It’s not all in our head: The autism-associated variant in Neuroligin-3 causes gastrointestinal dysfunction, microbial dysbiosis and resilience in a model of colitis. — The Association Specialists

It’s not all in our head: The autism-associated variant in Neuroligin-3 causes gastrointestinal dysfunction, microbial dysbiosis and resilience in a model of colitis. (21844)

Elisa L Hill-Yardin 1 2 , Samantha Matta 1 , Chalystha Lee 1 , Mohammed Alamoudi 1 , Vic Lin 1 , Angela Jimenez-Perez 1 , Yuansong Li 1 , Mitra Mohsenipour 1 , Suzanne Hosie 1 3 , Peter J Crack 4 , Anya Shindler 5 , Ashley E Franks 5
  1. Department of Medical Sciences, RMIT University, Bundoora, VIC, Australia
  2. Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC, Australia
  3. Biomedical Engineering, The University of Melbourne, Parkville, VIC, Australia
  4. Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, VIC, Australia
  5. Department of Physiology, Anatomy & Microbiology, La Trobe University, Bundoora, VIC, Australia

Gastrointestinal dysfunction and inflammatory disorders are common in autism spectrum disorder (ASD; autism). Many ASD-implicated genes impact brain function including a missense variant in Neuroligin-3 encoding a cell adhesion protein expressed at neuronal synapses. We aimed to assess the impact of the Nlgn3R451C variation on gastrointestinal function, the microbiome and inflammatory response in mice.

We investigated gut permeability, microbial diversity/abundance and colitis-severity in Nlgn3R451C mice. Gut permeability to FITC4kDa dextran was assessed in ex vivo gut sacs from 16-18h-food-deprived mice using a fluorescent plate reader. Colitis was induced via 3% DSS in drinking water. Fecal microbial DNA was analysed using Illumina 16S-RNA sequencing via the QIIME2 pathway with comparisons for alpha/beta diversity and abundance (RStudio). Severity of colitis was assessed via disease-activity-index (DAI; body-weight, stool consistency, rectal bleeding).  

Nlgn3R451C mice had increased small intestinal permeability. Microbial alpha diversity was unchanged in response to DSS-colitis. Colitis caused a shift in beta diversity in both WT and Nlgn3R451C mice.  Relative abundance analyses indicated a shift in Nlgn3R451C communities with an increase in Akkermansiace genus in response to colitis. Nlgn3R451C mice showed reduced DAI scores.

The Nlgn3R451C variant impacts gut function, microbiome and the inflammatory response. Altered microbial diversity in Nlgn3R451C mice provides potential therapeutic targets to improve gut health in autism. Nlgn3R451C mice showed resilience to DSS-induced colitis. Given that gut health and the microbiome impact mood and behaviour, targeting the gut could improve quality of life for people with profound autism and gut problems.