (weight loss, bloody diarrhea, and rectal bleeding) and colon length recorded. Sickness and anxiety-like behaviour were measured via open field (OF) and elevated plus maze (EPM). Nlgn3R451C mice had increased gut permeability compared to wild-types. DSS-treated mice showed colitis symptoms, however Nlgn3R451C and Nlgn3R451CxIFNAR1-/- mice demonstrated greater resilience to and recovery from colitis-related symptoms compared to wild-types. Nlgn3R451CxIFNAR1-/- mice were resilient to DSS-induced colon shortening. Both IFNAR1-/- and Nlgn3R451CxIFNAR1-/- mice were resilient to increased DSS-induced colonic permeability. Double mutant mice had reduced anxiety-like and enhanced exploratory behaviour during the EPM assay. Unsurprisingly, disrupting the type-I interferon pathway provides resilience to some impacts of DSS-induced colitis. Interestingly, DSS-treated Nlgn3R451C, IFNAR1-/-, and Nlgn3R451CxIFNAR1-/- mice showed resilience to sickness behaviour compared to wild-types (locomotor impairment, OF). We show that an autism-associated mutation in Neuroligin-3 increases gut permeability but provides resilience to colitis-related sickness behaviour.