Rescuing gut microbiome and social behavior defects in a <em>Drosophila Kdm5</em> Mutant, an ASD-like model

Abstract

Autism spectrum disorder (ASD) is a lifelong neurological and developmental disorder that has no cure. It is currently estimated that 1 in 44 children have autism and this number continues to increase. ASD is usually accompanied by gastrointestinal issues. The bidirectional connection known as the gut microbiota-brain axis (GUMBA) could offer a potential mechanism explaining how detrimental changes in the gastrointestinal system could lead to neurological issues. Importantly, it has been shown that probiotics can positively influence various neurological disorders including autism. A study done using Kdm5 loss-of-function (<em>Kdm5^LOF</em>) an autism-like <em>Drosophila</em> model has shown that a reduction of the probiotic <em>Lactiplantibacillus plantarum</em> was linked to intestinal defects and reduced social behavior. Supplementing this probiotic to the ASD-like model flies was able to rescue intestinal defects but not social behavior.<br /> <br /> The overarching goal of this thesis project is to identify new <em>Lactobacillus</em> species by using probiotic <em>Lactobacillus helveticus</em> and Fecal microbiota transplantation (FMT) to rescue both the intestinal and behavioral defect of a <em>Drosophila</em> ASD-like model. This was achieved by completing the following two specific aims: Aim 1, to test whether <em>L. helveticus</em> or a combination of this with <em>L. plantarum</em> rescued the intestinal and behavioral defects of <em>Kdm5^LOF</em> and an adult- and intestinal-specific <em>Kdm5</em> knockdown as <em>Drosophila</em> ASD-like models; and Aim 2, to determine if FMT could serve as a potential intervention to rescue intestinal and behavioral defects of an ASD-like recipient fly.<br /> <br /> Our data shows that <em>L. plantarum</em> seems to consistently rescue the microbial dysbiosis and social defects of <em>Kdm5^LOF</em> flies. When we performed a gut-specific knockdown of <em>Kdm5</em> in young adult female flies, we observed that this mutant recapitulates the phenotypes in <em>Kdm5^LOF</em>.<em> L. helveticus</em> was unable to rescue microbial dysbiosis of <em>Kdm5^LOF</em> flies and gut-specific <em>Kdm5</em> knockdown. We found that behavior could be modified differently by <em>L. helveticus</em> and a combination of <em>L. plantarum</em> and <em>L. helveticus</em>. We also found that <em>L. plantarum</em>, <em>L. helveticus</em> and the 1:1 combination of these probiotics rescued the social defect for both the <em>Kdm5^LOF</em> flies and the gut-specific <em>Kdm5</em> knockdown. We also find that FMT is an effective intervention that successfully rescued gut dysbiosis and social defects for <em>Kdm5^LOF</em>. Our findings uncovered that<em> L. plantarum</em> strain <em>Lp39</em> supplementation when administered as a probiotic, and FMT could be used as microbiota-based therapies to treat both GI and social behavior defects found in ASD.